Clinical Review

In 1992, the American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics (AAP) published their first joint guidelines on the prevention of early-onset neonatal group B streptococcal (GBS) infection.¹ In this initial statement, the organizations recommended universal culturing of obstetric patients at 28 weeks’ gestation and treatment of colonized women during labor if they had a recognized risk factor for neonatal GBS infection.

In 1996, the Centers for Disease Control and Prevention (CDC) published its first set of official guidelines on the topic and suggested that both universal screening and a risk-factor–based approach were reasonable options.² The 2002 update of the CDC guidelines strongly recommended universal screening of all pregnant women at 35 to 37 weeks’ gestation and intrapartum prophylaxis for all colonized women regardless of risk factors.³

The third set of CDC guidelines was published in 2010.⁴ The key features of this version were the elimination of erythromycin as an alternative to penicillin in patients who are allergic to beta-lactam antibiotics and the establishment of 4 hours as the critical interval for administration of prophylaxis prior to delivery. The 2010 publication was the last such report from the CDC. Since then ACOG and AAP have been tasked with providing updated practice guidelines. To that end, ACOG recently issued a new Committee Opinion on “Prevention of Group B Streptococcal Early-Onset Disease in Newborns.”⁵ Here we will highlight the key features of our current strategy for preventing neonatal GBS infection.

CASE Pregnant patient presents with many questions about GBS

A 26-year-old primigravid woman presents for her first prenatal appointment at 9 weeks’ gestation. Her older sister recently delivered a term infant that died in the first week of life from GBS sepsis. Understandably, she has many questions.

1. Your patient first wants to know, “What is this streptococcal organism and how likely am I to have this infection?”

Streptococcus agalactiae, also known as GBS, is a gram-positive encapsulated bacterium that produces beta hemolysis when grown on blood agar. Approximately 25% of pregnant women harbor this organism in the lower genital tract and/or rectum.⁶

GBS is one of the most important causes of neonatal infection, particularly in preterm infants. The frequency of infection is now 0.23 per 1,000 live births in the US.⁵

Neonatal infection can be divided into early-onset infection (occurring within the first 7 days of life) and late-onset infection (occurring from after the first week until the third month of life). Approximately 80% to 85% of cases of neonatal GBS infections are early in onset. Virtually all of the early-onset infections result from vertical transmission during delivery from a colonized mother to her infant.^5-7

2. “How dangerous is this infection to my baby and me? Are there certain factors that increase the risk of my baby becoming infected?”

GBS is responsible for approximately 2% to 3% of cases of either asymptomatic bacteriuria or acute cystitis. Women with urinary tract infections caused by GBS are at increased risk for preterm premature rupture of membranes and preterm delivery. Genital tract colonization also increases a woman’s risk for chorioamnionitis and endometritis, particularly after cesarean delivery (CD). In addition, GBS can be part of the polymicrobial flora in women who have a wound (incisional site) infection following CD.^6,7

Continue to: In colonized women, several risk factors...

In colonized women, several risk factors have been identified that increase the probability of early-onset neonatal GBS infection. These factors include: preterm labor, especially when complicated by premature rupture of membranes; intrapartum maternal fever (usually due to chorioamnionitis); rupture of membranes greater than 18 hours before delivery; previous delivery of an infected infant; young age; and black or Hispanic ethnicity. Approximately 25% of colonized women will have one of these risk factors.^5-7

These risk factors have a profound impact on neonatal attack rates and mortality. Without the interventions outlined below, the neonatal infection rate is 40% to 50% in the presence of a risk factor and less than 5% in the absence of a risk factor. In infected infants, neonatal mortality approaches 30% to 35% when a maternal risk factor is present, but is less than 5% when risk factors are absent.^5-7

3. “What will you do to determine if I am colonized with this organism?”

The current guidelines set forth in the ACOG Committee Opinion recommend that selected high-risk patients (patients with preterm labor or preterm premature rupture of membranes) be tested for GBS at the time of initial presentation. All other women should be tested for GBS during the interval 36 0/7 to 37 6/7 weeks’ gestation.⁵ Testing at this point in pregnancy is almost 90% sensitive for identifying patients who will be colonized at the time of admission for labor if no more than 5 weeks elapse between the time the culture is obtained and labor begins. The positive predictive value of this test is 87%, and the negative predictive value is 96%.⁸

ACOG’s previous guidelines provided for testing at 35 rather than 36 weeks. The change in the recommendations was based on 2 factors. First, all women with unknown GBS status who may deliver before 37 weeks already should be targeted for prophylaxis. Second, the new 5-week window now will include women who deliver up to 41 weeks’ gestation. Given current obstetric practice in the US, delivery beyond 41 weeks is unlikely.⁵

At the present time, the best test for identification of GBS colonization is bacteriologic culture. A cotton swab is placed into the lower third of the vagina, streaked along the perineum, and then placed into the rectum. The swab is withdrawn, placed in a culturette tube, and transported to the laboratory. In the laboratory, the swab is cultured for approximately 24 hours in a nutrient broth and then subcultured on a selective blood agar plate. Failure to sample both the vagina and rectum or failure to use selective broth and selective blood agar will reduce the yield of positive cultures by approximately 50%.^5-7

In recent years, researchers have become interested in the use of rapid nucleic acid amplification tests for the identification of GBS. These tests perform well if the test protocol provides for an 18- to 24-hour incubation in nutrient broth prior to application of the nucleic acid probe. When the tests are performed without this enrichment phase, sensitivities are inferior to those associated with bacteriologic culture. In addition, because the rapid tests do not isolate the organisms, they do not allow for antibiotic sensitivity testing.^5-7

Continue to: “If I test positive for GBS, how and when will you treat me?”...

4. “If I test positive for GBS, how and when will you treat me?”

The current ACOG guidelines recommend that all colonized women be treated intrapartum with prophylactic antibiotics regardless of whether risk factors are present. Treatment should be started at the time of admission and continued until the infant is delivered.⁵

The drugs of choice for intrapartum prophylaxis are intravenous penicillin or ampicillin. If the patient has a mild allergy to penicillin, cefazolin is the appropriate alternative. If the patient has a severe allergy to penicillin, the 2 options are vancomycin or clindamycin. If the latter drug is used, the laboratory must perform sensitivity testing because 13% to 20% of strains of GBS may be resistant to clindamycin. The frequency of resistance to erythromycin now ranges from 25% to 32%. Thus, erythromycin is no longer used for intrapartum prophylaxis.^5-7,9

The appropriate intravenous dosages of these antibiotics are listed in the TABLE.⁵ The new ACOG guidelines have revised the previous recommendations for dosing of penicillin, eliminating the 2.5 million-unit dose. They also have revised the dosing recommendations for vancomyin, eliminating the previous recommendation of 1 g every 12 hours.⁵ The new recommendations regarding vancomycin are particularly important and are based, at least in part, on an interesting report from Onwuchuruba and colleagues.¹⁰ These authors studied maternal and cord blood concentrations of vancomycin in mother-infant dyads receiving either the original recommended dosage of vancomycin (1 g every 12 hours) or a dosage of 15 to 20 mg/kg every 8 hours. With standard dosing, only 9% of neonates had therapeutic vancomycin serum concentrations at delivery. With the 20 mg/kg dose of vancomycin, the percent of neonates with therapeutic serum concentrations of vancomycin increased to 80%.

5. “For how long must I be treated in labor before my baby will be protected by the antibiotics?”

The current ACOG Committee Opinion stresses the importance of treating the colonized mother for at least 4 hours prior to delivery.⁵ This recommendation is based primarily on the landmark report by De Cueto and colleagues.¹¹ These authors evaluated colonized women who received intrapartum prophylaxis at varying times prior to delivery. Their primary endpoint was the percentage of newborns who were colonized with GBS. If the mothers had received antibiotics for less than 1 hour prior to delivery, 46% of neonates were colonized. This figure was equal to the rate of colonization in neonates whose mothers received no antibiotics. When the interval was 1 to 2 hours, the percentage was 29%. When mothers had received antibiotics for 2 to 4 hours, the neonatal colonization rate fell to 2.9%. When antibiotics had been administered for greater than 4 hours, the rate of neonatal colonization was only 1.2%.

Fairlie and colleagues recently reported the results of another interesting investigation comparing the effectiveness of prophylaxis based on duration of treatment and choice of individual antibiotics.¹² Prophylaxis with penicillin or ampicillin for 4 hours or more was 91% effective in preventing early-onset neonatal infection in term infants and 86% effective in preventing infection in preterm infants. These outcomes were superior to the outcomes in both term and preterm infants who received penicillin or ampicillin for less than 4 hours.

Continue to: “If I were to have a scheduled CD before the onset of labor and/or ruptured membranes, would I still need to receive antibiotics?”...

6. “If I were to have a scheduled CD before the onset of labor and/or ruptured membranes, would I still need to receive antibiotics?”

If a mother is scheduled to have a CD, for example because of a prior cesarean or because of a persistent fetal malpresentation, she should still have a GBS culture at 36 0/7 to 37 6/7 weeks’ gestation. The information obtained from this culture may be of value to both the obstetrician and pediatrician if the patient experiences labor or rupture of membranes prior to her scheduled surgery. If she does not experience spontaneous labor prior to her scheduled date of surgery, she does not require specific GBS prophylaxis at the time of her operation.⁵ Rather, she should receive prophylactic antibiotics to prevent post–cesarean infection, ideally, the combination of cefazolin (2 g IV) plus azithromycin (500 mg IV).¹⁴ Cefazolin, of course, provides excellent coverage of GBS.

7. “If I am colonized with GBS and I receive treatment during labor, will my baby be safe after delivery?”

The interventions outlined above will prevent almost 90% of early-onset GBS infections, but they are not foolproof.^5-7,15,16 Successful management of the neonate is dependent upon several factors, including:^5-7

• gestational age
• presence of maternal chorioamnionitis
• presence or absence of risk factors for early-onset infection
• duration (adequacy) of maternal treatment during labor
• presence of immediate clinical signs of infection in the neonate (such as fever, lethargy, hemodynamic instability, respiratory distress, or elevated or decreased white blood cell count).

If the mother is at term and receives intrapartum prophylaxis for at least 4 hours prior to delivery, the neonate usually will not require any special tests and simply will be observed for 24 to 48 hours for signs of infection.

If the mother delivers preterm and receives appropriate intrapartum prophylaxis, the pediatricians typically will obtain a complete blood count (CBC) and treat with prophylactic antibiotics (ampicillin plus gentamicin) for 48 hours if abnormalities are noted on the CBC or the baby exhibits signs of infection. If the CBC is normal and the baby shows no signs of infection, no treatment is indicated.

Regardless of gestational age, if the mother does not receive prophylaxis for at least 4 hours before delivery, the pediatricians usually will obtain a CBC and closely observe the baby in the hospital for signs of infection. If such signs develop or the CBC is abnormal, blood and cerebrospinal fluid cultures will be obtained. Antibiotic therapy (usually ampicillin plus gentamicin) is then initiated, and the drugs are continued until cultures return with no growth. If either culture is positive, antibiotics will then be continued for 7 to 10 days.

If the mother has documented chorioamnionitis and receives treatment intrapartum with appropriate antibiotics (usually ampicillin plus gentamicin), the pediatricians usually will obtain a CBC, C-reactive protein (CRP) level, and blood cultures and then start the infant on antibiotics, pending the result of the laboratory tests. If the CBC and CRP are reassuring, the cultures are negative after 48 hours, and the infant demonstrates no signs of clinical infection, many pediatricians will then discontinue antibiotics. Others may still continue the antibiotics for 7 to 10 days.

In 1992, the American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics (AAP) published their first joint guidelines on the prevention of early-onset neonatal group B streptococcal (GBS) infection.¹ In this initial statement, the organizations recommended universal culturing of obstetric patients at 28 weeks’ gestation and treatment of colonized women during labor if they had a recognized risk factor for neonatal GBS infection.

In 1996, the Centers for Disease Control and Prevention (CDC) published its first set of official guidelines on the topic and suggested that both universal screening and a risk-factor–based approach were reasonable options.² The 2002 update of the CDC guidelines strongly recommended universal screening of all pregnant women at 35 to 37 weeks’ gestation and intrapartum prophylaxis for all colonized women regardless of risk factors.³

The third set of CDC guidelines was published in 2010.⁴ The key features of this version were the elimination of erythromycin as an alternative to penicillin in patients who are allergic to beta-lactam antibiotics and the establishment of 4 hours as the critical interval for administration of prophylaxis prior to delivery. The 2010 publication was the last such report from the CDC. Since then ACOG and AAP have been tasked with providing updated practice guidelines. To that end, ACOG recently issued a new Committee Opinion on “Prevention of Group B Streptococcal Early-Onset Disease in Newborns.”⁵ Here we will highlight the key features of our current strategy for preventing neonatal GBS infection.

CASE Pregnant patient presents with many questions about GBS

A 26-year-old primigravid woman presents for her first prenatal appointment at 9 weeks’ gestation. Her older sister recently delivered a term infant that died in the first week of life from GBS sepsis. Understandably, she has many questions.

1. Your patient first wants to know, “What is this streptococcal organism and how likely am I to have this infection?”

Streptococcus agalactiae, also known as GBS, is a gram-positive encapsulated bacterium that produces beta hemolysis when grown on blood agar. Approximately 25% of pregnant women harbor this organism in the lower genital tract and/or rectum.⁶

GBS is one of the most important causes of neonatal infection, particularly in preterm infants. The frequency of infection is now 0.23 per 1,000 live births in the US.⁵

Neonatal infection can be divided into early-onset infection (occurring within the first 7 days of life) and late-onset infection (occurring from after the first week until the third month of life). Approximately 80% to 85% of cases of neonatal GBS infections are early in onset. Virtually all of the early-onset infections result from vertical transmission during delivery from a colonized mother to her infant.^5-7

2. “How dangerous is this infection to my baby and me? Are there certain factors that increase the risk of my baby becoming infected?”

GBS is responsible for approximately 2% to 3% of cases of either asymptomatic bacteriuria or acute cystitis. Women with urinary tract infections caused by GBS are at increased risk for preterm premature rupture of membranes and preterm delivery. Genital tract colonization also increases a woman’s risk for chorioamnionitis and endometritis, particularly after cesarean delivery (CD). In addition, GBS can be part of the polymicrobial flora in women who have a wound (incisional site) infection following CD.^6,7

Continue to: In colonized women, several risk factors...

In colonized women, several risk factors have been identified that increase the probability of early-onset neonatal GBS infection. These factors include: preterm labor, especially when complicated by premature rupture of membranes; intrapartum maternal fever (usually due to chorioamnionitis); rupture of membranes greater than 18 hours before delivery; previous delivery of an infected infant; young age; and black or Hispanic ethnicity. Approximately 25% of colonized women will have one of these risk factors.^5-7

These risk factors have a profound impact on neonatal attack rates and mortality. Without the interventions outlined below, the neonatal infection rate is 40% to 50% in the presence of a risk factor and less than 5% in the absence of a risk factor. In infected infants, neonatal mortality approaches 30% to 35% when a maternal risk factor is present, but is less than 5% when risk factors are absent.^5-7

3. “What will you do to determine if I am colonized with this organism?”

The current guidelines set forth in the ACOG Committee Opinion recommend that selected high-risk patients (patients with preterm labor or preterm premature rupture of membranes) be tested for GBS at the time of initial presentation. All other women should be tested for GBS during the interval 36 0/7 to 37 6/7 weeks’ gestation.⁵ Testing at this point in pregnancy is almost 90% sensitive for identifying patients who will be colonized at the time of admission for labor if no more than 5 weeks elapse between the time the culture is obtained and labor begins. The positive predictive value of this test is 87%, and the negative predictive value is 96%.⁸

ACOG’s previous guidelines provided for testing at 35 rather than 36 weeks. The change in the recommendations was based on 2 factors. First, all women with unknown GBS status who may deliver before 37 weeks already should be targeted for prophylaxis. Second, the new 5-week window now will include women who deliver up to 41 weeks’ gestation. Given current obstetric practice in the US, delivery beyond 41 weeks is unlikely.⁵

At the present time, the best test for identification of GBS colonization is bacteriologic culture. A cotton swab is placed into the lower third of the vagina, streaked along the perineum, and then placed into the rectum. The swab is withdrawn, placed in a culturette tube, and transported to the laboratory. In the laboratory, the swab is cultured for approximately 24 hours in a nutrient broth and then subcultured on a selective blood agar plate. Failure to sample both the vagina and rectum or failure to use selective broth and selective blood agar will reduce the yield of positive cultures by approximately 50%.^5-7

In recent years, researchers have become interested in the use of rapid nucleic acid amplification tests for the identification of GBS. These tests perform well if the test protocol provides for an 18- to 24-hour incubation in nutrient broth prior to application of the nucleic acid probe. When the tests are performed without this enrichment phase, sensitivities are inferior to those associated with bacteriologic culture. In addition, because the rapid tests do not isolate the organisms, they do not allow for antibiotic sensitivity testing.^5-7

Continue to: “If I test positive for GBS, how and when will you treat me?”...

4. “If I test positive for GBS, how and when will you treat me?”

The current ACOG guidelines recommend that all colonized women be treated intrapartum with prophylactic antibiotics regardless of whether risk factors are present. Treatment should be started at the time of admission and continued until the infant is delivered.⁵

The drugs of choice for intrapartum prophylaxis are intravenous penicillin or ampicillin. If the patient has a mild allergy to penicillin, cefazolin is the appropriate alternative. If the patient has a severe allergy to penicillin, the 2 options are vancomycin or clindamycin. If the latter drug is used, the laboratory must perform sensitivity testing because 13% to 20% of strains of GBS may be resistant to clindamycin. The frequency of resistance to erythromycin now ranges from 25% to 32%. Thus, erythromycin is no longer used for intrapartum prophylaxis.^5-7,9

The appropriate intravenous dosages of these antibiotics are listed in the TABLE.⁵ The new ACOG guidelines have revised the previous recommendations for dosing of penicillin, eliminating the 2.5 million-unit dose. They also have revised the dosing recommendations for vancomyin, eliminating the previous recommendation of 1 g every 12 hours.⁵ The new recommendations regarding vancomycin are particularly important and are based, at least in part, on an interesting report from Onwuchuruba and colleagues.¹⁰ These authors studied maternal and cord blood concentrations of vancomycin in mother-infant dyads receiving either the original recommended dosage of vancomycin (1 g every 12 hours) or a dosage of 15 to 20 mg/kg every 8 hours. With standard dosing, only 9% of neonates had therapeutic vancomycin serum concentrations at delivery. With the 20 mg/kg dose of vancomycin, the percent of neonates with therapeutic serum concentrations of vancomycin increased to 80%.

5. “For how long must I be treated in labor before my baby will be protected by the antibiotics?”

The current ACOG Committee Opinion stresses the importance of treating the colonized mother for at least 4 hours prior to delivery.⁵ This recommendation is based primarily on the landmark report by De Cueto and colleagues.¹¹ These authors evaluated colonized women who received intrapartum prophylaxis at varying times prior to delivery. Their primary endpoint was the percentage of newborns who were colonized with GBS. If the mothers had received antibiotics for less than 1 hour prior to delivery, 46% of neonates were colonized. This figure was equal to the rate of colonization in neonates whose mothers received no antibiotics. When the interval was 1 to 2 hours, the percentage was 29%. When mothers had received antibiotics for 2 to 4 hours, the neonatal colonization rate fell to 2.9%. When antibiotics had been administered for greater than 4 hours, the rate of neonatal colonization was only 1.2%.

Fairlie and colleagues recently reported the results of another interesting investigation comparing the effectiveness of prophylaxis based on duration of treatment and choice of individual antibiotics.¹² Prophylaxis with penicillin or ampicillin for 4 hours or more was 91% effective in preventing early-onset neonatal infection in term infants and 86% effective in preventing infection in preterm infants. These outcomes were superior to the outcomes in both term and preterm infants who received penicillin or ampicillin for less than 4 hours.

Continue to: “If I were to have a scheduled CD before the onset of labor and/or ruptured membranes, would I still need to receive antibiotics?”...

6. “If I were to have a scheduled CD before the onset of labor and/or ruptured membranes, would I still need to receive antibiotics?”

If a mother is scheduled to have a CD, for example because of a prior cesarean or because of a persistent fetal malpresentation, she should still have a GBS culture at 36 0/7 to 37 6/7 weeks’ gestation. The information obtained from this culture may be of value to both the obstetrician and pediatrician if the patient experiences labor or rupture of membranes prior to her scheduled surgery. If she does not experience spontaneous labor prior to her scheduled date of surgery, she does not require specific GBS prophylaxis at the time of her operation.⁵ Rather, she should receive prophylactic antibiotics to prevent post–cesarean infection, ideally, the combination of cefazolin (2 g IV) plus azithromycin (500 mg IV).¹⁴ Cefazolin, of course, provides excellent coverage of GBS.

7. “If I am colonized with GBS and I receive treatment during labor, will my baby be safe after delivery?”

The interventions outlined above will prevent almost 90% of early-onset GBS infections, but they are not foolproof.^5-7,15,16 Successful management of the neonate is dependent upon several factors, including:^5-7

• gestational age
• presence of maternal chorioamnionitis
• presence or absence of risk factors for early-onset infection
• duration (adequacy) of maternal treatment during labor
• presence of immediate clinical signs of infection in the neonate (such as fever, lethargy, hemodynamic instability, respiratory distress, or elevated or decreased white blood cell count).

If the mother is at term and receives intrapartum prophylaxis for at least 4 hours prior to delivery, the neonate usually will not require any special tests and simply will be observed for 24 to 48 hours for signs of infection.

If the mother delivers preterm and receives appropriate intrapartum prophylaxis, the pediatricians typically will obtain a complete blood count (CBC) and treat with prophylactic antibiotics (ampicillin plus gentamicin) for 48 hours if abnormalities are noted on the CBC or the baby exhibits signs of infection. If the CBC is normal and the baby shows no signs of infection, no treatment is indicated.

Regardless of gestational age, if the mother does not receive prophylaxis for at least 4 hours before delivery, the pediatricians usually will obtain a CBC and closely observe the baby in the hospital for signs of infection. If such signs develop or the CBC is abnormal, blood and cerebrospinal fluid cultures will be obtained. Antibiotic therapy (usually ampicillin plus gentamicin) is then initiated, and the drugs are continued until cultures return with no growth. If either culture is positive, antibiotics will then be continued for 7 to 10 days.

If the mother has documented chorioamnionitis and receives treatment intrapartum with appropriate antibiotics (usually ampicillin plus gentamicin), the pediatricians usually will obtain a CBC, C-reactive protein (CRP) level, and blood cultures and then start the infant on antibiotics, pending the result of the laboratory tests. If the CBC and CRP are reassuring, the cultures are negative after 48 hours, and the infant demonstrates no signs of clinical infection, many pediatricians will then discontinue antibiotics. Others may still continue the antibiotics for 7 to 10 days.

In 1992, the American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics (AAP) published their first joint guidelines on the prevention of early-onset neonatal group B streptococcal (GBS) infection.¹ In this initial statement, the organizations recommended universal culturing of obstetric patients at 28 weeks’ gestation and treatment of colonized women during labor if they had a recognized risk factor for neonatal GBS infection.

In 1996, the Centers for Disease Control and Prevention (CDC) published its first set of official guidelines on the topic and suggested that both universal screening and a risk-factor–based approach were reasonable options.² The 2002 update of the CDC guidelines strongly recommended universal screening of all pregnant women at 35 to 37 weeks’ gestation and intrapartum prophylaxis for all colonized women regardless of risk factors.³

The third set of CDC guidelines was published in 2010.⁴ The key features of this version were the elimination of erythromycin as an alternative to penicillin in patients who are allergic to beta-lactam antibiotics and the establishment of 4 hours as the critical interval for administration of prophylaxis prior to delivery. The 2010 publication was the last such report from the CDC. Since then ACOG and AAP have been tasked with providing updated practice guidelines. To that end, ACOG recently issued a new Committee Opinion on “Prevention of Group B Streptococcal Early-Onset Disease in Newborns.”⁵ Here we will highlight the key features of our current strategy for preventing neonatal GBS infection.

CASE Pregnant patient presents with many questions about GBS

A 26-year-old primigravid woman presents for her first prenatal appointment at 9 weeks’ gestation. Her older sister recently delivered a term infant that died in the first week of life from GBS sepsis. Understandably, she has many questions.

1. Your patient first wants to know, “What is this streptococcal organism and how likely am I to have this infection?”

Streptococcus agalactiae, also known as GBS, is a gram-positive encapsulated bacterium that produces beta hemolysis when grown on blood agar. Approximately 25% of pregnant women harbor this organism in the lower genital tract and/or rectum.⁶

GBS is one of the most important causes of neonatal infection, particularly in preterm infants. The frequency of infection is now 0.23 per 1,000 live births in the US.⁵

Neonatal infection can be divided into early-onset infection (occurring within the first 7 days of life) and late-onset infection (occurring from after the first week until the third month of life). Approximately 80% to 85% of cases of neonatal GBS infections are early in onset. Virtually all of the early-onset infections result from vertical transmission during delivery from a colonized mother to her infant.^5-7

2. “How dangerous is this infection to my baby and me? Are there certain factors that increase the risk of my baby becoming infected?”

GBS is responsible for approximately 2% to 3% of cases of either asymptomatic bacteriuria or acute cystitis. Women with urinary tract infections caused by GBS are at increased risk for preterm premature rupture of membranes and preterm delivery. Genital tract colonization also increases a woman’s risk for chorioamnionitis and endometritis, particularly after cesarean delivery (CD). In addition, GBS can be part of the polymicrobial flora in women who have a wound (incisional site) infection following CD.^6,7

Continue to: In colonized women, several risk factors...

In colonized women, several risk factors have been identified that increase the probability of early-onset neonatal GBS infection. These factors include: preterm labor, especially when complicated by premature rupture of membranes; intrapartum maternal fever (usually due to chorioamnionitis); rupture of membranes greater than 18 hours before delivery; previous delivery of an infected infant; young age; and black or Hispanic ethnicity. Approximately 25% of colonized women will have one of these risk factors.^5-7

These risk factors have a profound impact on neonatal attack rates and mortality. Without the interventions outlined below, the neonatal infection rate is 40% to 50% in the presence of a risk factor and less than 5% in the absence of a risk factor. In infected infants, neonatal mortality approaches 30% to 35% when a maternal risk factor is present, but is less than 5% when risk factors are absent.^5-7

3. “What will you do to determine if I am colonized with this organism?”

The current guidelines set forth in the ACOG Committee Opinion recommend that selected high-risk patients (patients with preterm labor or preterm premature rupture of membranes) be tested for GBS at the time of initial presentation. All other women should be tested for GBS during the interval 36 0/7 to 37 6/7 weeks’ gestation.⁵ Testing at this point in pregnancy is almost 90% sensitive for identifying patients who will be colonized at the time of admission for labor if no more than 5 weeks elapse between the time the culture is obtained and labor begins. The positive predictive value of this test is 87%, and the negative predictive value is 96%.⁸

ACOG’s previous guidelines provided for testing at 35 rather than 36 weeks. The change in the recommendations was based on 2 factors. First, all women with unknown GBS status who may deliver before 37 weeks already should be targeted for prophylaxis. Second, the new 5-week window now will include women who deliver up to 41 weeks’ gestation. Given current obstetric practice in the US, delivery beyond 41 weeks is unlikely.⁵

At the present time, the best test for identification of GBS colonization is bacteriologic culture. A cotton swab is placed into the lower third of the vagina, streaked along the perineum, and then placed into the rectum. The swab is withdrawn, placed in a culturette tube, and transported to the laboratory. In the laboratory, the swab is cultured for approximately 24 hours in a nutrient broth and then subcultured on a selective blood agar plate. Failure to sample both the vagina and rectum or failure to use selective broth and selective blood agar will reduce the yield of positive cultures by approximately 50%.^5-7

In recent years, researchers have become interested in the use of rapid nucleic acid amplification tests for the identification of GBS. These tests perform well if the test protocol provides for an 18- to 24-hour incubation in nutrient broth prior to application of the nucleic acid probe. When the tests are performed without this enrichment phase, sensitivities are inferior to those associated with bacteriologic culture. In addition, because the rapid tests do not isolate the organisms, they do not allow for antibiotic sensitivity testing.^5-7

Continue to: “If I test positive for GBS, how and when will you treat me?”...

4. “If I test positive for GBS, how and when will you treat me?”

The current ACOG guidelines recommend that all colonized women be treated intrapartum with prophylactic antibiotics regardless of whether risk factors are present. Treatment should be started at the time of admission and continued until the infant is delivered.⁵

The drugs of choice for intrapartum prophylaxis are intravenous penicillin or ampicillin. If the patient has a mild allergy to penicillin, cefazolin is the appropriate alternative. If the patient has a severe allergy to penicillin, the 2 options are vancomycin or clindamycin. If the latter drug is used, the laboratory must perform sensitivity testing because 13% to 20% of strains of GBS may be resistant to clindamycin. The frequency of resistance to erythromycin now ranges from 25% to 32%. Thus, erythromycin is no longer used for intrapartum prophylaxis.^5-7,9

The appropriate intravenous dosages of these antibiotics are listed in the TABLE.⁵ The new ACOG guidelines have revised the previous recommendations for dosing of penicillin, eliminating the 2.5 million-unit dose. They also have revised the dosing recommendations for vancomyin, eliminating the previous recommendation of 1 g every 12 hours.⁵ The new recommendations regarding vancomycin are particularly important and are based, at least in part, on an interesting report from Onwuchuruba and colleagues.¹⁰ These authors studied maternal and cord blood concentrations of vancomycin in mother-infant dyads receiving either the original recommended dosage of vancomycin (1 g every 12 hours) or a dosage of 15 to 20 mg/kg every 8 hours. With standard dosing, only 9% of neonates had therapeutic vancomycin serum concentrations at delivery. With the 20 mg/kg dose of vancomycin, the percent of neonates with therapeutic serum concentrations of vancomycin increased to 80%.

5. “For how long must I be treated in labor before my baby will be protected by the antibiotics?”

The current ACOG Committee Opinion stresses the importance of treating the colonized mother for at least 4 hours prior to delivery.⁵ This recommendation is based primarily on the landmark report by De Cueto and colleagues.¹¹ These authors evaluated colonized women who received intrapartum prophylaxis at varying times prior to delivery. Their primary endpoint was the percentage of newborns who were colonized with GBS. If the mothers had received antibiotics for less than 1 hour prior to delivery, 46% of neonates were colonized. This figure was equal to the rate of colonization in neonates whose mothers received no antibiotics. When the interval was 1 to 2 hours, the percentage was 29%. When mothers had received antibiotics for 2 to 4 hours, the neonatal colonization rate fell to 2.9%. When antibiotics had been administered for greater than 4 hours, the rate of neonatal colonization was only 1.2%.

Fairlie and colleagues recently reported the results of another interesting investigation comparing the effectiveness of prophylaxis based on duration of treatment and choice of individual antibiotics.¹² Prophylaxis with penicillin or ampicillin for 4 hours or more was 91% effective in preventing early-onset neonatal infection in term infants and 86% effective in preventing infection in preterm infants. These outcomes were superior to the outcomes in both term and preterm infants who received penicillin or ampicillin for less than 4 hours.

Continue to: “If I were to have a scheduled CD before the onset of labor and/or ruptured membranes, would I still need to receive antibiotics?”...

6. “If I were to have a scheduled CD before the onset of labor and/or ruptured membranes, would I still need to receive antibiotics?”

If a mother is scheduled to have a CD, for example because of a prior cesarean or because of a persistent fetal malpresentation, she should still have a GBS culture at 36 0/7 to 37 6/7 weeks’ gestation. The information obtained from this culture may be of value to both the obstetrician and pediatrician if the patient experiences labor or rupture of membranes prior to her scheduled surgery. If she does not experience spontaneous labor prior to her scheduled date of surgery, she does not require specific GBS prophylaxis at the time of her operation.⁵ Rather, she should receive prophylactic antibiotics to prevent post–cesarean infection, ideally, the combination of cefazolin (2 g IV) plus azithromycin (500 mg IV).¹⁴ Cefazolin, of course, provides excellent coverage of GBS.

7. “If I am colonized with GBS and I receive treatment during labor, will my baby be safe after delivery?”

The interventions outlined above will prevent almost 90% of early-onset GBS infections, but they are not foolproof.^5-7,15,16 Successful management of the neonate is dependent upon several factors, including:^5-7

• gestational age
• presence of maternal chorioamnionitis
• presence or absence of risk factors for early-onset infection
• duration (adequacy) of maternal treatment during labor
• presence of immediate clinical signs of infection in the neonate (such as fever, lethargy, hemodynamic instability, respiratory distress, or elevated or decreased white blood cell count).

If the mother is at term and receives intrapartum prophylaxis for at least 4 hours prior to delivery, the neonate usually will not require any special tests and simply will be observed for 24 to 48 hours for signs of infection.

If the mother delivers preterm and receives appropriate intrapartum prophylaxis, the pediatricians typically will obtain a complete blood count (CBC) and treat with prophylactic antibiotics (ampicillin plus gentamicin) for 48 hours if abnormalities are noted on the CBC or the baby exhibits signs of infection. If the CBC is normal and the baby shows no signs of infection, no treatment is indicated.

Regardless of gestational age, if the mother does not receive prophylaxis for at least 4 hours before delivery, the pediatricians usually will obtain a CBC and closely observe the baby in the hospital for signs of infection. If such signs develop or the CBC is abnormal, blood and cerebrospinal fluid cultures will be obtained. Antibiotic therapy (usually ampicillin plus gentamicin) is then initiated, and the drugs are continued until cultures return with no growth. If either culture is positive, antibiotics will then be continued for 7 to 10 days.

If the mother has documented chorioamnionitis and receives treatment intrapartum with appropriate antibiotics (usually ampicillin plus gentamicin), the pediatricians usually will obtain a CBC, C-reactive protein (CRP) level, and blood cultures and then start the infant on antibiotics, pending the result of the laboratory tests. If the CBC and CRP are reassuring, the cultures are negative after 48 hours, and the infant demonstrates no signs of clinical infection, many pediatricians will then discontinue antibiotics. Others may still continue the antibiotics for 7 to 10 days.

Recently, the FDA issued “black-box” warnings, its most prominent drug safety statements, for esketamine,¹ which is indicated for treatment-resistant depression, and the Z-drugs, which are indicated for insomnia² (Table 1). A black-box warning also comes with brexanolone, which was recently approved for postpartum depression.³ While these newly issued warnings serve as a timely reminder of the importance of black-box warnings, older black-box warnings also cover large areas of psychiatric prescribing, including all medications indicated for treating psychosis or schizophrenia (increased mortality in patients with dementia), and all psychotropic medications with a depression indication (suicidality in younger people).

In this article, we help busy prescribers navigate the landscape of black-box warnings by providing a concise review of how to use them in clinical practice, and where to find information to keep up-to-date.

What are black-box warnings?

A black-box warning is a summary of the potential serious or life-threatening risks of a specific prescription medication. The black-box warning is formatted within a black border found at the top of the manufacturer’s prescribing information document (also known as the package insert or product label). Below the black-box warning, potential risks appear in descending order in sections titled “Contraindications,” “Warnings and Precautions,” and “Adverse Reactions.”⁴ The FDA issues black-box warnings either during drug development, to take effect upon approval of a new agent, or (more commonly) based on post-marketing safety information,⁵ which the FDA continuously gathers from reports by patients, clinicians, and industry.⁶ Federal law mandates the existence of black-box warnings, stating in part that, “special problems, particularly those that may lead to death or serious injury, may be required by the [FDA] to be placed in a prominently displayed box” (21 CFR 201.57(e)).

When is a black-box warning necessary?

The FDA issues a black-box warning based upon its judgment of the seriousness of the adverse effect. However, by definition, these risks do not inherently outweigh the benefits a medication may offer to certain patients. According to the FDA,⁷ black-box warnings are placed when:

• an adverse reaction so significant exists that this potential negative effect must be considered in risks and benefits when prescribing the medication
• a serious adverse reaction exists that can be prevented, or the risk reduced, by appropriate use of the medication
• the FDA has approved the medication with restrictions to ensure safe use.

Table 2 shows examples of scenarios where black-box warnings have been issued.⁸ Black-box warnings may be placed on an individual agent or on an entire class of medications. For example, both antipsychotics and antidepressants have class-wide warnings. Finally, black-box warnings are not static, and their content may change; in a study of black-box warnings issued from 2007 to 2015, 29% were entirely new, 32% were considered major updates to existing black-box warnings, and 40% were minor updates.⁵

Critiques of black-box warnings focus on the absence of published, formal criteria for instituting such warnings, the lack of a consistent approach in their content, and the infrequent inclusion of any information on the relative size of the risk.⁹ Suggestions for improvement include offering guidance on how to implement the black-box warnings in a patient-centered, shared decision-making model by adding evidence profiles and implementation guides.¹⁰ Less frequently considered, black-box warnings may be discontinued if new evidence demonstrates that the risk is lower than previously appreciated; however, similarly to their placement, no explicit criteria for the removal of black-box warnings have been made public.¹¹

When a medication poses an especially high safety risk, the FDA may require the manufacturer to implement a Risk Evaluation and Mitigation Strategy (REMS) program. These programs can describe specific steps to improve medication safety, known as elements to assure safe use (ETASU).⁴ A familiar example is the clozapine REMS. In order to reduce the risk of severe neutropenia, the clozapine REMS requires prescribers (and pharmacists) to complete specialized training (making up the ETASU). Surprisingly, not every medication with a REMS has a corresponding black-box warning¹²; more understandably, many medications with black-box warnings do not have an associated REMS, because their risks are evaluated to be manageable by an individual prescriber’s clinical judgment. Most recently, esketamine carries both a black-box warning and a REMS. The black-box warning focuses on adverse effects (Table 1), while the REMS focuses on specific steps used to lessen these risks, including requiring use of a patient enrollment and monitoring form, a fact sheet for patients, and health care setting and pharmacy enrollment forms.¹³

Continue to: Psychotropic medications and black-box warnings

Psychotropic medications and black-box warnings

Psychotropic medications have a large number of black-box warnings.¹⁴ Because it is difficult to find black-box warnings for multiple medications in one place, we have provided 2 convenient resources to address this gap: a concise summary guide (Table 3) and a more detailed database (Table 4, Table 5, Table 6, Table 7, and Table 8). In these Tables, the possible risk mitigations, off-label uses, and monitoring are not meant to be formal recommendations or endorsements but are for independent clinician consideration only.

The information in these Tables was drawn from publicly available data, primarily the Micromedex and FDA web sites (see Related Resources). Because this information changes over time, at the end of this article we suggest ways for clinicians to stay updated with black-box warnings and build on the information provided in this article. These tools can be useful for day-to-day clinical practice in addition to studying for professional examinations. The following are selected high-profile black-box warnings.

Antidepressants and suicide risk. As a class, antidepressants carry a black-box warning on suicide risk in patients age ≤24. Initially issued in 2005, this warning was extended in 2007 to indicate that depression itself is associated with an increased risk of suicide. This black-box warning is used for an entire class of medications as well as for a specific patient population (age ≤24). Moreover, it indicates that suicide rates in patients age >65 were lower among patients using antidepressants.

Among psychotropic medication black-box warnings, this warning has perhaps been the most controversial. For example, it has been suggested that this black-box warning may have inadvertently increased suicide rates by discouraging clinicians from prescribing antidepressants,¹⁵ although this also has been called into question.¹⁶ This black-box warning illustrates that the consequences of issuing black-box warnings can be very difficult to assess, which makes their clinical effects highly complex and challenging to evaluate.¹⁴

Antipsychotics and dementia-related psychosis. This warning was initially issued in 2005 for second-generation antipsychotics and extended to first-generation antipsychotics in 2008. Anti­psychotics as a class carry a black-box warning for increased risk of death in patients with dementia (major neuro­cognitive disorder). This warning extends to the recently approved antipsychotic pimavanserin, even though this agent’s proposed mechanism of action differs from that of other antipsychotics.¹⁷ However, it specifically allows for use in Parkinson’s disease psychosis, which is pimavanserin’s indication.¹⁸ In light of recent research suggesting pimavanserin is effective in dementia-related psychosis,¹⁹ it bears watching whether this agent becomes the first antipsychotic to have this warning removed.

Continue to: This class warning has...

This class warning has had widespread effects. For example, it has prompted less use of antipsychotics in nursing home facilities, as a result of stricter Centers for Medicare and Medicaid Services regulations²⁰; overall, there is some evidence that there has been reduced prescribing of antipsychotics in general.²¹ Additionally, this black-box warning is unusual in that it warns about a specific off-label indication, which is itself poorly supported by evidence.²¹ Concomitantly, few other treatment options are available for this clinical situation. These medications are often seen as the only option for patients with dementia complicated by severe behavioral disturbance, and thus this black-box warning reflects real-world practices.¹⁴

Varenicline and neuropsychiatric complications. The withdrawal of the black-box warning on potential neuropsychiatric complications of using varenicline for smoking cessation shows that black-box warnings are not static and can, though infrequently, be removed as more safety data accumulates.¹¹ As additional post-marketing information emerged on this risk, this black-box warning was reconsidered and withdrawn in 2016.²² Its withdrawal could potentially make clinicians more comfortable prescribing varenicline and in turn, help to reduce smoking rates.

How to use black-box warnings

To enhance their clinical practice, prescribers can use black-box warnings to inform safe prescribing practices, to guide shared decision-making, and to improve documentation of their treatment decisions.

Informing safe prescribing practices. A prescriber should be aware of the main safety concerns contained in a medication’s black-box warning; at the same time, these warnings are not meant to unduly limit use when crucial treatment is needed.¹⁴ In issuing a black-box warning, the FDA has clearly stated the priority and seriousness of its concern. These safety issues must be balanced against the medication’s utility for a given patient, at the prescriber’s clinical judgment.

Guiding shared decision-making. Clinicians are not required to disclose black-box warnings to patients, and there are no criteria that clearly define the role of these warnings in patient care. As is often noted, the FDA does not regulate the practice of medicine.⁶ However, given the seriousness of the potential adverse effects delineated by black-box warnings, it is reasonable for clinicians to have a solid grasp of black-box warnings for all medications they prescribe, and to be able to relate these warnings to patients, in appropriate language. This patient-centered discussion should include weighing the risks and benefits with the patient and educating the patient about the risks and strategies to mitigate those risks. This discussion can be augmented by patient handouts, which are often offered by pharmaceutical manufacturers, and by shared decision-making tools. A proactive discussion with patients and families about black-box warnings and other risks discussed in product labels can help reduce fears associated with taking medications and may improve adherence.

Continue to: Improving documentation of treatment decisions

Improving documentation of treatment decisions. Fluent knowledge of black-box warnings may help clinicians improve documentation of their treatment decisions, particularly the risks and benefits of their medication choices. Fluency with black-box warnings will help clinicians accurately document both their awareness of these risks, and how these risks informed their risk-benefit analysis in specific clinical situations.

Despite the clear importance the FDA places on black-box warnings, they are not often a topic of study in training or in postgraduate continuing education, and as a result, not all clinicians may be equally conversant with black-box warnings. While black-box warnings do change over time, many psychotropic medication black-box warnings are long-standing and well-established, and they evolve slowly enough to make mastering these warnings worthwhile in order to make the most informed clinical decisions for patient care.

Keeping up-to-date

There are practical and useful ways for busy clinicians to stay up-to-date with black-box warnings. Although these resources exist in multiple locations, together they provide convenient ways to keep current.

The FDA provides access to black-box warnings via its comprehensive database, DRUGS@FDA (https://www.accessdata.fda.gov/scripts/cder/daf/). Detailed information about REMS (and corresponding ETASU and other information related to REMS programs) is available at REMS@FDA (https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm). Clinicians can make safety reports that may contribute to FDA decision-making on black-box warnings by contacting MedWatch (https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program), the FDA’s adverse events reporting system. MedWatch releases safety information reports, which can be followed on Twitter @FDAMedWatch. Note that FDA information generally is organized by specific drug, and not into categories, such as psychotropic medications.

BlackBoxRx (www.blackboxrx.com) is a subscription-based web service that some clinicians may have access to via facility or academic resources as part of a larger FormWeb software package. Individuals also can subscribe (currently, $89/year).

Continue to: Micromedex

Micromedex (www.micromedex.com), which is widely available through medical libraries, is a subscription-based web service that provides black-box warning information from a separate tab that is easily accessed in each drug’s information front page. There is also an alphabetical list of black-box warnings under a separate tab on the Micromedex landing page.

ePocrates (www.epocrates.com) is a subscription-based service that provides extensive drug information, including black-box warnings, in a convenient mobile app.

Bottom Line

Black-box warnings are the most prominent drug safety warnings issued by the FDA. Many psychotropic medications carry black-box warnings that are crucial to everyday psychiatric prescribing. A better understanding of blackbox warnings can enhance your clinical practice by informing safe prescribing practices, guiding shared decision-making, and improving documentation of your treatment decisions.

Related Resources

• US Food and Drug Administration. DRUGS@FDA: FDAapproved drug products. www.accessdata.fda.gov/scripts/cder/daf/.
• US Food and Drug Administration. Drug safety and availability. www.fda.gov/drugs/drug-safety-and-availability. Updated October 10, 2019.
• BlackBoxRx. www.blackboxrx.com. (Subscription required.)
• Mircromedex. www.micromedex.com. (Subscription required.)
• ePocrates. www.epocrates.com. (Subscription required.)

Drug Brand Names

Amitriptyline • Elavil, Vanatrip
Amoxatine • Strattera
Amoxapine • Asendin
Aripiprazole • Abilify
Asenapine • Saphris
Brexanolone • Zulresso
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Disulfiram • Antabuse
Doxepin • Prudoxin, Silenor
Droperidol • Inapsine
Duloxetine • Cymbalta
Escitalopram • Lexapro
Esketamine • Spravato
Eszopiclone • Lunesta
Fluoxetine • Prozac
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Haloperidol • Haldol
Iloperidone • Fanapt
Imipramine • Tofranil
Isocarboxazid • Marplan
Lamotrigine • Lamictal
Levomilnacipran • Fetzima
Levothyroxine • Synthroid
Linezolid • Zyvox
Lisdexamfetamine • Vyvanse
Lithium • Eskalith, Lithobid
Loxapine • Loxitane
Lurasidone • Latuda
Maprotiline • Ludiomil
Methadone • Dolophine, Methadose
Methylphenidate • Ritalin, Concerta
Midazolam • Versed
Milnacipran • Savella
Mirtazapine • Remeron
Naltrexone • Revia, Vivitrol
Nefazodone • Serzone
Nortriptyline • Aventyl, Pamelor
Olanzapine • Zyprexa
Paliperidone • Invega
Paroxetine • Paxil
Perphenazine • Trilafon
Phenelzine • Nardil
Pimavanserin • Nuplazid
Prochlorperazine • Compro
Protriptyline • Vivactil
Quetiapine • Seroquel
Risperidone • Risperdal
Selegiline • Emsam
Sertraline • Zoloft
Thioridazine • Mellaril
Thiothixene • Navane
Tranylcypromine • Parnate
Trazodone • Desyrel, Oleptro
Trifluoperazine • Stelazine
Trimipramine • Surmontil
Valproate • Depakote
Varenicline • Chantix, Wellbutrin
Vilazodone • Viibryd
Venlafaxine • Effexor
Vortioxetine • Trintellix
Zaleplon • Sonata
Ziprasidone • Geodon
Zolpidem • Ambien

Recently, the FDA issued “black-box” warnings, its most prominent drug safety statements, for esketamine,¹ which is indicated for treatment-resistant depression, and the Z-drugs, which are indicated for insomnia² (Table 1). A black-box warning also comes with brexanolone, which was recently approved for postpartum depression.³ While these newly issued warnings serve as a timely reminder of the importance of black-box warnings, older black-box warnings also cover large areas of psychiatric prescribing, including all medications indicated for treating psychosis or schizophrenia (increased mortality in patients with dementia), and all psychotropic medications with a depression indication (suicidality in younger people).

In this article, we help busy prescribers navigate the landscape of black-box warnings by providing a concise review of how to use them in clinical practice, and where to find information to keep up-to-date.

What are black-box warnings?

A black-box warning is a summary of the potential serious or life-threatening risks of a specific prescription medication. The black-box warning is formatted within a black border found at the top of the manufacturer’s prescribing information document (also known as the package insert or product label). Below the black-box warning, potential risks appear in descending order in sections titled “Contraindications,” “Warnings and Precautions,” and “Adverse Reactions.”⁴ The FDA issues black-box warnings either during drug development, to take effect upon approval of a new agent, or (more commonly) based on post-marketing safety information,⁵ which the FDA continuously gathers from reports by patients, clinicians, and industry.⁶ Federal law mandates the existence of black-box warnings, stating in part that, “special problems, particularly those that may lead to death or serious injury, may be required by the [FDA] to be placed in a prominently displayed box” (21 CFR 201.57(e)).

When is a black-box warning necessary?

The FDA issues a black-box warning based upon its judgment of the seriousness of the adverse effect. However, by definition, these risks do not inherently outweigh the benefits a medication may offer to certain patients. According to the FDA,⁷ black-box warnings are placed when:

• an adverse reaction so significant exists that this potential negative effect must be considered in risks and benefits when prescribing the medication
• a serious adverse reaction exists that can be prevented, or the risk reduced, by appropriate use of the medication
• the FDA has approved the medication with restrictions to ensure safe use.

Table 2 shows examples of scenarios where black-box warnings have been issued.⁸ Black-box warnings may be placed on an individual agent or on an entire class of medications. For example, both antipsychotics and antidepressants have class-wide warnings. Finally, black-box warnings are not static, and their content may change; in a study of black-box warnings issued from 2007 to 2015, 29% were entirely new, 32% were considered major updates to existing black-box warnings, and 40% were minor updates.⁵

Critiques of black-box warnings focus on the absence of published, formal criteria for instituting such warnings, the lack of a consistent approach in their content, and the infrequent inclusion of any information on the relative size of the risk.⁹ Suggestions for improvement include offering guidance on how to implement the black-box warnings in a patient-centered, shared decision-making model by adding evidence profiles and implementation guides.¹⁰ Less frequently considered, black-box warnings may be discontinued if new evidence demonstrates that the risk is lower than previously appreciated; however, similarly to their placement, no explicit criteria for the removal of black-box warnings have been made public.¹¹

When a medication poses an especially high safety risk, the FDA may require the manufacturer to implement a Risk Evaluation and Mitigation Strategy (REMS) program. These programs can describe specific steps to improve medication safety, known as elements to assure safe use (ETASU).⁴ A familiar example is the clozapine REMS. In order to reduce the risk of severe neutropenia, the clozapine REMS requires prescribers (and pharmacists) to complete specialized training (making up the ETASU). Surprisingly, not every medication with a REMS has a corresponding black-box warning¹²; more understandably, many medications with black-box warnings do not have an associated REMS, because their risks are evaluated to be manageable by an individual prescriber’s clinical judgment. Most recently, esketamine carries both a black-box warning and a REMS. The black-box warning focuses on adverse effects (Table 1), while the REMS focuses on specific steps used to lessen these risks, including requiring use of a patient enrollment and monitoring form, a fact sheet for patients, and health care setting and pharmacy enrollment forms.¹³

Continue to: Psychotropic medications and black-box warnings

Psychotropic medications and black-box warnings

Psychotropic medications have a large number of black-box warnings.¹⁴ Because it is difficult to find black-box warnings for multiple medications in one place, we have provided 2 convenient resources to address this gap: a concise summary guide (Table 3) and a more detailed database (Table 4, Table 5, Table 6, Table 7, and Table 8). In these Tables, the possible risk mitigations, off-label uses, and monitoring are not meant to be formal recommendations or endorsements but are for independent clinician consideration only.

The information in these Tables was drawn from publicly available data, primarily the Micromedex and FDA web sites (see Related Resources). Because this information changes over time, at the end of this article we suggest ways for clinicians to stay updated with black-box warnings and build on the information provided in this article. These tools can be useful for day-to-day clinical practice in addition to studying for professional examinations. The following are selected high-profile black-box warnings.

Antidepressants and suicide risk. As a class, antidepressants carry a black-box warning on suicide risk in patients age ≤24. Initially issued in 2005, this warning was extended in 2007 to indicate that depression itself is associated with an increased risk of suicide. This black-box warning is used for an entire class of medications as well as for a specific patient population (age ≤24). Moreover, it indicates that suicide rates in patients age >65 were lower among patients using antidepressants.

Among psychotropic medication black-box warnings, this warning has perhaps been the most controversial. For example, it has been suggested that this black-box warning may have inadvertently increased suicide rates by discouraging clinicians from prescribing antidepressants,¹⁵ although this also has been called into question.¹⁶ This black-box warning illustrates that the consequences of issuing black-box warnings can be very difficult to assess, which makes their clinical effects highly complex and challenging to evaluate.¹⁴

Antipsychotics and dementia-related psychosis. This warning was initially issued in 2005 for second-generation antipsychotics and extended to first-generation antipsychotics in 2008. Anti­psychotics as a class carry a black-box warning for increased risk of death in patients with dementia (major neuro­cognitive disorder). This warning extends to the recently approved antipsychotic pimavanserin, even though this agent’s proposed mechanism of action differs from that of other antipsychotics.¹⁷ However, it specifically allows for use in Parkinson’s disease psychosis, which is pimavanserin’s indication.¹⁸ In light of recent research suggesting pimavanserin is effective in dementia-related psychosis,¹⁹ it bears watching whether this agent becomes the first antipsychotic to have this warning removed.

Continue to: This class warning has...

This class warning has had widespread effects. For example, it has prompted less use of antipsychotics in nursing home facilities, as a result of stricter Centers for Medicare and Medicaid Services regulations²⁰; overall, there is some evidence that there has been reduced prescribing of antipsychotics in general.²¹ Additionally, this black-box warning is unusual in that it warns about a specific off-label indication, which is itself poorly supported by evidence.²¹ Concomitantly, few other treatment options are available for this clinical situation. These medications are often seen as the only option for patients with dementia complicated by severe behavioral disturbance, and thus this black-box warning reflects real-world practices.¹⁴

Varenicline and neuropsychiatric complications. The withdrawal of the black-box warning on potential neuropsychiatric complications of using varenicline for smoking cessation shows that black-box warnings are not static and can, though infrequently, be removed as more safety data accumulates.¹¹ As additional post-marketing information emerged on this risk, this black-box warning was reconsidered and withdrawn in 2016.²² Its withdrawal could potentially make clinicians more comfortable prescribing varenicline and in turn, help to reduce smoking rates.

How to use black-box warnings

To enhance their clinical practice, prescribers can use black-box warnings to inform safe prescribing practices, to guide shared decision-making, and to improve documentation of their treatment decisions.

Informing safe prescribing practices. A prescriber should be aware of the main safety concerns contained in a medication’s black-box warning; at the same time, these warnings are not meant to unduly limit use when crucial treatment is needed.¹⁴ In issuing a black-box warning, the FDA has clearly stated the priority and seriousness of its concern. These safety issues must be balanced against the medication’s utility for a given patient, at the prescriber’s clinical judgment.

Guiding shared decision-making. Clinicians are not required to disclose black-box warnings to patients, and there are no criteria that clearly define the role of these warnings in patient care. As is often noted, the FDA does not regulate the practice of medicine.⁶ However, given the seriousness of the potential adverse effects delineated by black-box warnings, it is reasonable for clinicians to have a solid grasp of black-box warnings for all medications they prescribe, and to be able to relate these warnings to patients, in appropriate language. This patient-centered discussion should include weighing the risks and benefits with the patient and educating the patient about the risks and strategies to mitigate those risks. This discussion can be augmented by patient handouts, which are often offered by pharmaceutical manufacturers, and by shared decision-making tools. A proactive discussion with patients and families about black-box warnings and other risks discussed in product labels can help reduce fears associated with taking medications and may improve adherence.

Continue to: Improving documentation of treatment decisions

Improving documentation of treatment decisions. Fluent knowledge of black-box warnings may help clinicians improve documentation of their treatment decisions, particularly the risks and benefits of their medication choices. Fluency with black-box warnings will help clinicians accurately document both their awareness of these risks, and how these risks informed their risk-benefit analysis in specific clinical situations.

Despite the clear importance the FDA places on black-box warnings, they are not often a topic of study in training or in postgraduate continuing education, and as a result, not all clinicians may be equally conversant with black-box warnings. While black-box warnings do change over time, many psychotropic medication black-box warnings are long-standing and well-established, and they evolve slowly enough to make mastering these warnings worthwhile in order to make the most informed clinical decisions for patient care.

Keeping up-to-date

There are practical and useful ways for busy clinicians to stay up-to-date with black-box warnings. Although these resources exist in multiple locations, together they provide convenient ways to keep current.

The FDA provides access to black-box warnings via its comprehensive database, DRUGS@FDA (https://www.accessdata.fda.gov/scripts/cder/daf/). Detailed information about REMS (and corresponding ETASU and other information related to REMS programs) is available at REMS@FDA (https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm). Clinicians can make safety reports that may contribute to FDA decision-making on black-box warnings by contacting MedWatch (https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program), the FDA’s adverse events reporting system. MedWatch releases safety information reports, which can be followed on Twitter @FDAMedWatch. Note that FDA information generally is organized by specific drug, and not into categories, such as psychotropic medications.

BlackBoxRx (www.blackboxrx.com) is a subscription-based web service that some clinicians may have access to via facility or academic resources as part of a larger FormWeb software package. Individuals also can subscribe (currently, $89/year).

Continue to: Micromedex

Micromedex (www.micromedex.com), which is widely available through medical libraries, is a subscription-based web service that provides black-box warning information from a separate tab that is easily accessed in each drug’s information front page. There is also an alphabetical list of black-box warnings under a separate tab on the Micromedex landing page.

ePocrates (www.epocrates.com) is a subscription-based service that provides extensive drug information, including black-box warnings, in a convenient mobile app.

Bottom Line

Black-box warnings are the most prominent drug safety warnings issued by the FDA. Many psychotropic medications carry black-box warnings that are crucial to everyday psychiatric prescribing. A better understanding of blackbox warnings can enhance your clinical practice by informing safe prescribing practices, guiding shared decision-making, and improving documentation of your treatment decisions.

Related Resources

• US Food and Drug Administration. DRUGS@FDA: FDAapproved drug products. www.accessdata.fda.gov/scripts/cder/daf/.
• US Food and Drug Administration. Drug safety and availability. www.fda.gov/drugs/drug-safety-and-availability. Updated October 10, 2019.
• BlackBoxRx. www.blackboxrx.com. (Subscription required.)
• Mircromedex. www.micromedex.com. (Subscription required.)
• ePocrates. www.epocrates.com. (Subscription required.)

Drug Brand Names

Amitriptyline • Elavil, Vanatrip
Amoxatine • Strattera
Amoxapine • Asendin
Aripiprazole • Abilify
Asenapine • Saphris
Brexanolone • Zulresso
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Disulfiram • Antabuse
Doxepin • Prudoxin, Silenor
Droperidol • Inapsine
Duloxetine • Cymbalta
Escitalopram • Lexapro
Esketamine • Spravato
Eszopiclone • Lunesta
Fluoxetine • Prozac
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Haloperidol • Haldol
Iloperidone • Fanapt
Imipramine • Tofranil
Isocarboxazid • Marplan
Lamotrigine • Lamictal
Levomilnacipran • Fetzima
Levothyroxine • Synthroid
Linezolid • Zyvox
Lisdexamfetamine • Vyvanse
Lithium • Eskalith, Lithobid
Loxapine • Loxitane
Lurasidone • Latuda
Maprotiline • Ludiomil
Methadone • Dolophine, Methadose
Methylphenidate • Ritalin, Concerta
Midazolam • Versed
Milnacipran • Savella
Mirtazapine • Remeron
Naltrexone • Revia, Vivitrol
Nefazodone • Serzone
Nortriptyline • Aventyl, Pamelor
Olanzapine • Zyprexa
Paliperidone • Invega
Paroxetine • Paxil
Perphenazine • Trilafon
Phenelzine • Nardil
Pimavanserin • Nuplazid
Prochlorperazine • Compro
Protriptyline • Vivactil
Quetiapine • Seroquel
Risperidone • Risperdal
Selegiline • Emsam
Sertraline • Zoloft
Thioridazine • Mellaril
Thiothixene • Navane
Tranylcypromine • Parnate
Trazodone • Desyrel, Oleptro
Trifluoperazine • Stelazine
Trimipramine • Surmontil
Valproate • Depakote
Varenicline • Chantix, Wellbutrin
Vilazodone • Viibryd
Venlafaxine • Effexor
Vortioxetine • Trintellix
Zaleplon • Sonata
Ziprasidone • Geodon
Zolpidem • Ambien

Recently, the FDA issued “black-box” warnings, its most prominent drug safety statements, for esketamine,¹ which is indicated for treatment-resistant depression, and the Z-drugs, which are indicated for insomnia² (Table 1). A black-box warning also comes with brexanolone, which was recently approved for postpartum depression.³ While these newly issued warnings serve as a timely reminder of the importance of black-box warnings, older black-box warnings also cover large areas of psychiatric prescribing, including all medications indicated for treating psychosis or schizophrenia (increased mortality in patients with dementia), and all psychotropic medications with a depression indication (suicidality in younger people).

In this article, we help busy prescribers navigate the landscape of black-box warnings by providing a concise review of how to use them in clinical practice, and where to find information to keep up-to-date.

What are black-box warnings?

A black-box warning is a summary of the potential serious or life-threatening risks of a specific prescription medication. The black-box warning is formatted within a black border found at the top of the manufacturer’s prescribing information document (also known as the package insert or product label). Below the black-box warning, potential risks appear in descending order in sections titled “Contraindications,” “Warnings and Precautions,” and “Adverse Reactions.”⁴ The FDA issues black-box warnings either during drug development, to take effect upon approval of a new agent, or (more commonly) based on post-marketing safety information,⁵ which the FDA continuously gathers from reports by patients, clinicians, and industry.⁶ Federal law mandates the existence of black-box warnings, stating in part that, “special problems, particularly those that may lead to death or serious injury, may be required by the [FDA] to be placed in a prominently displayed box” (21 CFR 201.57(e)).

When is a black-box warning necessary?

The FDA issues a black-box warning based upon its judgment of the seriousness of the adverse effect. However, by definition, these risks do not inherently outweigh the benefits a medication may offer to certain patients. According to the FDA,⁷ black-box warnings are placed when:

• an adverse reaction so significant exists that this potential negative effect must be considered in risks and benefits when prescribing the medication
• a serious adverse reaction exists that can be prevented, or the risk reduced, by appropriate use of the medication
• the FDA has approved the medication with restrictions to ensure safe use.

Table 2 shows examples of scenarios where black-box warnings have been issued.⁸ Black-box warnings may be placed on an individual agent or on an entire class of medications. For example, both antipsychotics and antidepressants have class-wide warnings. Finally, black-box warnings are not static, and their content may change; in a study of black-box warnings issued from 2007 to 2015, 29% were entirely new, 32% were considered major updates to existing black-box warnings, and 40% were minor updates.⁵

Critiques of black-box warnings focus on the absence of published, formal criteria for instituting such warnings, the lack of a consistent approach in their content, and the infrequent inclusion of any information on the relative size of the risk.⁹ Suggestions for improvement include offering guidance on how to implement the black-box warnings in a patient-centered, shared decision-making model by adding evidence profiles and implementation guides.¹⁰ Less frequently considered, black-box warnings may be discontinued if new evidence demonstrates that the risk is lower than previously appreciated; however, similarly to their placement, no explicit criteria for the removal of black-box warnings have been made public.¹¹

When a medication poses an especially high safety risk, the FDA may require the manufacturer to implement a Risk Evaluation and Mitigation Strategy (REMS) program. These programs can describe specific steps to improve medication safety, known as elements to assure safe use (ETASU).⁴ A familiar example is the clozapine REMS. In order to reduce the risk of severe neutropenia, the clozapine REMS requires prescribers (and pharmacists) to complete specialized training (making up the ETASU). Surprisingly, not every medication with a REMS has a corresponding black-box warning¹²; more understandably, many medications with black-box warnings do not have an associated REMS, because their risks are evaluated to be manageable by an individual prescriber’s clinical judgment. Most recently, esketamine carries both a black-box warning and a REMS. The black-box warning focuses on adverse effects (Table 1), while the REMS focuses on specific steps used to lessen these risks, including requiring use of a patient enrollment and monitoring form, a fact sheet for patients, and health care setting and pharmacy enrollment forms.¹³

Continue to: Psychotropic medications and black-box warnings

Psychotropic medications and black-box warnings

Psychotropic medications have a large number of black-box warnings.¹⁴ Because it is difficult to find black-box warnings for multiple medications in one place, we have provided 2 convenient resources to address this gap: a concise summary guide (Table 3) and a more detailed database (Table 4, Table 5, Table 6, Table 7, and Table 8). In these Tables, the possible risk mitigations, off-label uses, and monitoring are not meant to be formal recommendations or endorsements but are for independent clinician consideration only.

The information in these Tables was drawn from publicly available data, primarily the Micromedex and FDA web sites (see Related Resources). Because this information changes over time, at the end of this article we suggest ways for clinicians to stay updated with black-box warnings and build on the information provided in this article. These tools can be useful for day-to-day clinical practice in addition to studying for professional examinations. The following are selected high-profile black-box warnings.

Antidepressants and suicide risk. As a class, antidepressants carry a black-box warning on suicide risk in patients age ≤24. Initially issued in 2005, this warning was extended in 2007 to indicate that depression itself is associated with an increased risk of suicide. This black-box warning is used for an entire class of medications as well as for a specific patient population (age ≤24). Moreover, it indicates that suicide rates in patients age >65 were lower among patients using antidepressants.

Among psychotropic medication black-box warnings, this warning has perhaps been the most controversial. For example, it has been suggested that this black-box warning may have inadvertently increased suicide rates by discouraging clinicians from prescribing antidepressants,¹⁵ although this also has been called into question.¹⁶ This black-box warning illustrates that the consequences of issuing black-box warnings can be very difficult to assess, which makes their clinical effects highly complex and challenging to evaluate.¹⁴

Antipsychotics and dementia-related psychosis. This warning was initially issued in 2005 for second-generation antipsychotics and extended to first-generation antipsychotics in 2008. Anti­psychotics as a class carry a black-box warning for increased risk of death in patients with dementia (major neuro­cognitive disorder). This warning extends to the recently approved antipsychotic pimavanserin, even though this agent’s proposed mechanism of action differs from that of other antipsychotics.¹⁷ However, it specifically allows for use in Parkinson’s disease psychosis, which is pimavanserin’s indication.¹⁸ In light of recent research suggesting pimavanserin is effective in dementia-related psychosis,¹⁹ it bears watching whether this agent becomes the first antipsychotic to have this warning removed.

Continue to: This class warning has...

This class warning has had widespread effects. For example, it has prompted less use of antipsychotics in nursing home facilities, as a result of stricter Centers for Medicare and Medicaid Services regulations²⁰; overall, there is some evidence that there has been reduced prescribing of antipsychotics in general.²¹ Additionally, this black-box warning is unusual in that it warns about a specific off-label indication, which is itself poorly supported by evidence.²¹ Concomitantly, few other treatment options are available for this clinical situation. These medications are often seen as the only option for patients with dementia complicated by severe behavioral disturbance, and thus this black-box warning reflects real-world practices.¹⁴

Varenicline and neuropsychiatric complications. The withdrawal of the black-box warning on potential neuropsychiatric complications of using varenicline for smoking cessation shows that black-box warnings are not static and can, though infrequently, be removed as more safety data accumulates.¹¹ As additional post-marketing information emerged on this risk, this black-box warning was reconsidered and withdrawn in 2016.²² Its withdrawal could potentially make clinicians more comfortable prescribing varenicline and in turn, help to reduce smoking rates.

How to use black-box warnings

To enhance their clinical practice, prescribers can use black-box warnings to inform safe prescribing practices, to guide shared decision-making, and to improve documentation of their treatment decisions.

Informing safe prescribing practices. A prescriber should be aware of the main safety concerns contained in a medication’s black-box warning; at the same time, these warnings are not meant to unduly limit use when crucial treatment is needed.¹⁴ In issuing a black-box warning, the FDA has clearly stated the priority and seriousness of its concern. These safety issues must be balanced against the medication’s utility for a given patient, at the prescriber’s clinical judgment.

Guiding shared decision-making. Clinicians are not required to disclose black-box warnings to patients, and there are no criteria that clearly define the role of these warnings in patient care. As is often noted, the FDA does not regulate the practice of medicine.⁶ However, given the seriousness of the potential adverse effects delineated by black-box warnings, it is reasonable for clinicians to have a solid grasp of black-box warnings for all medications they prescribe, and to be able to relate these warnings to patients, in appropriate language. This patient-centered discussion should include weighing the risks and benefits with the patient and educating the patient about the risks and strategies to mitigate those risks. This discussion can be augmented by patient handouts, which are often offered by pharmaceutical manufacturers, and by shared decision-making tools. A proactive discussion with patients and families about black-box warnings and other risks discussed in product labels can help reduce fears associated with taking medications and may improve adherence.

Continue to: Improving documentation of treatment decisions

Improving documentation of treatment decisions. Fluent knowledge of black-box warnings may help clinicians improve documentation of their treatment decisions, particularly the risks and benefits of their medication choices. Fluency with black-box warnings will help clinicians accurately document both their awareness of these risks, and how these risks informed their risk-benefit analysis in specific clinical situations.

Despite the clear importance the FDA places on black-box warnings, they are not often a topic of study in training or in postgraduate continuing education, and as a result, not all clinicians may be equally conversant with black-box warnings. While black-box warnings do change over time, many psychotropic medication black-box warnings are long-standing and well-established, and they evolve slowly enough to make mastering these warnings worthwhile in order to make the most informed clinical decisions for patient care.

Keeping up-to-date

There are practical and useful ways for busy clinicians to stay up-to-date with black-box warnings. Although these resources exist in multiple locations, together they provide convenient ways to keep current.

The FDA provides access to black-box warnings via its comprehensive database, DRUGS@FDA (https://www.accessdata.fda.gov/scripts/cder/daf/). Detailed information about REMS (and corresponding ETASU and other information related to REMS programs) is available at REMS@FDA (https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm). Clinicians can make safety reports that may contribute to FDA decision-making on black-box warnings by contacting MedWatch (https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program), the FDA’s adverse events reporting system. MedWatch releases safety information reports, which can be followed on Twitter @FDAMedWatch. Note that FDA information generally is organized by specific drug, and not into categories, such as psychotropic medications.

BlackBoxRx (www.blackboxrx.com) is a subscription-based web service that some clinicians may have access to via facility or academic resources as part of a larger FormWeb software package. Individuals also can subscribe (currently, $89/year).

Continue to: Micromedex

Micromedex (www.micromedex.com), which is widely available through medical libraries, is a subscription-based web service that provides black-box warning information from a separate tab that is easily accessed in each drug’s information front page. There is also an alphabetical list of black-box warnings under a separate tab on the Micromedex landing page.

ePocrates (www.epocrates.com) is a subscription-based service that provides extensive drug information, including black-box warnings, in a convenient mobile app.

Bottom Line

Black-box warnings are the most prominent drug safety warnings issued by the FDA. Many psychotropic medications carry black-box warnings that are crucial to everyday psychiatric prescribing. A better understanding of blackbox warnings can enhance your clinical practice by informing safe prescribing practices, guiding shared decision-making, and improving documentation of your treatment decisions.

Related Resources

• US Food and Drug Administration. DRUGS@FDA: FDAapproved drug products. www.accessdata.fda.gov/scripts/cder/daf/.
• US Food and Drug Administration. Drug safety and availability. www.fda.gov/drugs/drug-safety-and-availability. Updated October 10, 2019.
• BlackBoxRx. www.blackboxrx.com. (Subscription required.)
• Mircromedex. www.micromedex.com. (Subscription required.)
• ePocrates. www.epocrates.com. (Subscription required.)

Drug Brand Names

Amitriptyline • Elavil, Vanatrip
Amoxatine • Strattera
Amoxapine • Asendin
Aripiprazole • Abilify
Asenapine • Saphris
Brexanolone • Zulresso
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Disulfiram • Antabuse
Doxepin • Prudoxin, Silenor
Droperidol • Inapsine
Duloxetine • Cymbalta
Escitalopram • Lexapro
Esketamine • Spravato
Eszopiclone • Lunesta
Fluoxetine • Prozac
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Haloperidol • Haldol
Iloperidone • Fanapt
Imipramine • Tofranil
Isocarboxazid • Marplan
Lamotrigine • Lamictal
Levomilnacipran • Fetzima
Levothyroxine • Synthroid
Linezolid • Zyvox
Lisdexamfetamine • Vyvanse
Lithium • Eskalith, Lithobid
Loxapine • Loxitane
Lurasidone • Latuda
Maprotiline • Ludiomil
Methadone • Dolophine, Methadose
Methylphenidate • Ritalin, Concerta
Midazolam • Versed
Milnacipran • Savella
Mirtazapine • Remeron
Naltrexone • Revia, Vivitrol
Nefazodone • Serzone
Nortriptyline • Aventyl, Pamelor
Olanzapine • Zyprexa
Paliperidone • Invega
Paroxetine • Paxil
Perphenazine • Trilafon
Phenelzine • Nardil
Pimavanserin • Nuplazid
Prochlorperazine • Compro
Protriptyline • Vivactil
Quetiapine • Seroquel
Risperidone • Risperdal
Selegiline • Emsam
Sertraline • Zoloft
Thioridazine • Mellaril
Thiothixene • Navane
Tranylcypromine • Parnate
Trazodone • Desyrel, Oleptro
Trifluoperazine • Stelazine
Trimipramine • Surmontil
Valproate • Depakote
Varenicline • Chantix, Wellbutrin
Vilazodone • Viibryd
Venlafaxine • Effexor
Vortioxetine • Trintellix
Zaleplon • Sonata
Ziprasidone • Geodon
Zolpidem • Ambien

CASE Pregnant woman with chronic opioid use and HIV, recently diagnosed with HCV 

A 34-year-old primigravid woman at 35 weeks' gestation has a history of chronic opioid use. She previously was diagnosed with human immunodeficiency virus (HIV) infection and has been treated with a 3-drug combination antiretroviral regimen. Her most recent HIV viral load was 750 copies/mL. Three weeks ago, she tested positive for hepatitis C virus (HCV) infection. Liver function tests showed mild elevations in transaminase levels. The viral genotype is 1, and the viral load is 2.6 million copies/mL. 
 

How should this patient be delivered? Should she be encouraged to breastfeed her neonate? 

The scope of HCV infection 

Hepatitis C virus is a positive-sense, enveloped, single-stranded RNA virus that belongs to the Flaviviridae family.¹ There are 7 confirmed major genotypes of HCV and 67 confirmed subtypes.² HCV possesses several important virulence factors. First, the virus's replication is prone to frequent mutations because its RNA polymerase lacks proofreading activity, resulting in significant genetic diversity. The great degree of heterogeneity among HCV leads to high antigenic variability, which is one of the main reasons there is not yet a vaccine for HCV.³ Additionally, HCV's genomic plasticity plays a role in the emergence of drug-resistant variants.⁴ 

Virus transmission. Worldwide, approximately 130 to 170 million people are infected with HCV.⁵ HCV infections are caused primarily by exposure to infected blood, through sharing needles for intravenous drug injection and through receiving a blood transfusion.⁶ Other routes of transmission include exposure through sexual contact, occupational injury, and perinatal acquisition. 

The risk of acquiring HCV varies for each of these transmission mechanisms. Blood transfusion is no longer a common mechanism of transmission in places where blood donations are screened for HCV antibodies and viral RNA. Additionally, unintentional needle-stick injury is the only occupational risk factor associated with HCV infection, and health care workers do not have a greater prevalence of HCV than the general population. Moreover, sexual transmission is not a particularly efficient mechanism for spread of HCV.⁷ Therefore, unsafe intravenous injections are now the leading cause of HCV infection.⁶ 

Consequences of HCV infection. Once infected with HCV, about 25% of people spontaneously clear the virus and approximately 75% progress to chronic HCV infection.⁵ The consequences of long-term infection with HCV include end-stage liver disease, cirrhosis, and hepatocellular carcinoma. 

Approximately 30% of people infected with HCV will develop cirrhosis and another 2% will develop hepatocellular carcinoma.⁸ Liver transplant is the only treatment option for patients with decompensated cirrhosis or hepatocellular carcinoma as a result of HCV infection. Currently, HCV infection is the leading indication for liver transplant in the United States.⁹ 

Continue to: Risk of perinatal HCV transmission...

Risk of perinatal HCV transmission 

Approximately 1% to 8% of pregnant women worldwide are infected with HCV.¹⁰ In the United States, 1% to 2.5% of pregnant women are infected.¹¹ Of these, about 6% transmit the infection to their offspring. The risk of HCV vertical transmission increases to about 11% if the mother is co-infected with HIV.¹² Vertical transmission is the primary method by which children become infected with HCV.¹³ 

Several risk factors increase the likelihood of HCV transmission from mother to child, including HIV co-infection, internal fetal monitoring, and longer duration of membrane rupture.¹⁴ The effect that mode of delivery has on vertical transmission rates, however, is still debated, and a Cochrane Review found that there were no randomized controlled trials assessing the effect of mode of delivery on mother-to-infant HCV transmission.¹⁵ 

Serology and genotyping used in diagnosis 

The serological enzyme immunoassay is the first test used in screening for HCV infection. Currently, third- and fourth-generation enzyme immunoassays are used in the United States.¹⁶ However, even these newer serological assays cannot consistently and precisely distinguish between acute and chronic HCV infections.¹⁷ After the initial diagnosis is made with serology, it usually is confirmed by assays that detect the virus's genomic RNA in the patient's serum or plasma. 

The patient's HCV genotype should be identified so that the best treatment options can be determined. HCV genotyping can be accomplished using reverse transcription quantitative polymerase chain reaction (RT-qPCR) amplification. Three different RT-qPCR assessments usually are performed using different primers and probes specific to different genotypes of HCV. While direct sequencing of the HCV genome also can be performed, this method is usually not used clinically due to its technical complexity.¹⁶ 

Modern treatments are effective 

Introduced in 2011, direct-acting antiviral therapies are now the recommended treatment for HCV infection. These drugs inhibit the virus's replication by targeting different proteins involved in the HCV replication cycle. They are remarkably successful and have achieved sustained virologic response (SVR) rates greater than 90%.¹¹ The World Health Organization recommends several pangenotypic (that is, agents that work against all genotypes) direct-acting antiviral regimens for the treatment of chronic HCV infection in adults without cirrhosis (TABLE 1).^18,19 

Unfortunately, experience with these drugs in pregnant women is lacking. Many direct-acting antiviral agents have not been tested systematically in pregnant women, and, accordingly, most information about their effects in pregnant women comes from animal models.¹¹ 

Continue to: Perinatal transmission rates and effect of mode of delivery...

Perinatal transmission rates and effect of mode of delivery 

We compiled data from 11 studies that reported the perinatal transmission rate of HCV associated with various modes of delivery. These studies were selected from a MEDLINE literature review from 1999 to 2019. The studies were screened first by title and, subsequently, by abstract. Inclusion was restricted to randomized controlled trials, cohort studies, and case-control studies written in English. Study quality was assessed as good, fair, or poor based on the study design, sample size, and statistical analyses performed. The results from the total population of each study are reported in TABLE 2.^14,20-29 

Three studies separated data based on the mother's HIV status. The perinatal transmission rates of HCV for mothers co-infected with HIV are reported in TABLE 3.^23,27 The results for HIV-negative mothers are reported in TABLE 4.^14,23 

Finally, 2 studies grouped mothers according to their HCV viral load. All of the mothers in these studies were anti-HCV antibody positive, and the perinatal transmission rates for the total study populations were reported previously in TABLE 2. The results for mothers who had detectable HCV RNA are reported in TABLE 5.^20,21 High viral load was defined as 
≥ 2.5 x 10⁶ Eq/mL in the study by Okamoto and colleagues, which is equivalent to ≥ 6.0 x 10⁵ IU/mL in the study by Murakami and colleagues due to the different assays that were used.^20,21 The perinatal transmission rates for mothers with a high viral load are presented in TABLE 6.^20,21

Continue to: For most, CD does not reduce HCV transmission...

For most, CD does not reduce HCV transmission 

Nine of the 11 studies found that the mode of delivery did not have a statistically significant impact on the vertical transmission rate of HCV in the total study populations.^14,22-29 The remaining 2 studies found that the perinatal transmission rate of HCV was lower with cesarean delivery (CD) than with vaginal delivery.^20,21 When considered together, the results of these 11 studies indicate that CD does not provide a significant reduction in the HCV transmission rate in the general population. 

Our review confirms the findings of others, including a systematic review by the US Preventive Services Task Force.30 That investigation also failed to demonstrate any measurable increase in risk of HCV transmission as a result of breastfeeding. 

Cesarean delivery may benefit 2 groups. Careful assessment of these studies, however, suggests that 2 select groups of patients with HCV may benefit from CD: 

• mothers co-infected with HIV, and 
• mothers with high viral loads of HCV. 

In both of these populations, the vertical transmission rate of HCV was significantly reduced with CD compared with vaginal delivery. Therefore, CD should be strongly considered in mothers with HCV who are co-infected with HIV and/or in mothers who have a high viral load of HCV. 

CASE Our recommendation for mode of delivery 

The patient in our case scenario has both HIV infection and a very high HCV viral load. We would therefore recommend a planned CD at 38 to 39 weeks' gestation, prior to the onset of labor or membrane rupture. Although HCV infection is not a contraindication to breastfeeding, the mother's HIV infection is a distinct contraindication. 

CASE Pregnant woman with chronic opioid use and HIV, recently diagnosed with HCV 

A 34-year-old primigravid woman at 35 weeks' gestation has a history of chronic opioid use. She previously was diagnosed with human immunodeficiency virus (HIV) infection and has been treated with a 3-drug combination antiretroviral regimen. Her most recent HIV viral load was 750 copies/mL. Three weeks ago, she tested positive for hepatitis C virus (HCV) infection. Liver function tests showed mild elevations in transaminase levels. The viral genotype is 1, and the viral load is 2.6 million copies/mL. 
 

How should this patient be delivered? Should she be encouraged to breastfeed her neonate? 

The scope of HCV infection 

Hepatitis C virus is a positive-sense, enveloped, single-stranded RNA virus that belongs to the Flaviviridae family.¹ There are 7 confirmed major genotypes of HCV and 67 confirmed subtypes.² HCV possesses several important virulence factors. First, the virus's replication is prone to frequent mutations because its RNA polymerase lacks proofreading activity, resulting in significant genetic diversity. The great degree of heterogeneity among HCV leads to high antigenic variability, which is one of the main reasons there is not yet a vaccine for HCV.³ Additionally, HCV's genomic plasticity plays a role in the emergence of drug-resistant variants.⁴ 

Virus transmission. Worldwide, approximately 130 to 170 million people are infected with HCV.⁵ HCV infections are caused primarily by exposure to infected blood, through sharing needles for intravenous drug injection and through receiving a blood transfusion.⁶ Other routes of transmission include exposure through sexual contact, occupational injury, and perinatal acquisition. 

The risk of acquiring HCV varies for each of these transmission mechanisms. Blood transfusion is no longer a common mechanism of transmission in places where blood donations are screened for HCV antibodies and viral RNA. Additionally, unintentional needle-stick injury is the only occupational risk factor associated with HCV infection, and health care workers do not have a greater prevalence of HCV than the general population. Moreover, sexual transmission is not a particularly efficient mechanism for spread of HCV.⁷ Therefore, unsafe intravenous injections are now the leading cause of HCV infection.⁶ 

Consequences of HCV infection. Once infected with HCV, about 25% of people spontaneously clear the virus and approximately 75% progress to chronic HCV infection.⁵ The consequences of long-term infection with HCV include end-stage liver disease, cirrhosis, and hepatocellular carcinoma. 

Approximately 30% of people infected with HCV will develop cirrhosis and another 2% will develop hepatocellular carcinoma.⁸ Liver transplant is the only treatment option for patients with decompensated cirrhosis or hepatocellular carcinoma as a result of HCV infection. Currently, HCV infection is the leading indication for liver transplant in the United States.⁹ 

Continue to: Risk of perinatal HCV transmission...

Risk of perinatal HCV transmission 

Approximately 1% to 8% of pregnant women worldwide are infected with HCV.¹⁰ In the United States, 1% to 2.5% of pregnant women are infected.¹¹ Of these, about 6% transmit the infection to their offspring. The risk of HCV vertical transmission increases to about 11% if the mother is co-infected with HIV.¹² Vertical transmission is the primary method by which children become infected with HCV.¹³ 

Several risk factors increase the likelihood of HCV transmission from mother to child, including HIV co-infection, internal fetal monitoring, and longer duration of membrane rupture.¹⁴ The effect that mode of delivery has on vertical transmission rates, however, is still debated, and a Cochrane Review found that there were no randomized controlled trials assessing the effect of mode of delivery on mother-to-infant HCV transmission.¹⁵ 

Serology and genotyping used in diagnosis 

The serological enzyme immunoassay is the first test used in screening for HCV infection. Currently, third- and fourth-generation enzyme immunoassays are used in the United States.¹⁶ However, even these newer serological assays cannot consistently and precisely distinguish between acute and chronic HCV infections.¹⁷ After the initial diagnosis is made with serology, it usually is confirmed by assays that detect the virus's genomic RNA in the patient's serum or plasma. 

The patient's HCV genotype should be identified so that the best treatment options can be determined. HCV genotyping can be accomplished using reverse transcription quantitative polymerase chain reaction (RT-qPCR) amplification. Three different RT-qPCR assessments usually are performed using different primers and probes specific to different genotypes of HCV. While direct sequencing of the HCV genome also can be performed, this method is usually not used clinically due to its technical complexity.¹⁶ 

Modern treatments are effective 

Introduced in 2011, direct-acting antiviral therapies are now the recommended treatment for HCV infection. These drugs inhibit the virus's replication by targeting different proteins involved in the HCV replication cycle. They are remarkably successful and have achieved sustained virologic response (SVR) rates greater than 90%.¹¹ The World Health Organization recommends several pangenotypic (that is, agents that work against all genotypes) direct-acting antiviral regimens for the treatment of chronic HCV infection in adults without cirrhosis (TABLE 1).^18,19 

Unfortunately, experience with these drugs in pregnant women is lacking. Many direct-acting antiviral agents have not been tested systematically in pregnant women, and, accordingly, most information about their effects in pregnant women comes from animal models.¹¹ 

Continue to: Perinatal transmission rates and effect of mode of delivery...

Perinatal transmission rates and effect of mode of delivery 

We compiled data from 11 studies that reported the perinatal transmission rate of HCV associated with various modes of delivery. These studies were selected from a MEDLINE literature review from 1999 to 2019. The studies were screened first by title and, subsequently, by abstract. Inclusion was restricted to randomized controlled trials, cohort studies, and case-control studies written in English. Study quality was assessed as good, fair, or poor based on the study design, sample size, and statistical analyses performed. The results from the total population of each study are reported in TABLE 2.^14,20-29 

Three studies separated data based on the mother's HIV status. The perinatal transmission rates of HCV for mothers co-infected with HIV are reported in TABLE 3.^23,27 The results for HIV-negative mothers are reported in TABLE 4.^14,23 

Finally, 2 studies grouped mothers according to their HCV viral load. All of the mothers in these studies were anti-HCV antibody positive, and the perinatal transmission rates for the total study populations were reported previously in TABLE 2. The results for mothers who had detectable HCV RNA are reported in TABLE 5.^20,21 High viral load was defined as 
≥ 2.5 x 10⁶ Eq/mL in the study by Okamoto and colleagues, which is equivalent to ≥ 6.0 x 10⁵ IU/mL in the study by Murakami and colleagues due to the different assays that were used.^20,21 The perinatal transmission rates for mothers with a high viral load are presented in TABLE 6.^20,21

Continue to: For most, CD does not reduce HCV transmission...

For most, CD does not reduce HCV transmission 

Nine of the 11 studies found that the mode of delivery did not have a statistically significant impact on the vertical transmission rate of HCV in the total study populations.^14,22-29 The remaining 2 studies found that the perinatal transmission rate of HCV was lower with cesarean delivery (CD) than with vaginal delivery.^20,21 When considered together, the results of these 11 studies indicate that CD does not provide a significant reduction in the HCV transmission rate in the general population. 

Our review confirms the findings of others, including a systematic review by the US Preventive Services Task Force.30 That investigation also failed to demonstrate any measurable increase in risk of HCV transmission as a result of breastfeeding. 

Cesarean delivery may benefit 2 groups. Careful assessment of these studies, however, suggests that 2 select groups of patients with HCV may benefit from CD: 

• mothers co-infected with HIV, and 
• mothers with high viral loads of HCV. 

In both of these populations, the vertical transmission rate of HCV was significantly reduced with CD compared with vaginal delivery. Therefore, CD should be strongly considered in mothers with HCV who are co-infected with HIV and/or in mothers who have a high viral load of HCV. 

CASE Our recommendation for mode of delivery 

The patient in our case scenario has both HIV infection and a very high HCV viral load. We would therefore recommend a planned CD at 38 to 39 weeks' gestation, prior to the onset of labor or membrane rupture. Although HCV infection is not a contraindication to breastfeeding, the mother's HIV infection is a distinct contraindication. 

CASE Pregnant woman with chronic opioid use and HIV, recently diagnosed with HCV 

A 34-year-old primigravid woman at 35 weeks' gestation has a history of chronic opioid use. She previously was diagnosed with human immunodeficiency virus (HIV) infection and has been treated with a 3-drug combination antiretroviral regimen. Her most recent HIV viral load was 750 copies/mL. Three weeks ago, she tested positive for hepatitis C virus (HCV) infection. Liver function tests showed mild elevations in transaminase levels. The viral genotype is 1, and the viral load is 2.6 million copies/mL. 
 

How should this patient be delivered? Should she be encouraged to breastfeed her neonate? 

The scope of HCV infection 

Hepatitis C virus is a positive-sense, enveloped, single-stranded RNA virus that belongs to the Flaviviridae family.¹ There are 7 confirmed major genotypes of HCV and 67 confirmed subtypes.² HCV possesses several important virulence factors. First, the virus's replication is prone to frequent mutations because its RNA polymerase lacks proofreading activity, resulting in significant genetic diversity. The great degree of heterogeneity among HCV leads to high antigenic variability, which is one of the main reasons there is not yet a vaccine for HCV.³ Additionally, HCV's genomic plasticity plays a role in the emergence of drug-resistant variants.⁴ 

Virus transmission. Worldwide, approximately 130 to 170 million people are infected with HCV.⁵ HCV infections are caused primarily by exposure to infected blood, through sharing needles for intravenous drug injection and through receiving a blood transfusion.⁶ Other routes of transmission include exposure through sexual contact, occupational injury, and perinatal acquisition. 

The risk of acquiring HCV varies for each of these transmission mechanisms. Blood transfusion is no longer a common mechanism of transmission in places where blood donations are screened for HCV antibodies and viral RNA. Additionally, unintentional needle-stick injury is the only occupational risk factor associated with HCV infection, and health care workers do not have a greater prevalence of HCV than the general population. Moreover, sexual transmission is not a particularly efficient mechanism for spread of HCV.⁷ Therefore, unsafe intravenous injections are now the leading cause of HCV infection.⁶ 

Consequences of HCV infection. Once infected with HCV, about 25% of people spontaneously clear the virus and approximately 75% progress to chronic HCV infection.⁵ The consequences of long-term infection with HCV include end-stage liver disease, cirrhosis, and hepatocellular carcinoma. 

Approximately 30% of people infected with HCV will develop cirrhosis and another 2% will develop hepatocellular carcinoma.⁸ Liver transplant is the only treatment option for patients with decompensated cirrhosis or hepatocellular carcinoma as a result of HCV infection. Currently, HCV infection is the leading indication for liver transplant in the United States.⁹ 

Continue to: Risk of perinatal HCV transmission...

Risk of perinatal HCV transmission 

Approximately 1% to 8% of pregnant women worldwide are infected with HCV.¹⁰ In the United States, 1% to 2.5% of pregnant women are infected.¹¹ Of these, about 6% transmit the infection to their offspring. The risk of HCV vertical transmission increases to about 11% if the mother is co-infected with HIV.¹² Vertical transmission is the primary method by which children become infected with HCV.¹³ 

Several risk factors increase the likelihood of HCV transmission from mother to child, including HIV co-infection, internal fetal monitoring, and longer duration of membrane rupture.¹⁴ The effect that mode of delivery has on vertical transmission rates, however, is still debated, and a Cochrane Review found that there were no randomized controlled trials assessing the effect of mode of delivery on mother-to-infant HCV transmission.¹⁵ 

Serology and genotyping used in diagnosis 

The serological enzyme immunoassay is the first test used in screening for HCV infection. Currently, third- and fourth-generation enzyme immunoassays are used in the United States.¹⁶ However, even these newer serological assays cannot consistently and precisely distinguish between acute and chronic HCV infections.¹⁷ After the initial diagnosis is made with serology, it usually is confirmed by assays that detect the virus's genomic RNA in the patient's serum or plasma. 

The patient's HCV genotype should be identified so that the best treatment options can be determined. HCV genotyping can be accomplished using reverse transcription quantitative polymerase chain reaction (RT-qPCR) amplification. Three different RT-qPCR assessments usually are performed using different primers and probes specific to different genotypes of HCV. While direct sequencing of the HCV genome also can be performed, this method is usually not used clinically due to its technical complexity.¹⁶ 

Modern treatments are effective 

Introduced in 2011, direct-acting antiviral therapies are now the recommended treatment for HCV infection. These drugs inhibit the virus's replication by targeting different proteins involved in the HCV replication cycle. They are remarkably successful and have achieved sustained virologic response (SVR) rates greater than 90%.¹¹ The World Health Organization recommends several pangenotypic (that is, agents that work against all genotypes) direct-acting antiviral regimens for the treatment of chronic HCV infection in adults without cirrhosis (TABLE 1).^18,19 

Unfortunately, experience with these drugs in pregnant women is lacking. Many direct-acting antiviral agents have not been tested systematically in pregnant women, and, accordingly, most information about their effects in pregnant women comes from animal models.¹¹ 

Continue to: Perinatal transmission rates and effect of mode of delivery...

Perinatal transmission rates and effect of mode of delivery 

We compiled data from 11 studies that reported the perinatal transmission rate of HCV associated with various modes of delivery. These studies were selected from a MEDLINE literature review from 1999 to 2019. The studies were screened first by title and, subsequently, by abstract. Inclusion was restricted to randomized controlled trials, cohort studies, and case-control studies written in English. Study quality was assessed as good, fair, or poor based on the study design, sample size, and statistical analyses performed. The results from the total population of each study are reported in TABLE 2.^14,20-29 

Three studies separated data based on the mother's HIV status. The perinatal transmission rates of HCV for mothers co-infected with HIV are reported in TABLE 3.^23,27 The results for HIV-negative mothers are reported in TABLE 4.^14,23 

Finally, 2 studies grouped mothers according to their HCV viral load. All of the mothers in these studies were anti-HCV antibody positive, and the perinatal transmission rates for the total study populations were reported previously in TABLE 2. The results for mothers who had detectable HCV RNA are reported in TABLE 5.^20,21 High viral load was defined as 
≥ 2.5 x 10⁶ Eq/mL in the study by Okamoto and colleagues, which is equivalent to ≥ 6.0 x 10⁵ IU/mL in the study by Murakami and colleagues due to the different assays that were used.^20,21 The perinatal transmission rates for mothers with a high viral load are presented in TABLE 6.^20,21

Continue to: For most, CD does not reduce HCV transmission...

For most, CD does not reduce HCV transmission 

Nine of the 11 studies found that the mode of delivery did not have a statistically significant impact on the vertical transmission rate of HCV in the total study populations.^14,22-29 The remaining 2 studies found that the perinatal transmission rate of HCV was lower with cesarean delivery (CD) than with vaginal delivery.^20,21 When considered together, the results of these 11 studies indicate that CD does not provide a significant reduction in the HCV transmission rate in the general population. 

Our review confirms the findings of others, including a systematic review by the US Preventive Services Task Force.30 That investigation also failed to demonstrate any measurable increase in risk of HCV transmission as a result of breastfeeding. 

Cesarean delivery may benefit 2 groups. Careful assessment of these studies, however, suggests that 2 select groups of patients with HCV may benefit from CD: 

• mothers co-infected with HIV, and 
• mothers with high viral loads of HCV. 

In both of these populations, the vertical transmission rate of HCV was significantly reduced with CD compared with vaginal delivery. Therefore, CD should be strongly considered in mothers with HCV who are co-infected with HIV and/or in mothers who have a high viral load of HCV. 

CASE Our recommendation for mode of delivery 

The patient in our case scenario has both HIV infection and a very high HCV viral load. We would therefore recommend a planned CD at 38 to 39 weeks' gestation, prior to the onset of labor or membrane rupture. Although HCV infection is not a contraindication to breastfeeding, the mother's HIV infection is a distinct contraindication. 

The statistics reveal a serious problem: This year, an estimated 63,030 Americans will be given a diagnosis of head and neck cancer (which includes laryngeal, oropharyngeal, sinonasal, nasopharyngeal, and salivary gland cancer¹); approximately 13,360 of them will die. Furthermore, thyroid cancer is the most rapidly increasing cancer diagnosis in the United States, with an estimated 56,870 cases in 2017.^1,2 Major risk factors for head and neck cancer are tobacco and alcohol exposure and infection with Epstein-Barr virus and human papillomavirus (HPV).³

In this article, we review the background for each of the principal types of head and neck cancer with which you should be familiar. We also discuss how to evaluate signs and symptoms that raise suspicion of these neoplasms; outline the diagnostic strategy in the face of such suspicion; and summarize accepted therapeutic approaches. Last, we describe the important role that you, the family physician, play in providing posttreatment care for these patients, especially prevention and management of late adverse effects of radiation therapy.

General characterizationsof these cancers

Approximately one-half of patients with head and neck cancer present initially with a nonspecific, persistent neck mass that should be deemed malignant until proven otherwise, because a delay in diagnosis is associated with a worse outcome.⁴ In a series of 100 patients with head and neck cancer, for example, delay in diagnosis occurred in nearly 25%—most often because of time spent providing inappropriate antibiotic treatment.⁵ Guidelines for management of neck masses recommend against the use of antibiotics in patients who do not have evidence of infection.⁶

Patients with a neck mass that has been present for longer than 2 weeks or that is ulcerated, fixed to underlying tissues, of firm consistency, or > 1.5 cm should have a physical examination that includes visualization of the base of tongue, pharynx, and larynx. The mass should be evaluated with fine-­needle aspiration (FNA) biopsy, which has a positive predictive value of 96% and negative predictive value of 90% for the diagnosis of a head and neck mass. (Note: Anticoagulation therapy is not an absolute contraindication to FNA, which is not associated with an increased risk of bleeding.⁶)

Laryngeal cancer

What you need to know. More than 90% of laryngeal cancers are squamous cell carcinoma (SCC). Smoking or heavy drinking (> 8 drinks/d), compared to neither behavior, is associated with an increased risk of laryngeal cancer (odds ratio, 9.4 and 2.5, respectively).⁷ The risk of cancer is directly proportional to the degree of tobacco exposure.

One-half of head and neck cancers present with a neck mass that warrants appropriate initial assessment, so as not to delay diagnosis.

Laryngeal cancer occurs in the supraglottic region in one-third of patients; in the glottic region in one-half; and in the subglottic region in a very few.⁸ Glottic cancer presents earlier than supraglottic cancer with hoarseness, whereas supraglottic cancer presents with more advanced disease, causing stridor, dysphagia, and throat pain. (Note: Guidelines recommend against prescribing acid suppressants in patients with hoarseness who do not have symptoms of reflux.⁹)

Stage 1 and Stage 2 laryngeal cancers are localized; Stages 3-4B are locally advanced or involve lymph nodes, or both; Stage 4C is metastatic disease. Overall, 60% of patients have Stage 3 or Stage 4 disease at diagnosis.¹⁰

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Laryngoscopy should be performed before computed tomography (CT) or magnetic resonance imaging is considered in a patient with hoarseness that does not resolve after 3 months—or sooner, if there is suspicion of malignancy.

How is it treated? Most patients presenting with Stage 1 or Stage 2 cancer can be treated with local radiation or, less commonly, larynx-preserving surgery. Patients with Stage 3 or Stage 4 disease can be treated with a combination of radiation and chemotherapy, which, compared to radiation alone, confers a decreased risk of local recurrence and increased laryngectomy-free survival.¹¹ Patients whose vocal cords are destroyed or who have recurrence following radiation and chemotherapy might need total laryngectomy and formation of a tracheostomy and prosthetic for voice creation.

Five-year overall survival for Stage 1 and Stage 2 supraglottic and glottic cancers is 80%—lower, however, for later-presenting subglottic cancers.¹²

Oropharyngeal cancer

What you need to know. The lifetime risk for cancer of the oropharynx is approximately 1%.¹³ SCC is responsible for approximately 90% of these cancers. Early detection is important: The 5-year survival rate is more than twice as high for localized disease (83%) than it is for metastatic disease (39%) at detection.¹³

At any given time, 7% of the US population has HPV infection of the oropharynx. Most of these cases clear spontaneously, but persistent high-risk HPV infection led to a 225% increase in HPV-positive oropharyngeal SCC from 1988 to 2004.¹⁴ The representative case of HPV-positive oropharyngeal SCC is a middle-aged (40- to 59-year-old) white male with a history of multiple sexual partners and with little or no tobacco exposure and low alcohol consumption.

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Oral cancers present with a lesion, often ulcerative, that should be examined by palpation with a gloved finger to describe the presence, color, and number of lesions; any tenderness; tissue consistency (soft, firm, hard); and fixation to underlying structures.¹⁵ The oropharynx should be examined without protrusion of the tongue, which obscures the oropharynx and can make it harder to depress the posterior part of the tongue.

A finding of leukoplakia (white plaques) and erythroplakia (red plaques) of the oropharynx might reflect benign hyperkeratosis or premalignant lesions; the plaques do not wipe off on examination. Referral to a dentist or otorhinolaryngologist for biopsy is indicated for all erythroplakia and leukoplakia, and for ulcers that persist longer than 2 weeks.¹⁶

(Note: Evidence is insufficient to support screening asymptomatic patients for oral and oropharyngeal cancers by physical examination. There is no US Food and Drug Administration-approved screening test for oral HPV infection.¹⁷)

How is it treated? A diagnosis of moderate dysplasia or carcinoma in situ should be treated with surgical excision to clear margins followed by routine monitoring every 3 to 6 months, for life.¹⁸ Topical medication, electrocautery, laser ablation, and cryosurgery are management options for less severe dysplasia.

Sinonasal cancer

What you need to know. Worldwide, sinonasal cancer accounts for approximately 0.7% of all new cancers but demonstrates strong genetic and regional associations, particularly among the Cantonese population of southern China.¹⁹ One-half of new sinonasal malignancies are SCC; the rest are adenocarcinoma, lymphoepithelial carcinoma, and rare subtypes.²⁰

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Presentation tends to mimic common, nonmalignant conditions, such as sinusitis, until invasion into adjacent structures. When sinonasal passages are involved, the history might include epistaxis or nasal discharge; facial or dental pain; unilateral nasal obstruction with unexplained onset later in life; and failure to respond to treatment of presumed rhinosinusitis. Physical examination should include assessment of cranial nerves, palpation of the sinuses, and anterior rhinoscopy.

Thin-cut CT of the paranasal sinuses is the first-line imaging study. Sinonasal endoscopy, with targeted biopsy of suspicious lesions, is the evaluation of choice when malignancy is suspected.

How is it treated? Surgery is the treatment of choice, with postoperative radiation for patients at higher risk of recurrence because of more extensive disase.¹² Five-year survival for advanced disease is poor (35%); only 15% of cases are diagnosed at a localized stage because presenting symptoms are nonspecific.²¹

Nasopharyngeal cancer

What you need to know. Nasopharyngeal cancer is rare in the United States and Europe, compared with China, where it is endemic (and where a variety of risk factors, including intake of salt-preserved fish, have been proposed²²). Epstein-Barr virus infection and a history of smoking increase the risk.

Patients with nasopharyngeal cancer can present with epistaxis, nasal obstruction, and auditory symptoms, such as serous otitis media. Direct extension of the tumor can lead to cranial-nerve palsy, most commonly III, V, VI, and XII.²³

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Three-quarters of patients present with a neck mass from lymph-node metastases. Patients with the risk factors for nasopharyngeal cancer noted above who present with concerning symptoms should have nasoendoscopy with biopsy.

How is it treated? Radiation is the primary treatment, which is combined with chemotherapy for more advanced disease.²³ Screening high-risk populations for antibodies to Epstein-Barr virus and performing nasopharyngeal endoscopy on patients who screen positive increases the detection rate of nasopharyngeal cancer; however, this strategy has not been shown to improve survival.⁹

Salivary gland tumors

What you need to know. Salivary gland neoplasms are a rare and heterogeneous entity, comprising 6% to 8% of head and neck cancers.²⁴ More than 70% of these tumors are located in the parotid gland; 8%, in the submandibular glands; 1%, in the sublingual glands; and the rest, in the minor salivary glands. Most salivary gland tumors are benign; the most prevalent malignant tumors are mucoepidermoid carcinoma (30%) and adenoid cystic carcinoma (10%).²⁵ Additional identified risk factors for a salivary gland tumor include irradiation, prior head and neck cancer, and environmental exposures, including hairdressing, rubber manufacturing, and exposure to nickel compounds.²⁶

What is the diagnostic strategy? The history and physical exam are essential to distinguish a salivary gland tumor from an infectious cause and sialolithiasis. Parotid tumors most commonly present as asymptomatic parotid swelling, although pain can be present in as many as 40% of malignant parotid tumors.²⁵ Facial nerve weakness is found in 25% of parotid tumors; although the differential diagnosis of facial nerve palsy is broad, suspicion of malignancy should be raised in the presence of a parotid mass, progressive unilateral symptoms, hemifacial spasm progressing to weakness, and a history of skin cancer on the face or scalp. Additional characteristics that favor a neoplastic cause are trismus and nontender lymphadenopathy.²⁵

In a series of 100 patients with head and neck cancer, a delay in diagnosis occurred in nearly 25%—most often because of time spent providing inappropriate antibiotic treatment.

In contrast, sialolithiasis is associated with intermittent pain caused by eating and is more common in the settings of dehydration and poor dental hygiene. Sialadenitis should be suspected when the presentation is fever, increased pain and swelling, erythema, and expression of pus from the salivary gland.

Continue to: If malignancy is suspected...

If malignancy is suspected, the initial diagnostic evaluation should include ultrasonography (US); concurrent FNA biopsy should be performed if a mass is detected.²⁷ US-guided FNA has a sensitivity of 73% to 86% for salivary neoplasm.⁷ CT and ­magnetic resonance imaging are useful for further characterization of tumors and can be advantageous for surgical planning.

How is it treated? Treatment of a salivary gland tumor involves surgical resection, followed by radiotherapy for patients in whom disease is more extensive or who exhibit high-risk pathology. Primary radiotherapy can be used in patients with an unresectable tumor. Typically, chemotherapy is used only for palliative purposes in relapsing disease, when a tumor is not amenable to radiotherapy, and in metastatic disease.²⁵

Prognosis varies by histotype but is generally favorable. The survival rates for a malignant salivary gland tumor are 83% at 1 year, 69% at 3 years, and 65% at 5 years.²⁸ Distant metastases are the most common cause of death, occurring primarily in the lungs (80%), bone (15%), and liver.²⁷ Factors that indicate poor prognosis include facial nerve involvement, trismus, a tumor > 4 cm, bone involvement, nodal spread, and recurrence.²⁵

Thyroid cancer

What you need to know. Thyroid cancer is the most rapidly increasing cancer diagnosis in the United States, with an annual incidence of 4.5%.¹ In the United States, most thyroid cancers are differentiated thyroid cancer (DTC), which includes papillary and follicular cancers. Less-differentiated medullary thyroid cancer (MTC), typically associated with multiple endocrine neoplasia (MEN) 2A or 2B, and undifferentiated or anaplastic thyroid cancer are less common. The increasing incidence of thyroid cancer is primarily the result of an increase in nonclinically relevant DTC.

What is the diagnostic strategy? Thyroid cancer usually presents as a thyroid nodule found by the patient or incidentally on physical examination or imaging. Other presenting signs and symptoms include hoarseness, voice changes, and dysphagia.

Continue to: Thyroid US is the study of...

Thyroid US is the study of choice for initial evaluation of the size and features of a nodule; findings are used to make recommendations for further workup. If further evaluation is indicated, FNA biopsy is the test of choice.²⁹

In 2016, the American Thyroid Association released updated guidelines for evaluating thyroid nodules (TABLE).³⁰ The US Preventive Services Task Force recommends against screening for thyroid cancer by neck palpation or US in asymptomatic patients because evidence of significant mortality benefit is lacking.³¹

How is it treated? Treatment of thyroid cancer focuses on local excision of the nodule by partial or total thyroidectomy (depending on the size and type of cancer) and surgical removal of involved lymph nodes. Differentiated thyroid cancer is categorized as high-, medium-, or low-risk, depending on tumor extension, incomplete tumor resection, size of lymph nodes > 3 cm, and distant metastases. Adjuvant treatment with radioactive iodine can be considered for intermediate-risk DTC and is recommended for high-risk DTC.³²

Following surgical treatment, thyroid-stimulating hormone suppression is recommended using levothyroxine.³³ Patients at higher risk of recurrence should have longer and more intense suppression of thyroid-stimulating hormone.³⁰ Levels of serum thyroglobulin and anti-thyroglobulin antibody should be followed postoperatively; rising values can indicate recurrent disease. The calcitonin level should be followed in patients with a history of MTC. Thyroid US should be performed 6 to 12 months postoperatively, then periodically, depending on determination of recurrence risk and any change in the thyroglobulin level.³⁰

Human papillomavirus is associated with an increasing number of cases of head and neck cancer.

(Note: Glucagon-like peptide-1 [GLP-1] receptor agonists, used to treat type 2 diabetes mellitus, carry a black-box warning for their risk of MTC and are contraindicated in patients who have a personal or family history of MTC, MEN2A, or MEN2B.³⁴)

Continue to: Anaplastic thyroid cancer...

Anaplastic thyroid cancer, a rare form of thyroid cancer, carries a high mortality rate, with a median survival of 5 months from diagnosis and 1-year survival of 20%. Patients require expeditious total thyroidectomy and neck dissection, followed by external-beam radiation with or without chemotherapy. If this strategy is not feasible, tracheostomy might be necessary to maintain a patent airway.² Family physicians treating a patient who has anaplastic thyroid cancer can fulfill a crucial role by ensuring that an advance directive is established, a surrogate decision-maker is appointed, and goals of care are well defined.

Follow-up care for head and neck Ca

The risk of adverse effects after radiation therapy for head and neck cancer calls for close monitoring, appropriate treatment, and referral and counseling as needed. See “Follow-up care after treatment of head and neck cancer.” ^35-39

CORRESPONDENCE
Anne Mounsey, MD, Family Medicine Residency, The University of North Carolina at Chapel Hill, 590 Manning Dr., Chapel Hill, NC 27599; [email protected]

The statistics reveal a serious problem: This year, an estimated 63,030 Americans will be given a diagnosis of head and neck cancer (which includes laryngeal, oropharyngeal, sinonasal, nasopharyngeal, and salivary gland cancer¹); approximately 13,360 of them will die. Furthermore, thyroid cancer is the most rapidly increasing cancer diagnosis in the United States, with an estimated 56,870 cases in 2017.^1,2 Major risk factors for head and neck cancer are tobacco and alcohol exposure and infection with Epstein-Barr virus and human papillomavirus (HPV).³

In this article, we review the background for each of the principal types of head and neck cancer with which you should be familiar. We also discuss how to evaluate signs and symptoms that raise suspicion of these neoplasms; outline the diagnostic strategy in the face of such suspicion; and summarize accepted therapeutic approaches. Last, we describe the important role that you, the family physician, play in providing posttreatment care for these patients, especially prevention and management of late adverse effects of radiation therapy.

General characterizationsof these cancers

Approximately one-half of patients with head and neck cancer present initially with a nonspecific, persistent neck mass that should be deemed malignant until proven otherwise, because a delay in diagnosis is associated with a worse outcome.⁴ In a series of 100 patients with head and neck cancer, for example, delay in diagnosis occurred in nearly 25%—most often because of time spent providing inappropriate antibiotic treatment.⁵ Guidelines for management of neck masses recommend against the use of antibiotics in patients who do not have evidence of infection.⁶

Patients with a neck mass that has been present for longer than 2 weeks or that is ulcerated, fixed to underlying tissues, of firm consistency, or > 1.5 cm should have a physical examination that includes visualization of the base of tongue, pharynx, and larynx. The mass should be evaluated with fine-­needle aspiration (FNA) biopsy, which has a positive predictive value of 96% and negative predictive value of 90% for the diagnosis of a head and neck mass. (Note: Anticoagulation therapy is not an absolute contraindication to FNA, which is not associated with an increased risk of bleeding.⁶)

Laryngeal cancer

What you need to know. More than 90% of laryngeal cancers are squamous cell carcinoma (SCC). Smoking or heavy drinking (> 8 drinks/d), compared to neither behavior, is associated with an increased risk of laryngeal cancer (odds ratio, 9.4 and 2.5, respectively).⁷ The risk of cancer is directly proportional to the degree of tobacco exposure.

One-half of head and neck cancers present with a neck mass that warrants appropriate initial assessment, so as not to delay diagnosis.

Laryngeal cancer occurs in the supraglottic region in one-third of patients; in the glottic region in one-half; and in the subglottic region in a very few.⁸ Glottic cancer presents earlier than supraglottic cancer with hoarseness, whereas supraglottic cancer presents with more advanced disease, causing stridor, dysphagia, and throat pain. (Note: Guidelines recommend against prescribing acid suppressants in patients with hoarseness who do not have symptoms of reflux.⁹)

Stage 1 and Stage 2 laryngeal cancers are localized; Stages 3-4B are locally advanced or involve lymph nodes, or both; Stage 4C is metastatic disease. Overall, 60% of patients have Stage 3 or Stage 4 disease at diagnosis.¹⁰

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Laryngoscopy should be performed before computed tomography (CT) or magnetic resonance imaging is considered in a patient with hoarseness that does not resolve after 3 months—or sooner, if there is suspicion of malignancy.

How is it treated? Most patients presenting with Stage 1 or Stage 2 cancer can be treated with local radiation or, less commonly, larynx-preserving surgery. Patients with Stage 3 or Stage 4 disease can be treated with a combination of radiation and chemotherapy, which, compared to radiation alone, confers a decreased risk of local recurrence and increased laryngectomy-free survival.¹¹ Patients whose vocal cords are destroyed or who have recurrence following radiation and chemotherapy might need total laryngectomy and formation of a tracheostomy and prosthetic for voice creation.

Five-year overall survival for Stage 1 and Stage 2 supraglottic and glottic cancers is 80%—lower, however, for later-presenting subglottic cancers.¹²

Oropharyngeal cancer

What you need to know. The lifetime risk for cancer of the oropharynx is approximately 1%.¹³ SCC is responsible for approximately 90% of these cancers. Early detection is important: The 5-year survival rate is more than twice as high for localized disease (83%) than it is for metastatic disease (39%) at detection.¹³

At any given time, 7% of the US population has HPV infection of the oropharynx. Most of these cases clear spontaneously, but persistent high-risk HPV infection led to a 225% increase in HPV-positive oropharyngeal SCC from 1988 to 2004.¹⁴ The representative case of HPV-positive oropharyngeal SCC is a middle-aged (40- to 59-year-old) white male with a history of multiple sexual partners and with little or no tobacco exposure and low alcohol consumption.

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Oral cancers present with a lesion, often ulcerative, that should be examined by palpation with a gloved finger to describe the presence, color, and number of lesions; any tenderness; tissue consistency (soft, firm, hard); and fixation to underlying structures.¹⁵ The oropharynx should be examined without protrusion of the tongue, which obscures the oropharynx and can make it harder to depress the posterior part of the tongue.

A finding of leukoplakia (white plaques) and erythroplakia (red plaques) of the oropharynx might reflect benign hyperkeratosis or premalignant lesions; the plaques do not wipe off on examination. Referral to a dentist or otorhinolaryngologist for biopsy is indicated for all erythroplakia and leukoplakia, and for ulcers that persist longer than 2 weeks.¹⁶

(Note: Evidence is insufficient to support screening asymptomatic patients for oral and oropharyngeal cancers by physical examination. There is no US Food and Drug Administration-approved screening test for oral HPV infection.¹⁷)

How is it treated? A diagnosis of moderate dysplasia or carcinoma in situ should be treated with surgical excision to clear margins followed by routine monitoring every 3 to 6 months, for life.¹⁸ Topical medication, electrocautery, laser ablation, and cryosurgery are management options for less severe dysplasia.

Sinonasal cancer

What you need to know. Worldwide, sinonasal cancer accounts for approximately 0.7% of all new cancers but demonstrates strong genetic and regional associations, particularly among the Cantonese population of southern China.¹⁹ One-half of new sinonasal malignancies are SCC; the rest are adenocarcinoma, lymphoepithelial carcinoma, and rare subtypes.²⁰

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Presentation tends to mimic common, nonmalignant conditions, such as sinusitis, until invasion into adjacent structures. When sinonasal passages are involved, the history might include epistaxis or nasal discharge; facial or dental pain; unilateral nasal obstruction with unexplained onset later in life; and failure to respond to treatment of presumed rhinosinusitis. Physical examination should include assessment of cranial nerves, palpation of the sinuses, and anterior rhinoscopy.

Thin-cut CT of the paranasal sinuses is the first-line imaging study. Sinonasal endoscopy, with targeted biopsy of suspicious lesions, is the evaluation of choice when malignancy is suspected.

How is it treated? Surgery is the treatment of choice, with postoperative radiation for patients at higher risk of recurrence because of more extensive disase.¹² Five-year survival for advanced disease is poor (35%); only 15% of cases are diagnosed at a localized stage because presenting symptoms are nonspecific.²¹

Nasopharyngeal cancer

What you need to know. Nasopharyngeal cancer is rare in the United States and Europe, compared with China, where it is endemic (and where a variety of risk factors, including intake of salt-preserved fish, have been proposed²²). Epstein-Barr virus infection and a history of smoking increase the risk.

Patients with nasopharyngeal cancer can present with epistaxis, nasal obstruction, and auditory symptoms, such as serous otitis media. Direct extension of the tumor can lead to cranial-nerve palsy, most commonly III, V, VI, and XII.²³

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Three-quarters of patients present with a neck mass from lymph-node metastases. Patients with the risk factors for nasopharyngeal cancer noted above who present with concerning symptoms should have nasoendoscopy with biopsy.

How is it treated? Radiation is the primary treatment, which is combined with chemotherapy for more advanced disease.²³ Screening high-risk populations for antibodies to Epstein-Barr virus and performing nasopharyngeal endoscopy on patients who screen positive increases the detection rate of nasopharyngeal cancer; however, this strategy has not been shown to improve survival.⁹

Salivary gland tumors

What you need to know. Salivary gland neoplasms are a rare and heterogeneous entity, comprising 6% to 8% of head and neck cancers.²⁴ More than 70% of these tumors are located in the parotid gland; 8%, in the submandibular glands; 1%, in the sublingual glands; and the rest, in the minor salivary glands. Most salivary gland tumors are benign; the most prevalent malignant tumors are mucoepidermoid carcinoma (30%) and adenoid cystic carcinoma (10%).²⁵ Additional identified risk factors for a salivary gland tumor include irradiation, prior head and neck cancer, and environmental exposures, including hairdressing, rubber manufacturing, and exposure to nickel compounds.²⁶

What is the diagnostic strategy? The history and physical exam are essential to distinguish a salivary gland tumor from an infectious cause and sialolithiasis. Parotid tumors most commonly present as asymptomatic parotid swelling, although pain can be present in as many as 40% of malignant parotid tumors.²⁵ Facial nerve weakness is found in 25% of parotid tumors; although the differential diagnosis of facial nerve palsy is broad, suspicion of malignancy should be raised in the presence of a parotid mass, progressive unilateral symptoms, hemifacial spasm progressing to weakness, and a history of skin cancer on the face or scalp. Additional characteristics that favor a neoplastic cause are trismus and nontender lymphadenopathy.²⁵

In a series of 100 patients with head and neck cancer, a delay in diagnosis occurred in nearly 25%—most often because of time spent providing inappropriate antibiotic treatment.

In contrast, sialolithiasis is associated with intermittent pain caused by eating and is more common in the settings of dehydration and poor dental hygiene. Sialadenitis should be suspected when the presentation is fever, increased pain and swelling, erythema, and expression of pus from the salivary gland.

Continue to: If malignancy is suspected...

If malignancy is suspected, the initial diagnostic evaluation should include ultrasonography (US); concurrent FNA biopsy should be performed if a mass is detected.²⁷ US-guided FNA has a sensitivity of 73% to 86% for salivary neoplasm.⁷ CT and ­magnetic resonance imaging are useful for further characterization of tumors and can be advantageous for surgical planning.

How is it treated? Treatment of a salivary gland tumor involves surgical resection, followed by radiotherapy for patients in whom disease is more extensive or who exhibit high-risk pathology. Primary radiotherapy can be used in patients with an unresectable tumor. Typically, chemotherapy is used only for palliative purposes in relapsing disease, when a tumor is not amenable to radiotherapy, and in metastatic disease.²⁵

Prognosis varies by histotype but is generally favorable. The survival rates for a malignant salivary gland tumor are 83% at 1 year, 69% at 3 years, and 65% at 5 years.²⁸ Distant metastases are the most common cause of death, occurring primarily in the lungs (80%), bone (15%), and liver.²⁷ Factors that indicate poor prognosis include facial nerve involvement, trismus, a tumor > 4 cm, bone involvement, nodal spread, and recurrence.²⁵

Thyroid cancer

What you need to know. Thyroid cancer is the most rapidly increasing cancer diagnosis in the United States, with an annual incidence of 4.5%.¹ In the United States, most thyroid cancers are differentiated thyroid cancer (DTC), which includes papillary and follicular cancers. Less-differentiated medullary thyroid cancer (MTC), typically associated with multiple endocrine neoplasia (MEN) 2A or 2B, and undifferentiated or anaplastic thyroid cancer are less common. The increasing incidence of thyroid cancer is primarily the result of an increase in nonclinically relevant DTC.

What is the diagnostic strategy? Thyroid cancer usually presents as a thyroid nodule found by the patient or incidentally on physical examination or imaging. Other presenting signs and symptoms include hoarseness, voice changes, and dysphagia.

Continue to: Thyroid US is the study of...

Thyroid US is the study of choice for initial evaluation of the size and features of a nodule; findings are used to make recommendations for further workup. If further evaluation is indicated, FNA biopsy is the test of choice.²⁹

In 2016, the American Thyroid Association released updated guidelines for evaluating thyroid nodules (TABLE).³⁰ The US Preventive Services Task Force recommends against screening for thyroid cancer by neck palpation or US in asymptomatic patients because evidence of significant mortality benefit is lacking.³¹

How is it treated? Treatment of thyroid cancer focuses on local excision of the nodule by partial or total thyroidectomy (depending on the size and type of cancer) and surgical removal of involved lymph nodes. Differentiated thyroid cancer is categorized as high-, medium-, or low-risk, depending on tumor extension, incomplete tumor resection, size of lymph nodes > 3 cm, and distant metastases. Adjuvant treatment with radioactive iodine can be considered for intermediate-risk DTC and is recommended for high-risk DTC.³²

Following surgical treatment, thyroid-stimulating hormone suppression is recommended using levothyroxine.³³ Patients at higher risk of recurrence should have longer and more intense suppression of thyroid-stimulating hormone.³⁰ Levels of serum thyroglobulin and anti-thyroglobulin antibody should be followed postoperatively; rising values can indicate recurrent disease. The calcitonin level should be followed in patients with a history of MTC. Thyroid US should be performed 6 to 12 months postoperatively, then periodically, depending on determination of recurrence risk and any change in the thyroglobulin level.³⁰

Human papillomavirus is associated with an increasing number of cases of head and neck cancer.

(Note: Glucagon-like peptide-1 [GLP-1] receptor agonists, used to treat type 2 diabetes mellitus, carry a black-box warning for their risk of MTC and are contraindicated in patients who have a personal or family history of MTC, MEN2A, or MEN2B.³⁴)

Continue to: Anaplastic thyroid cancer...

Anaplastic thyroid cancer, a rare form of thyroid cancer, carries a high mortality rate, with a median survival of 5 months from diagnosis and 1-year survival of 20%. Patients require expeditious total thyroidectomy and neck dissection, followed by external-beam radiation with or without chemotherapy. If this strategy is not feasible, tracheostomy might be necessary to maintain a patent airway.² Family physicians treating a patient who has anaplastic thyroid cancer can fulfill a crucial role by ensuring that an advance directive is established, a surrogate decision-maker is appointed, and goals of care are well defined.

Follow-up care for head and neck Ca

The risk of adverse effects after radiation therapy for head and neck cancer calls for close monitoring, appropriate treatment, and referral and counseling as needed. See “Follow-up care after treatment of head and neck cancer.” ^35-39

CORRESPONDENCE
Anne Mounsey, MD, Family Medicine Residency, The University of North Carolina at Chapel Hill, 590 Manning Dr., Chapel Hill, NC 27599; [email protected]

The statistics reveal a serious problem: This year, an estimated 63,030 Americans will be given a diagnosis of head and neck cancer (which includes laryngeal, oropharyngeal, sinonasal, nasopharyngeal, and salivary gland cancer¹); approximately 13,360 of them will die. Furthermore, thyroid cancer is the most rapidly increasing cancer diagnosis in the United States, with an estimated 56,870 cases in 2017.^1,2 Major risk factors for head and neck cancer are tobacco and alcohol exposure and infection with Epstein-Barr virus and human papillomavirus (HPV).³

In this article, we review the background for each of the principal types of head and neck cancer with which you should be familiar. We also discuss how to evaluate signs and symptoms that raise suspicion of these neoplasms; outline the diagnostic strategy in the face of such suspicion; and summarize accepted therapeutic approaches. Last, we describe the important role that you, the family physician, play in providing posttreatment care for these patients, especially prevention and management of late adverse effects of radiation therapy.

General characterizationsof these cancers

Approximately one-half of patients with head and neck cancer present initially with a nonspecific, persistent neck mass that should be deemed malignant until proven otherwise, because a delay in diagnosis is associated with a worse outcome.⁴ In a series of 100 patients with head and neck cancer, for example, delay in diagnosis occurred in nearly 25%—most often because of time spent providing inappropriate antibiotic treatment.⁵ Guidelines for management of neck masses recommend against the use of antibiotics in patients who do not have evidence of infection.⁶

Patients with a neck mass that has been present for longer than 2 weeks or that is ulcerated, fixed to underlying tissues, of firm consistency, or > 1.5 cm should have a physical examination that includes visualization of the base of tongue, pharynx, and larynx. The mass should be evaluated with fine-­needle aspiration (FNA) biopsy, which has a positive predictive value of 96% and negative predictive value of 90% for the diagnosis of a head and neck mass. (Note: Anticoagulation therapy is not an absolute contraindication to FNA, which is not associated with an increased risk of bleeding.⁶)

Laryngeal cancer

What you need to know. More than 90% of laryngeal cancers are squamous cell carcinoma (SCC). Smoking or heavy drinking (> 8 drinks/d), compared to neither behavior, is associated with an increased risk of laryngeal cancer (odds ratio, 9.4 and 2.5, respectively).⁷ The risk of cancer is directly proportional to the degree of tobacco exposure.

One-half of head and neck cancers present with a neck mass that warrants appropriate initial assessment, so as not to delay diagnosis.

Laryngeal cancer occurs in the supraglottic region in one-third of patients; in the glottic region in one-half; and in the subglottic region in a very few.⁸ Glottic cancer presents earlier than supraglottic cancer with hoarseness, whereas supraglottic cancer presents with more advanced disease, causing stridor, dysphagia, and throat pain. (Note: Guidelines recommend against prescribing acid suppressants in patients with hoarseness who do not have symptoms of reflux.⁹)

Stage 1 and Stage 2 laryngeal cancers are localized; Stages 3-4B are locally advanced or involve lymph nodes, or both; Stage 4C is metastatic disease. Overall, 60% of patients have Stage 3 or Stage 4 disease at diagnosis.¹⁰

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Laryngoscopy should be performed before computed tomography (CT) or magnetic resonance imaging is considered in a patient with hoarseness that does not resolve after 3 months—or sooner, if there is suspicion of malignancy.

How is it treated? Most patients presenting with Stage 1 or Stage 2 cancer can be treated with local radiation or, less commonly, larynx-preserving surgery. Patients with Stage 3 or Stage 4 disease can be treated with a combination of radiation and chemotherapy, which, compared to radiation alone, confers a decreased risk of local recurrence and increased laryngectomy-free survival.¹¹ Patients whose vocal cords are destroyed or who have recurrence following radiation and chemotherapy might need total laryngectomy and formation of a tracheostomy and prosthetic for voice creation.

Five-year overall survival for Stage 1 and Stage 2 supraglottic and glottic cancers is 80%—lower, however, for later-presenting subglottic cancers.¹²

Oropharyngeal cancer

What you need to know. The lifetime risk for cancer of the oropharynx is approximately 1%.¹³ SCC is responsible for approximately 90% of these cancers. Early detection is important: The 5-year survival rate is more than twice as high for localized disease (83%) than it is for metastatic disease (39%) at detection.¹³

At any given time, 7% of the US population has HPV infection of the oropharynx. Most of these cases clear spontaneously, but persistent high-risk HPV infection led to a 225% increase in HPV-positive oropharyngeal SCC from 1988 to 2004.¹⁴ The representative case of HPV-positive oropharyngeal SCC is a middle-aged (40- to 59-year-old) white male with a history of multiple sexual partners and with little or no tobacco exposure and low alcohol consumption.

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Oral cancers present with a lesion, often ulcerative, that should be examined by palpation with a gloved finger to describe the presence, color, and number of lesions; any tenderness; tissue consistency (soft, firm, hard); and fixation to underlying structures.¹⁵ The oropharynx should be examined without protrusion of the tongue, which obscures the oropharynx and can make it harder to depress the posterior part of the tongue.

A finding of leukoplakia (white plaques) and erythroplakia (red plaques) of the oropharynx might reflect benign hyperkeratosis or premalignant lesions; the plaques do not wipe off on examination. Referral to a dentist or otorhinolaryngologist for biopsy is indicated for all erythroplakia and leukoplakia, and for ulcers that persist longer than 2 weeks.¹⁶

(Note: Evidence is insufficient to support screening asymptomatic patients for oral and oropharyngeal cancers by physical examination. There is no US Food and Drug Administration-approved screening test for oral HPV infection.¹⁷)

How is it treated? A diagnosis of moderate dysplasia or carcinoma in situ should be treated with surgical excision to clear margins followed by routine monitoring every 3 to 6 months, for life.¹⁸ Topical medication, electrocautery, laser ablation, and cryosurgery are management options for less severe dysplasia.

Sinonasal cancer

What you need to know. Worldwide, sinonasal cancer accounts for approximately 0.7% of all new cancers but demonstrates strong genetic and regional associations, particularly among the Cantonese population of southern China.¹⁹ One-half of new sinonasal malignancies are SCC; the rest are adenocarcinoma, lymphoepithelial carcinoma, and rare subtypes.²⁰

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Presentation tends to mimic common, nonmalignant conditions, such as sinusitis, until invasion into adjacent structures. When sinonasal passages are involved, the history might include epistaxis or nasal discharge; facial or dental pain; unilateral nasal obstruction with unexplained onset later in life; and failure to respond to treatment of presumed rhinosinusitis. Physical examination should include assessment of cranial nerves, palpation of the sinuses, and anterior rhinoscopy.

Thin-cut CT of the paranasal sinuses is the first-line imaging study. Sinonasal endoscopy, with targeted biopsy of suspicious lesions, is the evaluation of choice when malignancy is suspected.

How is it treated? Surgery is the treatment of choice, with postoperative radiation for patients at higher risk of recurrence because of more extensive disase.¹² Five-year survival for advanced disease is poor (35%); only 15% of cases are diagnosed at a localized stage because presenting symptoms are nonspecific.²¹

Nasopharyngeal cancer

What you need to know. Nasopharyngeal cancer is rare in the United States and Europe, compared with China, where it is endemic (and where a variety of risk factors, including intake of salt-preserved fish, have been proposed²²). Epstein-Barr virus infection and a history of smoking increase the risk.

Patients with nasopharyngeal cancer can present with epistaxis, nasal obstruction, and auditory symptoms, such as serous otitis media. Direct extension of the tumor can lead to cranial-nerve palsy, most commonly III, V, VI, and XII.²³

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Three-quarters of patients present with a neck mass from lymph-node metastases. Patients with the risk factors for nasopharyngeal cancer noted above who present with concerning symptoms should have nasoendoscopy with biopsy.

How is it treated? Radiation is the primary treatment, which is combined with chemotherapy for more advanced disease.²³ Screening high-risk populations for antibodies to Epstein-Barr virus and performing nasopharyngeal endoscopy on patients who screen positive increases the detection rate of nasopharyngeal cancer; however, this strategy has not been shown to improve survival.⁹

Salivary gland tumors

What you need to know. Salivary gland neoplasms are a rare and heterogeneous entity, comprising 6% to 8% of head and neck cancers.²⁴ More than 70% of these tumors are located in the parotid gland; 8%, in the submandibular glands; 1%, in the sublingual glands; and the rest, in the minor salivary glands. Most salivary gland tumors are benign; the most prevalent malignant tumors are mucoepidermoid carcinoma (30%) and adenoid cystic carcinoma (10%).²⁵ Additional identified risk factors for a salivary gland tumor include irradiation, prior head and neck cancer, and environmental exposures, including hairdressing, rubber manufacturing, and exposure to nickel compounds.²⁶

What is the diagnostic strategy? The history and physical exam are essential to distinguish a salivary gland tumor from an infectious cause and sialolithiasis. Parotid tumors most commonly present as asymptomatic parotid swelling, although pain can be present in as many as 40% of malignant parotid tumors.²⁵ Facial nerve weakness is found in 25% of parotid tumors; although the differential diagnosis of facial nerve palsy is broad, suspicion of malignancy should be raised in the presence of a parotid mass, progressive unilateral symptoms, hemifacial spasm progressing to weakness, and a history of skin cancer on the face or scalp. Additional characteristics that favor a neoplastic cause are trismus and nontender lymphadenopathy.²⁵

In a series of 100 patients with head and neck cancer, a delay in diagnosis occurred in nearly 25%—most often because of time spent providing inappropriate antibiotic treatment.

In contrast, sialolithiasis is associated with intermittent pain caused by eating and is more common in the settings of dehydration and poor dental hygiene. Sialadenitis should be suspected when the presentation is fever, increased pain and swelling, erythema, and expression of pus from the salivary gland.

Continue to: If malignancy is suspected...

If malignancy is suspected, the initial diagnostic evaluation should include ultrasonography (US); concurrent FNA biopsy should be performed if a mass is detected.²⁷ US-guided FNA has a sensitivity of 73% to 86% for salivary neoplasm.⁷ CT and ­magnetic resonance imaging are useful for further characterization of tumors and can be advantageous for surgical planning.

How is it treated? Treatment of a salivary gland tumor involves surgical resection, followed by radiotherapy for patients in whom disease is more extensive or who exhibit high-risk pathology. Primary radiotherapy can be used in patients with an unresectable tumor. Typically, chemotherapy is used only for palliative purposes in relapsing disease, when a tumor is not amenable to radiotherapy, and in metastatic disease.²⁵

Prognosis varies by histotype but is generally favorable. The survival rates for a malignant salivary gland tumor are 83% at 1 year, 69% at 3 years, and 65% at 5 years.²⁸ Distant metastases are the most common cause of death, occurring primarily in the lungs (80%), bone (15%), and liver.²⁷ Factors that indicate poor prognosis include facial nerve involvement, trismus, a tumor > 4 cm, bone involvement, nodal spread, and recurrence.²⁵

Thyroid cancer

What you need to know. Thyroid cancer is the most rapidly increasing cancer diagnosis in the United States, with an annual incidence of 4.5%.¹ In the United States, most thyroid cancers are differentiated thyroid cancer (DTC), which includes papillary and follicular cancers. Less-differentiated medullary thyroid cancer (MTC), typically associated with multiple endocrine neoplasia (MEN) 2A or 2B, and undifferentiated or anaplastic thyroid cancer are less common. The increasing incidence of thyroid cancer is primarily the result of an increase in nonclinically relevant DTC.

What is the diagnostic strategy? Thyroid cancer usually presents as a thyroid nodule found by the patient or incidentally on physical examination or imaging. Other presenting signs and symptoms include hoarseness, voice changes, and dysphagia.

Continue to: Thyroid US is the study of...

Thyroid US is the study of choice for initial evaluation of the size and features of a nodule; findings are used to make recommendations for further workup. If further evaluation is indicated, FNA biopsy is the test of choice.²⁹

In 2016, the American Thyroid Association released updated guidelines for evaluating thyroid nodules (TABLE).³⁰ The US Preventive Services Task Force recommends against screening for thyroid cancer by neck palpation or US in asymptomatic patients because evidence of significant mortality benefit is lacking.³¹

How is it treated? Treatment of thyroid cancer focuses on local excision of the nodule by partial or total thyroidectomy (depending on the size and type of cancer) and surgical removal of involved lymph nodes. Differentiated thyroid cancer is categorized as high-, medium-, or low-risk, depending on tumor extension, incomplete tumor resection, size of lymph nodes > 3 cm, and distant metastases. Adjuvant treatment with radioactive iodine can be considered for intermediate-risk DTC and is recommended for high-risk DTC.³²

Following surgical treatment, thyroid-stimulating hormone suppression is recommended using levothyroxine.³³ Patients at higher risk of recurrence should have longer and more intense suppression of thyroid-stimulating hormone.³⁰ Levels of serum thyroglobulin and anti-thyroglobulin antibody should be followed postoperatively; rising values can indicate recurrent disease. The calcitonin level should be followed in patients with a history of MTC. Thyroid US should be performed 6 to 12 months postoperatively, then periodically, depending on determination of recurrence risk and any change in the thyroglobulin level.³⁰

Human papillomavirus is associated with an increasing number of cases of head and neck cancer.

(Note: Glucagon-like peptide-1 [GLP-1] receptor agonists, used to treat type 2 diabetes mellitus, carry a black-box warning for their risk of MTC and are contraindicated in patients who have a personal or family history of MTC, MEN2A, or MEN2B.³⁴)

Continue to: Anaplastic thyroid cancer...

Anaplastic thyroid cancer, a rare form of thyroid cancer, carries a high mortality rate, with a median survival of 5 months from diagnosis and 1-year survival of 20%. Patients require expeditious total thyroidectomy and neck dissection, followed by external-beam radiation with or without chemotherapy. If this strategy is not feasible, tracheostomy might be necessary to maintain a patent airway.² Family physicians treating a patient who has anaplastic thyroid cancer can fulfill a crucial role by ensuring that an advance directive is established, a surrogate decision-maker is appointed, and goals of care are well defined.

Follow-up care for head and neck Ca

The risk of adverse effects after radiation therapy for head and neck cancer calls for close monitoring, appropriate treatment, and referral and counseling as needed. See “Follow-up care after treatment of head and neck cancer.” ^35-39

CORRESPONDENCE
Anne Mounsey, MD, Family Medicine Residency, The University of North Carolina at Chapel Hill, 590 Manning Dr., Chapel Hill, NC 27599; [email protected]

The association between type 2 diabetes (T2D) and cardiovascular (CV) disease is well-established:

• Type 2 diabetes approximately doubles the risk of coronary artery disease, stroke, and peripheral arterial disease, independent of conventional risk factors¹
• CV disease is the leading cause of morbidity and mortality in patients with T2D
• CV disease is the largest contributor to direct and indirect costs of the health care of patients who have T2D.²

In recent years, new classes of agents for treating T2D have been introduced (TABLE 1). Prior to 2008, the US Food and Drug Administration (FDA) approved drugs in those new classes based simply on their effectiveness in reducing the blood glucose level. Concerns about the CV safety of specific drugs (eg, rosiglitazone, muraglitazar) emerged from a number of trials, suggesting that these agents might increase the risk of CV events.^3,4

All glucose-lowering medications used to treat type 2 diabetes are not equally effective in reducing CV complications.

Consequently, in 2008, the FDA issued guidance to the pharmaceutical industry: Preapproval and postapproval trials of all new antidiabetic drugs must now assess potential excess CV risk.⁵ CV outcomes trials (CVOTs), performed in accordance with FDA guidelines, have therefore become the focus of evaluating novel treatment options. In most CVOTs, combined primary CV endpoints have included CV mortality, nonfatal myocardial infarction (MI), and nonfatal stroke—taken together, what is known as the composite of these 3 major adverse CV events, or MACE-3.

To date, 15 CVOTs have been completed, assessing 3 novel classes of antihyperglycemic agents:

• dipeptidyl peptidase-4 (DPP-4) inhibitors
• glucagon-like peptide-1 (GLP-1) receptor agonists
• sodium–glucose cotransporter-2 (SGLT-2) inhibitors.

None of these trials identified any increased incidence of MACE; 7 found CV benefit. This review summarizes what the CVOTs revealed about these antihyperglycemic agents and their ability to yield a reduction in MACE and a decrease in all-cause mortality in patients with T2D and elevated CV disease risk. Armed with this information, you will have the tools you need to offer patients with T2D CV benefit while managing their primary disease.

Cardiovascular outcomes trials: DPP-4 inhibitors

Four trials. Trials of DPP-4 inhibitors that have been completed and reported are of saxagliptin (SAVOR-TIMI 53⁶), alogliptin (EXAMINE⁷), sitagliptin (TECOS⁸), and linagliptin (CARMELINA⁹); others are in progress. In general, researchers enrolled patients at high risk of CV events, although inclusion criteria varied substantially. Consistently, these studies demonstrated that DPP-4 inhibition neither increased nor decreased (ie, were noninferior) the 3-point MACE (SAVOR-TIMI 53 noninferiority, P < .001; EXAMINE, P < .001; TECOS, P < .001).

Continue to: Rather than improve...

Rather than improve CV outcomes, there was some evidence that DPP-4 inhibitors might be associated with an increased risk of hospitalization for heart failure (HHF). In the SAVOR-TIMI 53 trial, patients randomized to saxagliptin had a 0.7% absolute increase in risk of HHF (P = .98).⁶ In the EXAMINE trial, patients treated with alogliptin showed a nonsignificant trend for HHF.¹⁰ In both the TECOS and CARMELINA trials, no difference was recorded in the rate of HHF.^8,9,11 Subsequent meta-analysis that summarized the risk of HHF in CVOTs with DPP-4 inhibitors indicated a nonsignificant trend to increased risk.¹²

It’s likely that the CV benefits result from mechanisms other than a reduction in the serum glucose level, given the short time frame of the studies and the magnitude of the CV benefit.

From these trials alone, it appears that DPP-4 inhibitors are unlikely to provide CV benefit. Data from additional trials are needed to evaluate the possible association between these medications and heart failure (HF). However, largely as a result of the findings from SAVOR-TIMI 53 and EXAMINE, the FDA issued a Drug Safety Communication in April 2016, adding warnings about HF to the labeling of saxagliptin and alogliptin.¹³

CARMELINA was designed to also evaluate kidney outcomes in patients with T2D. As with other DPP-4 inhibitor trials, the primary aim was to establish noninferiority, compared with placebo, for time to MACE-3 (P < .001). Secondary outcomes were defined as time to first occurrence of end-stage renal disease, death due to renal failure, and sustained decrease from baseline of ≥ 40% in the estimated glomerular filtration rate. The incidence of the secondary kidney composite results was not significantly different between groups randomized to linagliptin or placebo.⁹

Cardiovascular outcomes trials: GLP-1 receptor agonists

ELIXA. The CV safety of GLP-1 receptor agonists has been evaluated in several randomized clinical trials. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial was the first¹⁴: Lixisenatide was studied in 6068 patients with recent hospitalization for acute coronary syndrome. Lixisenatide therapy was neutral with regard to CV outcomes, which met the primary endpoint: noninferiority to placebo (P < .001). There was no increase in either HF or HHF.

Continue to: LEADER

LEADER. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results trial (LEADER) evaluated long-term effects of liraglutide, compared to placebo, on CV events in patients with T2D.¹⁵ It was a multicenter, double-blind, placebocontrolled study that followed 9340 participants, most (81%) of whom had established CV disease, over 5 years. LEADER is considered a landmark study because it was the first large CVOT to show significant benefit for a GLP-1 receptor agonist.

Liraglutide demonstrated reductions in first occurrence of death from CV causes, nonfatal MI or nonfatal stroke, overall CV mortality, and all-cause mortality. The composite MACE-3 showed a relative risk reduction (RRR) of 13%, equivalent to an absolute risk reduction (ARR) of 1.9% (noninferiority, P < .001; superiority, P < .01). The RRR was 22% for death from CV causes, with an ARR of 1.3% (P = .007); the RRR for death from any cause was 15%, with an ARR of 1.4% (P = .02).

In addition, there was a lower rate of nephropathy (1.5 events for every 100 patient–years in the liraglutide group [P = .003], compared with 1.9 events every 100 patient–years in the placebo group).¹⁵

Results clearly demonstrated benefit. No significant difference was seen in the liraglutide rate of HHF, compared to the rate in the placebo group.

SUSTAIN-6. Evidence for the CV benefit of GLP-1 receptor agonists was also demonstrated in the phase 3 Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6).¹⁶ This was a study of 3297 patients with T2D at high risk of CV disease and with a mean hemoglobin A_1c (HbA_1c) value of 8.7%, 83% of whom had established CV disease. Patients were randomized to semaglutide or placebo. Note: SUSTAIN-6 was a noninferiority safety study; as such, it was not actually designed to assess or establish superiority.

Continue to: The incidence of MACE-3...

The incidence of MACE-3 was significantly reduced among patients treated with semaglutide (P = .02) after median followup of 2.1 years. The expanded composite outcome (death from CV causes, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina or HF), also showed a significant reduction with semaglutide (P = .002), compared with placebo. There was no difference in the overall hospitalization rate or rate of death from any cause.

EXSCEL. The Exenatide Study of Cardiovascular Event Lowering trial (EXSCEL)^17,18 was a phase III/IV, double-blind, pragmatic placebo-controlled study of 14,752 patients at any level of CV risk, for a median 3.2 years. The study population was intentionally more diverse than in earlier GLP-1 receptor agonist studies. The researchers hypothesized that patients at increased risk of MACE would experience a comparatively greater relative treatment benefit with exenatide than those at lower risk. That did not prove to be the case.

EXSCEL did confirm noninferiority compared with placebo (P < .001), but once-weekly exenatide resulted in a nonsignificant reduction in major adverse CV events, and a trend for RRR in all-cause mortality (RRR = 14%; ARR = 1% [P = .06]).

HARMONY OUTCOMES. The Albiglutide and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Cardiovascular Disease study (HARMONY OUTCOMES)¹⁹ was a double-blind, randomized, placebocontrolled trial conducted at 610 sites across 28 countries. The study investigated albiglutide, 30 to 50 mg once weekly, compared with placebo. It included 9463 patients ages ≥ 40 years with T2D who had an HbA_1c > 7% (median value, 8.7%) and established CV disease. Patients were evaluated for a median 1.6 years.

Albiglutide reduced the risk of CV causes of death, nonfatal MI, and nonfatal stroke by an RRR of 22%, (ARR, 2%) (noninferiority, P < .0001; superiority, P < .0006).

Continue to: REWIND

REWIND. The Researching Cardiovascular Events with a Weekly INcretin in Diabetes trial (REWIND),²⁰ the most recently completed GLP-1 receptor agonist CVOT (presented at the 2019 American Diabetes Association [ADA] Conference in June and published simultaneously in The Lancet), was a multicenter, randomized, double-blind placebo-controlled trial designed to assess the effect of weekly dulaglutide, 1.5 mg, compared with placebo, in 9901 participants enrolled at 371 sites in 24 countries. Mean patient age was 66.2 years, with women constituting 4589 (46.3%) of participants.

REWIND was distinct from other CVOTs in several ways:

• Other CVOTs were designed to show noninferiority compared with placebo regarding CV events; REWIND was designed to establish superiority
• In contrast to trials of other GLP-1 receptor agonists, in which most patients had established CV disease, only 31% of REWIND participants had a history of CV disease or a prior CV event (although 69% did have CV risk factors without underlying disease)
• REWIND was much longer (median follow-up, 5.4 years) than other GLP-1 receptor agonist trials (median follow-up, 1.5 to 3.8 years).

In REWIND, the primary composite outcome of MACE-3 occurred in 12% of participants assigned to dulaglutide, compared with 13.1% assigned to placebo (P = .026). This equated to 2.4 events for every 100 person– years on dulaglutide, compared with 2.7 events for every 100 person–years on placebo. There was a consistent effect on all MACE-3 components, although the greatest reductions were observed in nonfatal stroke (P = .017). Overall risk reduction was the same for primary and secondary prevention cohorts (P = .97), as well as in patients with either an HbA_1c value < 7.2% or ≥ 7.2% (P = .75). Risk reduction was consistent across age, sex, duration of T2D, and body mass index.

Dulaglutide did not significantly affect the incidence of all-cause mortality, heart failure, revascularization, or hospital admission. Forty-seven percent of patients taking dulaglutide reported gastrointestinal adverse effects (P = .0001).

Cases of bullous pemphigoid have been reported after initiation of DPP-4 inhibitor therapy.

In a separate analysis of secondary outcomes, ²¹ dulaglutide reduced the composite renal outcomes of new-onset macroalbuminuria (P = .0001); decline of ≥ 30% in the estimated glomerular filtration rate (P = .066); and chronic renal replacement therapy (P = .39). Investigators estimated that 1 composite renal outcome event would be prevented for every 31 patients treated with dulaglutide for a median 5.4 years.

Continue to: Cardiovascular outcomes trials...

Cardiovascular outcomes trials: SGLT-2 inhibitors

EMPA-REG OUTCOME. The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) was also a landmark study because it was the first dedicated CVOT to show that an antihyperglycemic agent 1) decreased CV mortality and all-cause mortality, and 2) reduced HHF in patients with T2D and established CV disease.22 In this trial, 7020 patients with T2D who were at high risk of CV events were randomized and treated with empagliflozin, 10 or 25 mg, or placebo, in addition to standard care, and were followed for a median 2.6 years.

In October, the FDA approved dapaglifozin to reduce the risk of hospitalization for heart failure in adults with T2D and established CV disease.

Compared with placebo, empagliflozin resulted in an RRR of 14% (ARR, 1.6%) in the primary endpoint of CV death, nonfatal MI, and stroke, confirming study drug superiority (P = .04). When compared with placebo, the empagliflozin group had an RRR of 38% in CV mortality, (ARR < 2.2%) (P < .001); an RRR of 35% in HHF (ARR, 1.4%) (P = .002); and an RRR of 32% (ARR, 2.6%) in death from any cause (P < .001).

CANVAS. The Canagliflozin Cardiovascular Assessment Study (CANVAS) integrated 2 multicenter, placebo-controlled, randomized trials with 10,142 participants and a mean follow-up of 3.6 years.²³ Patients were randomized to receive canagliflozin (100-300 mg/d) or placebo. Approximately two-thirds of patients had a history of CV disease (therefore representing secondary prevention); one-third had CV risk factors only (primary prevention).

In CANVAS, patients receiving canagliflozin had a risk reduction in MACE-3, establishing superiority compared with placebo (P < .001). There was also a significant reduction in progression of albuminuria (P < .05). Superiority was not shown for the secondary outcome of death from any cause. Canagliflozin had no effect on the primary endpoint (MACE-3) in the subgroup of participants who did not have a history of CV disease. Similar to what was found with empagliflozin in EMPA-REG OUTCOME, CANVAS participants had a reduced risk of HHF.

Continue to: Patients on canagliflozin...

Patients on canagliflozin unexpectedly had an increased incidence of amputations (6.3 participants, compared with 3.4 participants, for every 1000 patient–years). This finding led to a black box warning for canagliflozin about the risk of lower-limb amputation.

DECLARE-TIMI 58. The Dapagliflozin Effect of Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 trial (DECLARETIMI 58) was the largest SGLT-2 inhibitor outcomes trial to date, enrolling 17,160 patients with T2D who also had established CV disease or multiple risk factors for atherosclerotic CV disease. The trial compared dapagliflozin, 10 mg/d, and placebo, following patients for a median 4.2 years.²⁴ Unlike CANVAS and EMPA-REG OUTCOME, DECLARE-TIMI 58 included CV death and HHF as primary outcomes, in addition to MACE-3.

Dapagliflozin was noninferior to placebo with regard to MACE-3. However, its use did result in a lower rate of CV death and HHF by an RRR of 17% (ARR, 1.9%). Risk reduction was greatest in patients with HF who had a reduced ejection fraction (ARR = 9.2%).²⁵

In October, the FDA approved dapagliflozin to reduce the risk of HHF in adults with T2D and established CV disease or multiple CV risk factors. Before initiating the drug, physicians should evaluate the patient's renal function and monitor periodically.

Meta-analyses of SGLT-2 inhibitors

Systematic review. Usman et al released a meta-analysis in 2018 that included 35 randomized, placebo-controlled trials (including EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58) that had assessed the use of SGLT-2 inhibitors in nearly 35,000 patients with T2D.²⁶ This review concluded that, as a class, SGLT-2 inhibitors reduce all-cause mortality, major adverse cardiac events, nonfatal MI, and HF and HHF, compared with placebo.

Continue to: CVD-REAL

CVD-REAL. A separate study, Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL), of 154,528 patients who were treated with canagliflozin, dapagliflozin, or empagliflozin, showed that initiation of SGLT-2 inhibitors, compared with other glucose- lowering therapies, was associated with a 39% reduction in HHF; a 51% reduction in death from any cause; and a 46% reduction in the composite of HHF or death (P < .001).²⁷

CVD-REAL was unique because it was the largest real-world study to assess the effectiveness of SGLT-2 inhibitors on HHF and mortality. The study utilized data from patients in the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom, based on information obtained from medical claims, primary care and hospital records, and national registries that compared patients who were either newly started on an SGLT-2 inhibitor or another glucose-lowering drug. The drug used by most patients in the trial was canagliflozin (53%), followed by dapagliflozin (42%), and empagliflozin (5%).

In this meta-analysis, similar therapeutic effects were seen across countries, regardless of geographic differences, in the use of specific SGLT-2 inhibitors, suggesting a class effect. Of particular significance was that most (87%) patients enrolled in CVD-REAL did not have prior CV disease. Despite this, results for examined outcomes in CVD-REAL were similar to what was seen in other SGLT-2 inhibitor trials that were designed to study patients with established CV disease.

Risk of adverse effects of newer antidiabetic agents

DPP-4 inhibitors. Alogliptin and sitagliptin carry a black-box warning about potential risk of HF. In SAVOR-TIMI, a 27% increase was detected in the rate of HHF after approximately 2 years of saxagliptin therapy.⁶ Although HF should not be considered a class effect for DPP-4 inhibitors, patients who have risk factors for HF should be monitored for signs and symptoms of HF.

Continue to: Cases of acute pancreatitis...

Cases of acute pancreatitis have been reported in association with all DPP-4 inhibitors available in the United States. A combined analysis of DDP-4 inhibitor trials suggested an increased relative risk of 79% and an absolute risk of 0.13%, which translates to 1 or 2 additional cases of acute pancreatitis for every 1000 patients treated for 2 years.²⁸

There have been numerous postmarketing reports of severe joint pain in patients taking a DPP-4 inhibitor. Most recently, cases of bullous pemphigoid have been reported after initiation of DPP-4 inhibitor therapy.²⁹

GLP-1 receptor agonists carry a black box warning for medullary thyroid (C-cell) tumor risk. GLP-1 receptor agonists are contraindicated in patients with a personal or family history of this cancer, although this FDA warning is based solely on observations from animal models.

In addition, GLP-1 receptor agonists can increase the risk of cholecystitis and pancreatitis. Not uncommonly, they cause gastrointestinal symptoms when first started and when the dosage is titrated upward. Most GLP-1 receptor agonists can be used in patients with renal impairment, although data regarding their use in Stages 4 and 5 chronic kidney disease are limited.³⁰ Semaglutide was found, in the SUSTAIN-6 trial, to be associated with an increased rate of complications of retinopathy, including vitreous hemorrhage and blindness (P = .02)³¹

SGLT-2 inhibitors are associated with an increased incidence of genitourinary infection, bone fracture (canagliflozin), amputation (canagliflozin), and euglycemic diabetic ketoacidosis. Agents in this class should be avoided in patients with moderate or severe renal impairment, primarily due to a lack of efficacy. They are contraindicated in patients with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2. (Dapagliflozin is not recommended when eGFR is < 45 mL/min/ 1.73 m2.) These agents carry an FDA warning about the risk of acute kidney injury.³⁰

Continue to: Summing up

Summing up

All glucose-lowering medications used to treat T2D are not equally effective in reducing CV complications. Recent CVOTs have uncovered evidence that certain antidiabetic agents might confer CV and all-cause mortality benefits (TABLE 2^{6,7,9,11,14-17,19-24}).

Discussion of proposed mechanisms for CV outcome superiority of these agents is beyond the scope of this review. It is generally believed that benefits result from mechanisms other than a reduction in the serum glucose level, given the relatively short time frame of the studies and the magnitude of the CV benefit. It is almost certain that mechanisms of CV benefit in the 2 landmark studies—LEADER and EMPA-REG OUTCOME—are distinct from each other.³²

See “When planning T2D pharmacotherapy, include newer agents that offer CV benefit,” ^33-38 for a stepwise approach to treating T2D, including the role of agents that have efficacy in modifying the risk of CV disease.

ACKNOWLEDGMENTS
Linda Speer, MD, Kevin Phelps, DO, and Jay Shubrook, DO, provided support and editorial assistance.

CORRESPONDENCE
Robert Gotfried, DO, FAAFP, Department of Family Medicine, University of Toledo College of Medicine, 3333 Glendale Avenue, Toledo, OH 43614; [email protected].

The association between type 2 diabetes (T2D) and cardiovascular (CV) disease is well-established:

• Type 2 diabetes approximately doubles the risk of coronary artery disease, stroke, and peripheral arterial disease, independent of conventional risk factors¹
• CV disease is the leading cause of morbidity and mortality in patients with T2D
• CV disease is the largest contributor to direct and indirect costs of the health care of patients who have T2D.²

In recent years, new classes of agents for treating T2D have been introduced (TABLE 1). Prior to 2008, the US Food and Drug Administration (FDA) approved drugs in those new classes based simply on their effectiveness in reducing the blood glucose level. Concerns about the CV safety of specific drugs (eg, rosiglitazone, muraglitazar) emerged from a number of trials, suggesting that these agents might increase the risk of CV events.^3,4

All glucose-lowering medications used to treat type 2 diabetes are not equally effective in reducing CV complications.

Consequently, in 2008, the FDA issued guidance to the pharmaceutical industry: Preapproval and postapproval trials of all new antidiabetic drugs must now assess potential excess CV risk.⁵ CV outcomes trials (CVOTs), performed in accordance with FDA guidelines, have therefore become the focus of evaluating novel treatment options. In most CVOTs, combined primary CV endpoints have included CV mortality, nonfatal myocardial infarction (MI), and nonfatal stroke—taken together, what is known as the composite of these 3 major adverse CV events, or MACE-3.

To date, 15 CVOTs have been completed, assessing 3 novel classes of antihyperglycemic agents:

• dipeptidyl peptidase-4 (DPP-4) inhibitors
• glucagon-like peptide-1 (GLP-1) receptor agonists
• sodium–glucose cotransporter-2 (SGLT-2) inhibitors.

None of these trials identified any increased incidence of MACE; 7 found CV benefit. This review summarizes what the CVOTs revealed about these antihyperglycemic agents and their ability to yield a reduction in MACE and a decrease in all-cause mortality in patients with T2D and elevated CV disease risk. Armed with this information, you will have the tools you need to offer patients with T2D CV benefit while managing their primary disease.

Cardiovascular outcomes trials: DPP-4 inhibitors

Four trials. Trials of DPP-4 inhibitors that have been completed and reported are of saxagliptin (SAVOR-TIMI 53⁶), alogliptin (EXAMINE⁷), sitagliptin (TECOS⁸), and linagliptin (CARMELINA⁹); others are in progress. In general, researchers enrolled patients at high risk of CV events, although inclusion criteria varied substantially. Consistently, these studies demonstrated that DPP-4 inhibition neither increased nor decreased (ie, were noninferior) the 3-point MACE (SAVOR-TIMI 53 noninferiority, P < .001; EXAMINE, P < .001; TECOS, P < .001).

Continue to: Rather than improve...

Rather than improve CV outcomes, there was some evidence that DPP-4 inhibitors might be associated with an increased risk of hospitalization for heart failure (HHF). In the SAVOR-TIMI 53 trial, patients randomized to saxagliptin had a 0.7% absolute increase in risk of HHF (P = .98).⁶ In the EXAMINE trial, patients treated with alogliptin showed a nonsignificant trend for HHF.¹⁰ In both the TECOS and CARMELINA trials, no difference was recorded in the rate of HHF.^8,9,11 Subsequent meta-analysis that summarized the risk of HHF in CVOTs with DPP-4 inhibitors indicated a nonsignificant trend to increased risk.¹²

It’s likely that the CV benefits result from mechanisms other than a reduction in the serum glucose level, given the short time frame of the studies and the magnitude of the CV benefit.

From these trials alone, it appears that DPP-4 inhibitors are unlikely to provide CV benefit. Data from additional trials are needed to evaluate the possible association between these medications and heart failure (HF). However, largely as a result of the findings from SAVOR-TIMI 53 and EXAMINE, the FDA issued a Drug Safety Communication in April 2016, adding warnings about HF to the labeling of saxagliptin and alogliptin.¹³

CARMELINA was designed to also evaluate kidney outcomes in patients with T2D. As with other DPP-4 inhibitor trials, the primary aim was to establish noninferiority, compared with placebo, for time to MACE-3 (P < .001). Secondary outcomes were defined as time to first occurrence of end-stage renal disease, death due to renal failure, and sustained decrease from baseline of ≥ 40% in the estimated glomerular filtration rate. The incidence of the secondary kidney composite results was not significantly different between groups randomized to linagliptin or placebo.⁹

Cardiovascular outcomes trials: GLP-1 receptor agonists

ELIXA. The CV safety of GLP-1 receptor agonists has been evaluated in several randomized clinical trials. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial was the first¹⁴: Lixisenatide was studied in 6068 patients with recent hospitalization for acute coronary syndrome. Lixisenatide therapy was neutral with regard to CV outcomes, which met the primary endpoint: noninferiority to placebo (P < .001). There was no increase in either HF or HHF.

Continue to: LEADER

LEADER. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results trial (LEADER) evaluated long-term effects of liraglutide, compared to placebo, on CV events in patients with T2D.¹⁵ It was a multicenter, double-blind, placebocontrolled study that followed 9340 participants, most (81%) of whom had established CV disease, over 5 years. LEADER is considered a landmark study because it was the first large CVOT to show significant benefit for a GLP-1 receptor agonist.

Liraglutide demonstrated reductions in first occurrence of death from CV causes, nonfatal MI or nonfatal stroke, overall CV mortality, and all-cause mortality. The composite MACE-3 showed a relative risk reduction (RRR) of 13%, equivalent to an absolute risk reduction (ARR) of 1.9% (noninferiority, P < .001; superiority, P < .01). The RRR was 22% for death from CV causes, with an ARR of 1.3% (P = .007); the RRR for death from any cause was 15%, with an ARR of 1.4% (P = .02).

In addition, there was a lower rate of nephropathy (1.5 events for every 100 patient–years in the liraglutide group [P = .003], compared with 1.9 events every 100 patient–years in the placebo group).¹⁵

Results clearly demonstrated benefit. No significant difference was seen in the liraglutide rate of HHF, compared to the rate in the placebo group.

SUSTAIN-6. Evidence for the CV benefit of GLP-1 receptor agonists was also demonstrated in the phase 3 Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6).¹⁶ This was a study of 3297 patients with T2D at high risk of CV disease and with a mean hemoglobin A_1c (HbA_1c) value of 8.7%, 83% of whom had established CV disease. Patients were randomized to semaglutide or placebo. Note: SUSTAIN-6 was a noninferiority safety study; as such, it was not actually designed to assess or establish superiority.

Continue to: The incidence of MACE-3...

The incidence of MACE-3 was significantly reduced among patients treated with semaglutide (P = .02) after median followup of 2.1 years. The expanded composite outcome (death from CV causes, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina or HF), also showed a significant reduction with semaglutide (P = .002), compared with placebo. There was no difference in the overall hospitalization rate or rate of death from any cause.

EXSCEL. The Exenatide Study of Cardiovascular Event Lowering trial (EXSCEL)^17,18 was a phase III/IV, double-blind, pragmatic placebo-controlled study of 14,752 patients at any level of CV risk, for a median 3.2 years. The study population was intentionally more diverse than in earlier GLP-1 receptor agonist studies. The researchers hypothesized that patients at increased risk of MACE would experience a comparatively greater relative treatment benefit with exenatide than those at lower risk. That did not prove to be the case.

EXSCEL did confirm noninferiority compared with placebo (P < .001), but once-weekly exenatide resulted in a nonsignificant reduction in major adverse CV events, and a trend for RRR in all-cause mortality (RRR = 14%; ARR = 1% [P = .06]).

HARMONY OUTCOMES. The Albiglutide and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Cardiovascular Disease study (HARMONY OUTCOMES)¹⁹ was a double-blind, randomized, placebocontrolled trial conducted at 610 sites across 28 countries. The study investigated albiglutide, 30 to 50 mg once weekly, compared with placebo. It included 9463 patients ages ≥ 40 years with T2D who had an HbA_1c > 7% (median value, 8.7%) and established CV disease. Patients were evaluated for a median 1.6 years.

Albiglutide reduced the risk of CV causes of death, nonfatal MI, and nonfatal stroke by an RRR of 22%, (ARR, 2%) (noninferiority, P < .0001; superiority, P < .0006).

Continue to: REWIND

REWIND. The Researching Cardiovascular Events with a Weekly INcretin in Diabetes trial (REWIND),²⁰ the most recently completed GLP-1 receptor agonist CVOT (presented at the 2019 American Diabetes Association [ADA] Conference in June and published simultaneously in The Lancet), was a multicenter, randomized, double-blind placebo-controlled trial designed to assess the effect of weekly dulaglutide, 1.5 mg, compared with placebo, in 9901 participants enrolled at 371 sites in 24 countries. Mean patient age was 66.2 years, with women constituting 4589 (46.3%) of participants.

REWIND was distinct from other CVOTs in several ways:

• Other CVOTs were designed to show noninferiority compared with placebo regarding CV events; REWIND was designed to establish superiority
• In contrast to trials of other GLP-1 receptor agonists, in which most patients had established CV disease, only 31% of REWIND participants had a history of CV disease or a prior CV event (although 69% did have CV risk factors without underlying disease)
• REWIND was much longer (median follow-up, 5.4 years) than other GLP-1 receptor agonist trials (median follow-up, 1.5 to 3.8 years).

In REWIND, the primary composite outcome of MACE-3 occurred in 12% of participants assigned to dulaglutide, compared with 13.1% assigned to placebo (P = .026). This equated to 2.4 events for every 100 person– years on dulaglutide, compared with 2.7 events for every 100 person–years on placebo. There was a consistent effect on all MACE-3 components, although the greatest reductions were observed in nonfatal stroke (P = .017). Overall risk reduction was the same for primary and secondary prevention cohorts (P = .97), as well as in patients with either an HbA_1c value < 7.2% or ≥ 7.2% (P = .75). Risk reduction was consistent across age, sex, duration of T2D, and body mass index.

Dulaglutide did not significantly affect the incidence of all-cause mortality, heart failure, revascularization, or hospital admission. Forty-seven percent of patients taking dulaglutide reported gastrointestinal adverse effects (P = .0001).

Cases of bullous pemphigoid have been reported after initiation of DPP-4 inhibitor therapy.

In a separate analysis of secondary outcomes, ²¹ dulaglutide reduced the composite renal outcomes of new-onset macroalbuminuria (P = .0001); decline of ≥ 30% in the estimated glomerular filtration rate (P = .066); and chronic renal replacement therapy (P = .39). Investigators estimated that 1 composite renal outcome event would be prevented for every 31 patients treated with dulaglutide for a median 5.4 years.

Continue to: Cardiovascular outcomes trials...

Cardiovascular outcomes trials: SGLT-2 inhibitors

EMPA-REG OUTCOME. The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) was also a landmark study because it was the first dedicated CVOT to show that an antihyperglycemic agent 1) decreased CV mortality and all-cause mortality, and 2) reduced HHF in patients with T2D and established CV disease.22 In this trial, 7020 patients with T2D who were at high risk of CV events were randomized and treated with empagliflozin, 10 or 25 mg, or placebo, in addition to standard care, and were followed for a median 2.6 years.

In October, the FDA approved dapaglifozin to reduce the risk of hospitalization for heart failure in adults with T2D and established CV disease.

Compared with placebo, empagliflozin resulted in an RRR of 14% (ARR, 1.6%) in the primary endpoint of CV death, nonfatal MI, and stroke, confirming study drug superiority (P = .04). When compared with placebo, the empagliflozin group had an RRR of 38% in CV mortality, (ARR < 2.2%) (P < .001); an RRR of 35% in HHF (ARR, 1.4%) (P = .002); and an RRR of 32% (ARR, 2.6%) in death from any cause (P < .001).

CANVAS. The Canagliflozin Cardiovascular Assessment Study (CANVAS) integrated 2 multicenter, placebo-controlled, randomized trials with 10,142 participants and a mean follow-up of 3.6 years.²³ Patients were randomized to receive canagliflozin (100-300 mg/d) or placebo. Approximately two-thirds of patients had a history of CV disease (therefore representing secondary prevention); one-third had CV risk factors only (primary prevention).

In CANVAS, patients receiving canagliflozin had a risk reduction in MACE-3, establishing superiority compared with placebo (P < .001). There was also a significant reduction in progression of albuminuria (P < .05). Superiority was not shown for the secondary outcome of death from any cause. Canagliflozin had no effect on the primary endpoint (MACE-3) in the subgroup of participants who did not have a history of CV disease. Similar to what was found with empagliflozin in EMPA-REG OUTCOME, CANVAS participants had a reduced risk of HHF.

Continue to: Patients on canagliflozin...

Patients on canagliflozin unexpectedly had an increased incidence of amputations (6.3 participants, compared with 3.4 participants, for every 1000 patient–years). This finding led to a black box warning for canagliflozin about the risk of lower-limb amputation.

DECLARE-TIMI 58. The Dapagliflozin Effect of Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 trial (DECLARETIMI 58) was the largest SGLT-2 inhibitor outcomes trial to date, enrolling 17,160 patients with T2D who also had established CV disease or multiple risk factors for atherosclerotic CV disease. The trial compared dapagliflozin, 10 mg/d, and placebo, following patients for a median 4.2 years.²⁴ Unlike CANVAS and EMPA-REG OUTCOME, DECLARE-TIMI 58 included CV death and HHF as primary outcomes, in addition to MACE-3.

Dapagliflozin was noninferior to placebo with regard to MACE-3. However, its use did result in a lower rate of CV death and HHF by an RRR of 17% (ARR, 1.9%). Risk reduction was greatest in patients with HF who had a reduced ejection fraction (ARR = 9.2%).²⁵

In October, the FDA approved dapagliflozin to reduce the risk of HHF in adults with T2D and established CV disease or multiple CV risk factors. Before initiating the drug, physicians should evaluate the patient's renal function and monitor periodically.

Meta-analyses of SGLT-2 inhibitors

Systematic review. Usman et al released a meta-analysis in 2018 that included 35 randomized, placebo-controlled trials (including EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58) that had assessed the use of SGLT-2 inhibitors in nearly 35,000 patients with T2D.²⁶ This review concluded that, as a class, SGLT-2 inhibitors reduce all-cause mortality, major adverse cardiac events, nonfatal MI, and HF and HHF, compared with placebo.

Continue to: CVD-REAL

CVD-REAL. A separate study, Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL), of 154,528 patients who were treated with canagliflozin, dapagliflozin, or empagliflozin, showed that initiation of SGLT-2 inhibitors, compared with other glucose- lowering therapies, was associated with a 39% reduction in HHF; a 51% reduction in death from any cause; and a 46% reduction in the composite of HHF or death (P < .001).²⁷

CVD-REAL was unique because it was the largest real-world study to assess the effectiveness of SGLT-2 inhibitors on HHF and mortality. The study utilized data from patients in the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom, based on information obtained from medical claims, primary care and hospital records, and national registries that compared patients who were either newly started on an SGLT-2 inhibitor or another glucose-lowering drug. The drug used by most patients in the trial was canagliflozin (53%), followed by dapagliflozin (42%), and empagliflozin (5%).

In this meta-analysis, similar therapeutic effects were seen across countries, regardless of geographic differences, in the use of specific SGLT-2 inhibitors, suggesting a class effect. Of particular significance was that most (87%) patients enrolled in CVD-REAL did not have prior CV disease. Despite this, results for examined outcomes in CVD-REAL were similar to what was seen in other SGLT-2 inhibitor trials that were designed to study patients with established CV disease.

Risk of adverse effects of newer antidiabetic agents

DPP-4 inhibitors. Alogliptin and sitagliptin carry a black-box warning about potential risk of HF. In SAVOR-TIMI, a 27% increase was detected in the rate of HHF after approximately 2 years of saxagliptin therapy.⁶ Although HF should not be considered a class effect for DPP-4 inhibitors, patients who have risk factors for HF should be monitored for signs and symptoms of HF.

Continue to: Cases of acute pancreatitis...

Cases of acute pancreatitis have been reported in association with all DPP-4 inhibitors available in the United States. A combined analysis of DDP-4 inhibitor trials suggested an increased relative risk of 79% and an absolute risk of 0.13%, which translates to 1 or 2 additional cases of acute pancreatitis for every 1000 patients treated for 2 years.²⁸

There have been numerous postmarketing reports of severe joint pain in patients taking a DPP-4 inhibitor. Most recently, cases of bullous pemphigoid have been reported after initiation of DPP-4 inhibitor therapy.²⁹

GLP-1 receptor agonists carry a black box warning for medullary thyroid (C-cell) tumor risk. GLP-1 receptor agonists are contraindicated in patients with a personal or family history of this cancer, although this FDA warning is based solely on observations from animal models.

In addition, GLP-1 receptor agonists can increase the risk of cholecystitis and pancreatitis. Not uncommonly, they cause gastrointestinal symptoms when first started and when the dosage is titrated upward. Most GLP-1 receptor agonists can be used in patients with renal impairment, although data regarding their use in Stages 4 and 5 chronic kidney disease are limited.³⁰ Semaglutide was found, in the SUSTAIN-6 trial, to be associated with an increased rate of complications of retinopathy, including vitreous hemorrhage and blindness (P = .02)³¹

SGLT-2 inhibitors are associated with an increased incidence of genitourinary infection, bone fracture (canagliflozin), amputation (canagliflozin), and euglycemic diabetic ketoacidosis. Agents in this class should be avoided in patients with moderate or severe renal impairment, primarily due to a lack of efficacy. They are contraindicated in patients with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2. (Dapagliflozin is not recommended when eGFR is < 45 mL/min/ 1.73 m2.) These agents carry an FDA warning about the risk of acute kidney injury.³⁰

Continue to: Summing up

Summing up

All glucose-lowering medications used to treat T2D are not equally effective in reducing CV complications. Recent CVOTs have uncovered evidence that certain antidiabetic agents might confer CV and all-cause mortality benefits (TABLE 2^{6,7,9,11,14-17,19-24}).

Discussion of proposed mechanisms for CV outcome superiority of these agents is beyond the scope of this review. It is generally believed that benefits result from mechanisms other than a reduction in the serum glucose level, given the relatively short time frame of the studies and the magnitude of the CV benefit. It is almost certain that mechanisms of CV benefit in the 2 landmark studies—LEADER and EMPA-REG OUTCOME—are distinct from each other.³²

See “When planning T2D pharmacotherapy, include newer agents that offer CV benefit,” ^33-38 for a stepwise approach to treating T2D, including the role of agents that have efficacy in modifying the risk of CV disease.

ACKNOWLEDGMENTS
Linda Speer, MD, Kevin Phelps, DO, and Jay Shubrook, DO, provided support and editorial assistance.

CORRESPONDENCE
Robert Gotfried, DO, FAAFP, Department of Family Medicine, University of Toledo College of Medicine, 3333 Glendale Avenue, Toledo, OH 43614; [email protected].

The association between type 2 diabetes (T2D) and cardiovascular (CV) disease is well-established:

• Type 2 diabetes approximately doubles the risk of coronary artery disease, stroke, and peripheral arterial disease, independent of conventional risk factors¹
• CV disease is the leading cause of morbidity and mortality in patients with T2D
• CV disease is the largest contributor to direct and indirect costs of the health care of patients who have T2D.²

In recent years, new classes of agents for treating T2D have been introduced (TABLE 1). Prior to 2008, the US Food and Drug Administration (FDA) approved drugs in those new classes based simply on their effectiveness in reducing the blood glucose level. Concerns about the CV safety of specific drugs (eg, rosiglitazone, muraglitazar) emerged from a number of trials, suggesting that these agents might increase the risk of CV events.^3,4

All glucose-lowering medications used to treat type 2 diabetes are not equally effective in reducing CV complications.

Consequently, in 2008, the FDA issued guidance to the pharmaceutical industry: Preapproval and postapproval trials of all new antidiabetic drugs must now assess potential excess CV risk.⁵ CV outcomes trials (CVOTs), performed in accordance with FDA guidelines, have therefore become the focus of evaluating novel treatment options. In most CVOTs, combined primary CV endpoints have included CV mortality, nonfatal myocardial infarction (MI), and nonfatal stroke—taken together, what is known as the composite of these 3 major adverse CV events, or MACE-3.

To date, 15 CVOTs have been completed, assessing 3 novel classes of antihyperglycemic agents:

• dipeptidyl peptidase-4 (DPP-4) inhibitors
• glucagon-like peptide-1 (GLP-1) receptor agonists
• sodium–glucose cotransporter-2 (SGLT-2) inhibitors.

None of these trials identified any increased incidence of MACE; 7 found CV benefit. This review summarizes what the CVOTs revealed about these antihyperglycemic agents and their ability to yield a reduction in MACE and a decrease in all-cause mortality in patients with T2D and elevated CV disease risk. Armed with this information, you will have the tools you need to offer patients with T2D CV benefit while managing their primary disease.

Cardiovascular outcomes trials: DPP-4 inhibitors

Four trials. Trials of DPP-4 inhibitors that have been completed and reported are of saxagliptin (SAVOR-TIMI 53⁶), alogliptin (EXAMINE⁷), sitagliptin (TECOS⁸), and linagliptin (CARMELINA⁹); others are in progress. In general, researchers enrolled patients at high risk of CV events, although inclusion criteria varied substantially. Consistently, these studies demonstrated that DPP-4 inhibition neither increased nor decreased (ie, were noninferior) the 3-point MACE (SAVOR-TIMI 53 noninferiority, P < .001; EXAMINE, P < .001; TECOS, P < .001).

Continue to: Rather than improve...

Rather than improve CV outcomes, there was some evidence that DPP-4 inhibitors might be associated with an increased risk of hospitalization for heart failure (HHF). In the SAVOR-TIMI 53 trial, patients randomized to saxagliptin had a 0.7% absolute increase in risk of HHF (P = .98).⁶ In the EXAMINE trial, patients treated with alogliptin showed a nonsignificant trend for HHF.¹⁰ In both the TECOS and CARMELINA trials, no difference was recorded in the rate of HHF.^8,9,11 Subsequent meta-analysis that summarized the risk of HHF in CVOTs with DPP-4 inhibitors indicated a nonsignificant trend to increased risk.¹²

It’s likely that the CV benefits result from mechanisms other than a reduction in the serum glucose level, given the short time frame of the studies and the magnitude of the CV benefit.

From these trials alone, it appears that DPP-4 inhibitors are unlikely to provide CV benefit. Data from additional trials are needed to evaluate the possible association between these medications and heart failure (HF). However, largely as a result of the findings from SAVOR-TIMI 53 and EXAMINE, the FDA issued a Drug Safety Communication in April 2016, adding warnings about HF to the labeling of saxagliptin and alogliptin.¹³

CARMELINA was designed to also evaluate kidney outcomes in patients with T2D. As with other DPP-4 inhibitor trials, the primary aim was to establish noninferiority, compared with placebo, for time to MACE-3 (P < .001). Secondary outcomes were defined as time to first occurrence of end-stage renal disease, death due to renal failure, and sustained decrease from baseline of ≥ 40% in the estimated glomerular filtration rate. The incidence of the secondary kidney composite results was not significantly different between groups randomized to linagliptin or placebo.⁹

Cardiovascular outcomes trials: GLP-1 receptor agonists

ELIXA. The CV safety of GLP-1 receptor agonists has been evaluated in several randomized clinical trials. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial was the first¹⁴: Lixisenatide was studied in 6068 patients with recent hospitalization for acute coronary syndrome. Lixisenatide therapy was neutral with regard to CV outcomes, which met the primary endpoint: noninferiority to placebo (P < .001). There was no increase in either HF or HHF.

Continue to: LEADER

LEADER. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results trial (LEADER) evaluated long-term effects of liraglutide, compared to placebo, on CV events in patients with T2D.¹⁵ It was a multicenter, double-blind, placebocontrolled study that followed 9340 participants, most (81%) of whom had established CV disease, over 5 years. LEADER is considered a landmark study because it was the first large CVOT to show significant benefit for a GLP-1 receptor agonist.

Liraglutide demonstrated reductions in first occurrence of death from CV causes, nonfatal MI or nonfatal stroke, overall CV mortality, and all-cause mortality. The composite MACE-3 showed a relative risk reduction (RRR) of 13%, equivalent to an absolute risk reduction (ARR) of 1.9% (noninferiority, P < .001; superiority, P < .01). The RRR was 22% for death from CV causes, with an ARR of 1.3% (P = .007); the RRR for death from any cause was 15%, with an ARR of 1.4% (P = .02).

In addition, there was a lower rate of nephropathy (1.5 events for every 100 patient–years in the liraglutide group [P = .003], compared with 1.9 events every 100 patient–years in the placebo group).¹⁵

Results clearly demonstrated benefit. No significant difference was seen in the liraglutide rate of HHF, compared to the rate in the placebo group.

SUSTAIN-6. Evidence for the CV benefit of GLP-1 receptor agonists was also demonstrated in the phase 3 Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6).¹⁶ This was a study of 3297 patients with T2D at high risk of CV disease and with a mean hemoglobin A_1c (HbA_1c) value of 8.7%, 83% of whom had established CV disease. Patients were randomized to semaglutide or placebo. Note: SUSTAIN-6 was a noninferiority safety study; as such, it was not actually designed to assess or establish superiority.

Continue to: The incidence of MACE-3...

The incidence of MACE-3 was significantly reduced among patients treated with semaglutide (P = .02) after median followup of 2.1 years. The expanded composite outcome (death from CV causes, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina or HF), also showed a significant reduction with semaglutide (P = .002), compared with placebo. There was no difference in the overall hospitalization rate or rate of death from any cause.

EXSCEL. The Exenatide Study of Cardiovascular Event Lowering trial (EXSCEL)^17,18 was a phase III/IV, double-blind, pragmatic placebo-controlled study of 14,752 patients at any level of CV risk, for a median 3.2 years. The study population was intentionally more diverse than in earlier GLP-1 receptor agonist studies. The researchers hypothesized that patients at increased risk of MACE would experience a comparatively greater relative treatment benefit with exenatide than those at lower risk. That did not prove to be the case.

EXSCEL did confirm noninferiority compared with placebo (P < .001), but once-weekly exenatide resulted in a nonsignificant reduction in major adverse CV events, and a trend for RRR in all-cause mortality (RRR = 14%; ARR = 1% [P = .06]).

HARMONY OUTCOMES. The Albiglutide and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Cardiovascular Disease study (HARMONY OUTCOMES)¹⁹ was a double-blind, randomized, placebocontrolled trial conducted at 610 sites across 28 countries. The study investigated albiglutide, 30 to 50 mg once weekly, compared with placebo. It included 9463 patients ages ≥ 40 years with T2D who had an HbA_1c > 7% (median value, 8.7%) and established CV disease. Patients were evaluated for a median 1.6 years.

Albiglutide reduced the risk of CV causes of death, nonfatal MI, and nonfatal stroke by an RRR of 22%, (ARR, 2%) (noninferiority, P < .0001; superiority, P < .0006).

Continue to: REWIND

REWIND. The Researching Cardiovascular Events with a Weekly INcretin in Diabetes trial (REWIND),²⁰ the most recently completed GLP-1 receptor agonist CVOT (presented at the 2019 American Diabetes Association [ADA] Conference in June and published simultaneously in The Lancet), was a multicenter, randomized, double-blind placebo-controlled trial designed to assess the effect of weekly dulaglutide, 1.5 mg, compared with placebo, in 9901 participants enrolled at 371 sites in 24 countries. Mean patient age was 66.2 years, with women constituting 4589 (46.3%) of participants.

REWIND was distinct from other CVOTs in several ways:

• Other CVOTs were designed to show noninferiority compared with placebo regarding CV events; REWIND was designed to establish superiority
• In contrast to trials of other GLP-1 receptor agonists, in which most patients had established CV disease, only 31% of REWIND participants had a history of CV disease or a prior CV event (although 69% did have CV risk factors without underlying disease)
• REWIND was much longer (median follow-up, 5.4 years) than other GLP-1 receptor agonist trials (median follow-up, 1.5 to 3.8 years).

In REWIND, the primary composite outcome of MACE-3 occurred in 12% of participants assigned to dulaglutide, compared with 13.1% assigned to placebo (P = .026). This equated to 2.4 events for every 100 person– years on dulaglutide, compared with 2.7 events for every 100 person–years on placebo. There was a consistent effect on all MACE-3 components, although the greatest reductions were observed in nonfatal stroke (P = .017). Overall risk reduction was the same for primary and secondary prevention cohorts (P = .97), as well as in patients with either an HbA_1c value < 7.2% or ≥ 7.2% (P = .75). Risk reduction was consistent across age, sex, duration of T2D, and body mass index.

Dulaglutide did not significantly affect the incidence of all-cause mortality, heart failure, revascularization, or hospital admission. Forty-seven percent of patients taking dulaglutide reported gastrointestinal adverse effects (P = .0001).

Cases of bullous pemphigoid have been reported after initiation of DPP-4 inhibitor therapy.

In a separate analysis of secondary outcomes, ²¹ dulaglutide reduced the composite renal outcomes of new-onset macroalbuminuria (P = .0001); decline of ≥ 30% in the estimated glomerular filtration rate (P = .066); and chronic renal replacement therapy (P = .39). Investigators estimated that 1 composite renal outcome event would be prevented for every 31 patients treated with dulaglutide for a median 5.4 years.

Continue to: Cardiovascular outcomes trials...

Cardiovascular outcomes trials: SGLT-2 inhibitors

EMPA-REG OUTCOME. The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) was also a landmark study because it was the first dedicated CVOT to show that an antihyperglycemic agent 1) decreased CV mortality and all-cause mortality, and 2) reduced HHF in patients with T2D and established CV disease.22 In this trial, 7020 patients with T2D who were at high risk of CV events were randomized and treated with empagliflozin, 10 or 25 mg, or placebo, in addition to standard care, and were followed for a median 2.6 years.

In October, the FDA approved dapaglifozin to reduce the risk of hospitalization for heart failure in adults with T2D and established CV disease.

Compared with placebo, empagliflozin resulted in an RRR of 14% (ARR, 1.6%) in the primary endpoint of CV death, nonfatal MI, and stroke, confirming study drug superiority (P = .04). When compared with placebo, the empagliflozin group had an RRR of 38% in CV mortality, (ARR < 2.2%) (P < .001); an RRR of 35% in HHF (ARR, 1.4%) (P = .002); and an RRR of 32% (ARR, 2.6%) in death from any cause (P < .001).

CANVAS. The Canagliflozin Cardiovascular Assessment Study (CANVAS) integrated 2 multicenter, placebo-controlled, randomized trials with 10,142 participants and a mean follow-up of 3.6 years.²³ Patients were randomized to receive canagliflozin (100-300 mg/d) or placebo. Approximately two-thirds of patients had a history of CV disease (therefore representing secondary prevention); one-third had CV risk factors only (primary prevention).

In CANVAS, patients receiving canagliflozin had a risk reduction in MACE-3, establishing superiority compared with placebo (P < .001). There was also a significant reduction in progression of albuminuria (P < .05). Superiority was not shown for the secondary outcome of death from any cause. Canagliflozin had no effect on the primary endpoint (MACE-3) in the subgroup of participants who did not have a history of CV disease. Similar to what was found with empagliflozin in EMPA-REG OUTCOME, CANVAS participants had a reduced risk of HHF.

Continue to: Patients on canagliflozin...

Patients on canagliflozin unexpectedly had an increased incidence of amputations (6.3 participants, compared with 3.4 participants, for every 1000 patient–years). This finding led to a black box warning for canagliflozin about the risk of lower-limb amputation.

DECLARE-TIMI 58. The Dapagliflozin Effect of Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 trial (DECLARETIMI 58) was the largest SGLT-2 inhibitor outcomes trial to date, enrolling 17,160 patients with T2D who also had established CV disease or multiple risk factors for atherosclerotic CV disease. The trial compared dapagliflozin, 10 mg/d, and placebo, following patients for a median 4.2 years.²⁴ Unlike CANVAS and EMPA-REG OUTCOME, DECLARE-TIMI 58 included CV death and HHF as primary outcomes, in addition to MACE-3.

Dapagliflozin was noninferior to placebo with regard to MACE-3. However, its use did result in a lower rate of CV death and HHF by an RRR of 17% (ARR, 1.9%). Risk reduction was greatest in patients with HF who had a reduced ejection fraction (ARR = 9.2%).²⁵

In October, the FDA approved dapagliflozin to reduce the risk of HHF in adults with T2D and established CV disease or multiple CV risk factors. Before initiating the drug, physicians should evaluate the patient's renal function and monitor periodically.

Meta-analyses of SGLT-2 inhibitors

Systematic review. Usman et al released a meta-analysis in 2018 that included 35 randomized, placebo-controlled trials (including EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58) that had assessed the use of SGLT-2 inhibitors in nearly 35,000 patients with T2D.²⁶ This review concluded that, as a class, SGLT-2 inhibitors reduce all-cause mortality, major adverse cardiac events, nonfatal MI, and HF and HHF, compared with placebo.

Continue to: CVD-REAL

CVD-REAL. A separate study, Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL), of 154,528 patients who were treated with canagliflozin, dapagliflozin, or empagliflozin, showed that initiation of SGLT-2 inhibitors, compared with other glucose- lowering therapies, was associated with a 39% reduction in HHF; a 51% reduction in death from any cause; and a 46% reduction in the composite of HHF or death (P < .001).²⁷

CVD-REAL was unique because it was the largest real-world study to assess the effectiveness of SGLT-2 inhibitors on HHF and mortality. The study utilized data from patients in the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom, based on information obtained from medical claims, primary care and hospital records, and national registries that compared patients who were either newly started on an SGLT-2 inhibitor or another glucose-lowering drug. The drug used by most patients in the trial was canagliflozin (53%), followed by dapagliflozin (42%), and empagliflozin (5%).

In this meta-analysis, similar therapeutic effects were seen across countries, regardless of geographic differences, in the use of specific SGLT-2 inhibitors, suggesting a class effect. Of particular significance was that most (87%) patients enrolled in CVD-REAL did not have prior CV disease. Despite this, results for examined outcomes in CVD-REAL were similar to what was seen in other SGLT-2 inhibitor trials that were designed to study patients with established CV disease.

Risk of adverse effects of newer antidiabetic agents

DPP-4 inhibitors. Alogliptin and sitagliptin carry a black-box warning about potential risk of HF. In SAVOR-TIMI, a 27% increase was detected in the rate of HHF after approximately 2 years of saxagliptin therapy.⁶ Although HF should not be considered a class effect for DPP-4 inhibitors, patients who have risk factors for HF should be monitored for signs and symptoms of HF.

Continue to: Cases of acute pancreatitis...

Cases of acute pancreatitis have been reported in association with all DPP-4 inhibitors available in the United States. A combined analysis of DDP-4 inhibitor trials suggested an increased relative risk of 79% and an absolute risk of 0.13%, which translates to 1 or 2 additional cases of acute pancreatitis for every 1000 patients treated for 2 years.²⁸

There have been numerous postmarketing reports of severe joint pain in patients taking a DPP-4 inhibitor. Most recently, cases of bullous pemphigoid have been reported after initiation of DPP-4 inhibitor therapy.²⁹

GLP-1 receptor agonists carry a black box warning for medullary thyroid (C-cell) tumor risk. GLP-1 receptor agonists are contraindicated in patients with a personal or family history of this cancer, although this FDA warning is based solely on observations from animal models.

In addition, GLP-1 receptor agonists can increase the risk of cholecystitis and pancreatitis. Not uncommonly, they cause gastrointestinal symptoms when first started and when the dosage is titrated upward. Most GLP-1 receptor agonists can be used in patients with renal impairment, although data regarding their use in Stages 4 and 5 chronic kidney disease are limited.³⁰ Semaglutide was found, in the SUSTAIN-6 trial, to be associated with an increased rate of complications of retinopathy, including vitreous hemorrhage and blindness (P = .02)³¹

SGLT-2 inhibitors are associated with an increased incidence of genitourinary infection, bone fracture (canagliflozin), amputation (canagliflozin), and euglycemic diabetic ketoacidosis. Agents in this class should be avoided in patients with moderate or severe renal impairment, primarily due to a lack of efficacy. They are contraindicated in patients with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2. (Dapagliflozin is not recommended when eGFR is < 45 mL/min/ 1.73 m2.) These agents carry an FDA warning about the risk of acute kidney injury.³⁰

Continue to: Summing up

Summing up

All glucose-lowering medications used to treat T2D are not equally effective in reducing CV complications. Recent CVOTs have uncovered evidence that certain antidiabetic agents might confer CV and all-cause mortality benefits (TABLE 2^{6,7,9,11,14-17,19-24}).

Discussion of proposed mechanisms for CV outcome superiority of these agents is beyond the scope of this review. It is generally believed that benefits result from mechanisms other than a reduction in the serum glucose level, given the relatively short time frame of the studies and the magnitude of the CV benefit. It is almost certain that mechanisms of CV benefit in the 2 landmark studies—LEADER and EMPA-REG OUTCOME—are distinct from each other.³²

See “When planning T2D pharmacotherapy, include newer agents that offer CV benefit,” ^33-38 for a stepwise approach to treating T2D, including the role of agents that have efficacy in modifying the risk of CV disease.

ACKNOWLEDGMENTS
Linda Speer, MD, Kevin Phelps, DO, and Jay Shubrook, DO, provided support and editorial assistance.

CORRESPONDENCE
Robert Gotfried, DO, FAAFP, Department of Family Medicine, University of Toledo College of Medicine, 3333 Glendale Avenue, Toledo, OH 43614; [email protected].

Cardiovascular disease (CVD) remains the leading cause of global mortality. In 2015, 41.5% of the US population had at least 1 form of CVD and CVD accounted for nearly 18 million deaths worldwide.1,2 The major disease categories represented include myocardial infarction (MI), sudden death, strokes, calcific aortic valve stenosis (CAVS), and peripheral vascular disease.^1,2 In terms of health care costs, quality of life, and caregiver burden, the overall impact of disease prevalence continues to rise.^1,3-6 There is an urgent need for more precise and earlier CVD risk assessment to guide lifestyle and therapeutic interventions for prevention of disease progression as well as potential reversal of preclinical disease. Even at a young age, visible coronary atherosclerosis has been found in up to 11% of “healthy” active individuals during autopsies for trauma fatalities.^7,8

The impact of CVD on the US and global populations is profound. In 2011, CVD prevalence was predicted to reach 40% by 2030.9 That estimate was exceeded in 2015, and it is now predicted that by 2035, 45% of the US population will suffer from some form of clinical or preclinical CVD. In 2015, the decadeslong decline in CVD mortality was reversed for the first time since 1969, showing a 1% increase in deaths from CVD.¹ Nearly 300,000 of those using US Department of Veterans Affairs (VA) services were hospitalized for CVD between 2010 and 2014.¹⁰ The annual direct and indirect costs related to CVD in the US are estimated at $329.7 billion, and these costs are predicted to top $1 trillion by 2035.¹ Heart attack, coronary atherosclerosis, and stroke accounted for 3 of the 10 most expensive conditions treated in US hospitals in 2013.¹¹ Globally, the estimate for CVD-related direct and indirect costs was $863 billion in 2010 and may exceed $1 trillion by 2030.¹²

The nature of military service adds additional risk factors, such as posttraumatic stress disorder, depression, sleep disorders and physical trauma which increase CVD morbidity/ mortality in service members, veterans, and their families.^13-16 In addition, living in lowerincome areas (countries or neighborhoods) can increase the risk of both CVD incidence and fatalities, particularly in younger individuals.^17-20 The Military Health System (MHS) and VA are responsible for the care of those individuals who have voluntarily taken on these additional risks through their time in service. This responsibility calls for rapid translation to practice tools and resources that can support interventions to minimize as many modifiable risk factors as possible and improve longterm health. This strategy aligns with the World Health Organization’s (WHO) focus on prevention of disease progression through interventions targeting modifiable risk.^3-6,21-23 The driving force behind the launch of the US Department of Health and Human Services (HHS) Million Hearts program was the goal of preventing 1 million heart attacks and strokes by 2017 with risk reduction through aspirin, blood pressure control, cholesterol management, smoking cessation, sodium reduction, and physical activity.^24,25 While some reductions in CVD events have been documented, the outcomes fell short of the goals set, highlighting both the need and value of continued and expanded efforts for CVD risk reduction.²⁶

More precise assessment of risk factors during preventative care, as well as after a diagnosis of CVD, may improve the timeliness and precision of earlier interventions (both lifestyle and therapeutic) that reduce CVD morbidity and mortality^.27 Personalized or precision medicine approaches take into account differences in socioeconomic, environmental, and lifestyle factors that are potentially reversible, as well as gender, race, and ethnicity.^28-31 Current methods of predicting CVD risk have considerable room for improvement.²⁷ About 40% of patients with newly diagnosed CVD have normal traditional cholesterol profiles, including those whose first cardiac event proves fatal.^29-33 Currently available risk scores (hundreds have been described in the literature) mischaracterize risk in minority populations and women, and have shown deficiencies in identifying preclinical atherosclerosis.^34,35 The failure to recognize preclinical CVD in military personnel during their active duty life cycle results in missed opportunities for improved health and readiness sustainment.

Most CVD risk prediction models incorporate some form of blood lipids. Total cholesterol (TC) is most commonly used in clinical practice, along with high-density lipoprotein (HDLC), low-density lipoprotein (LDLC), and triglycerides (TG).^23,27,36 High LDLC and/or TC are well established as lipid-related CVD risk factors and are incorporated into many CVD risk scoring systems/models described in the literature.²⁷ LDLC reduction is commonly recommended as CVD prevention, but even with optimal statin treatment, there is still considerable residual risk for new and recurrent CVD events.^{28,32,34,35,37-42}

Incorporating novel biomarkers and alternative lipid measurements may improve risk prediction and aid targeted treatment, ultimately reducing CVD events.²⁷ Apolipoprotein B (ApoB) is a major atherogenic component embedded in LDL and VLDL correlating to non-HDLC and may be useful in the setting of triglycerides ≥ 200 mg/d as levels > 130 mg/ dL appear to be risk-enhancing, but measurements may be unreliable.⁴³ According to the 2018 Cholesterol Guidelines, lipoprotein(a) [Lp(a)] elevation also is recognized as a risk-enhancing factor that is particularly implicated when there is a strong family history of premature atherosclerotic CVD or personal history of CVD not explained by major risk factors.⁴³

Lp(a) elevation is a largely underrecognized category of lipid disorder that impacts up to 20% to 30% of the population globally and within the US, although there is considerable variability by geographic location and ethnicity.⁴⁴ Globally, Lp(a) elevation places > 1 billion people at moderate to high risk for CVD.44 Lp(a) has a strong genetic component and is recognized as a distinct and independent risk factor for MI, sudden death, strokes and CAVS. Lp(a) has an extensive body of evidence to support its distinct role both as a causal factor in CVD and as an augmentation to traditional risk factors.^44-48

Lipoproteni(a) Elevation Use For Diagnosis

The importance of Lp(a) elevation as a clinical diagnosis rather than a laboratory abnormality alone was brought forward by the Lipoprotein(a) Foundation. Its founder, Sandra Tremulis, is a survivor of an acute coronary event that occurred when she was 39-years old, despite running marathons and having none of the traditional CVD lifestyle risk factors.⁴⁹ This experience inspired her to create the Lipoprotein(a) Foundation to give a voice to families living with or at risk for CVD due to Lp(a) elevation.

As often happens in the progress of medicine, patients and their families drive change based on their personal experiences with the gaps in standard clinical practice. It was this foundation—not a member of the medical establishment—that submitted the formal request for the addition of new ICD-10-CM diagnostic and family history codes for Lp(a) elevation during the Centers for Disease Control and Prevention (CDC) September 2017 ICD-10-CM Coordination and Maintenance Committee meeting.⁵⁰ In June 2018, the final ICD-10-CM code addenda for 2019 was released and included the new codes E78.⁴¹ (Elevated Lp[a]) and Z83.430 (Family history of elevated Lp[a]).⁵² After the new codes were approved, both the American Heart Association and the National Lipid Association added recommendations regarding Lp(a) testing to their clinical practice guidelines.^43,52

Practically, these codes standardize billing and payment for legitimate clinical work and laboratory testing. Prior to the addition of Lp(a) elevation as a clinical diagnosis, testing and treatment of Lp(a) elevation was considered experimental and not medically necessary until after a cardiovascular event had already occurred. Services for Lp(a) elevation were therefore not reimbursed by many healthcare organizations and insurance companies. The new ICD-10-CM codes encourage the assessment of Lp(a) both in individuals with early onset major CVD events and in presumably fit, healthy individuals, particularly when there is a family history of Lp(a) elevation. Given that Lp(a) levels do not change significantly over time, the current understanding is that only a single measurement is needed to define the individual risk over a lifetime.^41,42,44,45 As therapies targeting Lp(a) levels evolve, repeated measurements may be indicated to monitor response and direct changes in management. “Elevated Lipoprotein(a)” is the first laboratory testing abnormality that has achieved the status of a clinical diagnosis.

Lp(a) Measurements

There is considerable complexity to the measurement of lipoproteins in blood samples due to heterogeneity in both density and size of particles as illustrated in the Figure.⁵³

For traditional lipids measured in clinical practice, the size and density ranges from small high-density lipoprotein (HDL) through LDLC and intermediate- density lipoprotein (IDL) to the largest least dense particles in the very low-density lipoprotein (VLDL) and chylomicron remnant fractions. Standard lipid profiles consist of mass concentration measurements (mg/dL) of TC, TG, HDLC, and LDLC.⁵³ Non-HDLC (calculated as: TC−HDLC) consists of all cholesterol found in atherogenic lipoproteins, including remnant-C and Lp(a). Until recently, the cholesterol content of Lp(a), corresponding to about 30% of Lp(a) total mass, was included in the TC, non-HDLC and LDLC measurements with no separate reporting by the majority of clinical laboratories.

After > 50 years of research on the structure and biochemistry of Lp(a), the physiology and biological functions of these complex and polymorphic lipoprotein particles are not fully understood. Lp(a) is composed of a lipoprotein particle similar in composition to LDL (protein and lipid), containing 1 molecule of ApoB wrapped around a core of cholesteryl ester and triglyceride with phospholipids and unesterified cholesterol at its surface.⁴⁸ The presence of a unique hydrophilic, highly glycosylated protein referred to as apolopoprotienA (apo[a]), covalently attached to ApoB-100 by a single disulfide bridge, differentiates Lp(a) from LDL.⁴⁸ Cholesterol rich ApoB is an important component within many lipoproteins pathogenic for atherosclerosis and CVD.^45,47,53

The apo(a) contributes to the increased density of Lp(a) compared to LDLC with associated reduced binding affinity to the LDL receptor. This reduced receptor binding affinity is a presumed mechanism for the lack of Lp(a) plasma level response to statin therapies, which increase hepatic LDL receptor activity.⁴⁷ Apo(a) evolved from the plasminogen gene through duplication and remodeling and demonstrates extensive heterogeneity in protein size, with > 40 different apo(a) isoforms resulting in > 40 different Lp(a) particle sizes. Size of the apo(a) particle is determined by the number of pleated structures known as kringles. Most people (> 80%) carry 2 different-sized apo(a) isoforms. Plasma Lp(a) level is determined by the net production of apo(a) in each isoform, and the smaller apo(a) isoforms are associated with higher plasma levels of Lp(a).⁴⁵

Given the heterogeneity in Lp(a) molecular weight, which can vary even within individuals, recommendations have been made for reporting results as particle numbers or concentrations (nmol/L or mmol/L) rather than as mass concentration (mg/dL).⁵⁵ However, the majority of the large CVD morbidity and mortality outcomes studies used Lp(a) mass concentration levels in mg/ dL to characterize risk levels.^56,57 There is no standardized method to convert Lp(a) measurements from mg/dL to nmol/L.⁵⁵ Current assays using WHO standardized reagents and controls are reliable for categorizing risk levels.⁵⁸

The European Atherosclerosis Society consensus panel recommended that desirable Lp(a) levels should be below the 80th percentile (< 50 mg/dL or < 125 nmol/L) in patients with intermediate or high CVD risk.⁵⁹ Subsequent epidemiological and Mendelian randomization studies have been performed in general populations with no history of CVD and demonstrated that increased CVD risk can be detected with Lp(a) levels as low as 25 to 30 mg/dL.^56,60-63 In secondary prevention populations with prior CVD and optimal treatment (statins, antiplatelet drugs), recurrent event risk was also increased with elevated Lp(a).^63-66

Using immunoturbidometric assays, Varvel and colleagues reported the prevalence of elevated Lp(a) mass concentration levels (mg/dL) in > 500,000 US patients undergoing clinical evaluations based on data from a referral laboratory of patients.⁵⁸ The mean Lp(a) levels were 34.0 mg/dL with median (interquartile range [IQR]) levels at 17 (7-47) mg/dL and overall range of 0 to 907 mg/dL.⁵⁸ Females had higher Lp(a) levels compared to males but no ethnic or racial breakdown was provided. Lp(a) levels > 30 mg/dL and > 50 mg/dL were present in 35% and 24% of subjects, respectively. Table 1 displays the relationship between various Lp(a) level cut-offs to mean levels of LDLC, estimated LDLC corrected for Lp(a), TC, HDLC, and TG.⁵⁸ The data demonstrate that Lp(a) elevation cannot be inferred from LDLC levels nor from any of the other traditional lipoprotein measures. Patients with high risk Lp(a) levels may have normal LDLC. While Lp(a) thresholds have been identified for stratification of CVD risk, the target levels for risk reduction have not been specifically defined, particularly since therapies are not widely available for reduction of Lp(a). Table 2 provides an overview of clinical lipoprotein measurements that may be reasonable targets for therapeutic interventions and reduction of CVD risk.^44,53,55 In general, existing studies suggest that radical reduction (> 80%) is required to impact long-term outcomes, particularly in individuals with severe disease.^68,69

LDLC reduction alone leaves a residual CVD risk that is greater than the risk reduced.40 In addition, the autoimmune inflammation and lipid specific autoantibodies play an important role in increased CVD morbidity and mortality risk.^70,71 The presence of autoantibodies such as antiphospholipid antibodies (without a specific autoimmune disease diagnosis) increases the risk of subclinical atherosclerosis.^72,73 Certain autoimmune diseases such as systemic lupus erythematosus are recognized as independent risk factors for CVD.^74,75 Autoantibodies appear to mediate CVD events and mortality risk, independent of traditional therapies for risk reduction.⁷³ Further research is needed to clarify the role of autoantibodies as markers of increased or decreased CVD risk and their mechanism of action.

Autoantibodies directed at new antigens in lipoproteins within atherosclerotic lesions can modulate the impact of atherosclerosis via activation of the innate and adaptive immune system.⁷⁶ The lipid-associated neopeptides are recognized as damage-associated or danger- associated molecular patterns (DAMPs), also known as alarmins, which signal molecules that can trigger and perpetuate noninfectious inflammatory responses.^77-79 Plasma autoantibodies (immunoglobulin M and G [IgM, IgG]) modify proinflammatory oxidation-specific epitopes on oxidized phospholipids (oxPL) within lipoproteins and are linked with markers of inflammation and CVD events.^80-82 Modified LDLC and ApoB-100 immune complexes with specific autoantibodies in the IgG class are associated with increased CVD.⁷⁶ These and other risk-modulating autoantibodies may explain some of the variability in CVD outcomes by ethnicity and between individuals.

Some antibodies to oxidized LDL (ox-LDL) may have a protective role in the development of atherosclerosis.^83,84 In a cohort of > 500 women, the number of carotid atherosclerotic plaques and total carotid plaque area were inversely correlated with a specific IgM autoantibody (MDA-p210).⁸⁴ High concentrations of Lp(a)- containing circulating immune complexes and Lp(a)-specific IgM and IgG have been described in patients with coronary heart disease (CHD).⁸⁵ Like ox-LDL, oxidized Lp(a) [ox-Lp(a)] is more potent than native Lp(a) in increasing atherosclerosis risk and is increased in patients with CHD compared to healthy controls.^86-88 Ox-Lp(a) levels may represent an even stronger risk marker for CVD than ox-LDL.⁸⁵

Possible Mechanisms of Pathogenesis

While the precise quantification of Lp(a) in human plasma (or serum) has been challenging, current clinical laboratories use standardized international reference reagents and controls in their assays. Most current Lp(a) assays are based on immunological methods (eg, immunonephelometry, immunoturbidimetry, or enzyme linked immunosorbent assay [ELISA]) using antibodies against apo(a).⁸⁹ Apo(a) contains 10 subtypes of kringle IV and 1 copy of kringle V. Some assays use antibodies against kringle-IV type 2; however, it has been recommended that newer methods should use antibodies against the specific bridging kringle-IV Type 9 domain, which has a more stable bond and is present as a single copy.^48,89 Other approaches to Lp(a) measurement include ultraperformance liquid chromatography/mass spectrometry that can determine both the concentration and particle size of apo(a).^48,90 For routine clinical care, currently available assays reporting in mg/dL can be considered fairly accurate for separating low-risk from moderate-to-high-risk patients.⁴⁵

The physiologic role of Lp(a) in humans remains to be fully defined and individuals with extremely low plasma Lp(a) levels present no disease or deficiency syndromes.⁹¹ Lp(a) accumulates in endothelial injuries and binds to components of the vessel wall and subendothelial matrix, presumably due to the strong lysine binding site in apo(a).⁴⁶ Mediated by apo(a), the binding stimulates chemotactic activation of monocytes/macrophages and thereby modulating angiogenesis and inflammation.⁸⁹ Lp(a) may contribute to CVD and CAVS via its LDL-like component, with proinflammatory effects of oxidized phospholipids (OxPL) on both ApoB and apo(a) and antifibrinolytic/prothrombotic effects of apo(a).⁹² In Vitro studies have demonstrated that apo(a) modifies cellular function of cultured vascular endothelial cells (promoting stress fiber formation, endothelial contraction and vascular permeability), smooth muscles, and monocytes/ macrophages (promoting differentiation of proinflammatory M1-1 type macrophages) via complex mechanisms of cell signaling and cytokine production.89 Lp(a) is the only monogenetic risk factor for aortic valve calcification and stenosis⁹³ and is strongly linked specifically with the single nucleotide polymorphism (SNP) rs10455872 in the gene LPA encoding for apo(a).⁹⁴

CVD Risk Predictive Value

There are a large number of studies demonstrating that Lp(a) elevations are an independent predictor of adverse cardiovascular outcomes including MI, sudden death, strokes, calcific aortic valve stenosis and peripheral vascular disease (Table 3). The Copenhagen City Heart Study and Copenhagen General Population Study are well known prospective population- based cohort studies that track outcomes through national patient registries.⁹⁵ These studies demonstrate increased risk for MI, CHD, CAVS, and heart failure when subjects with very high Lp(a) levels (50-115 mg/dL) are compared with subjects with very low Lp(a) levels (< 5 mg/dL).^96-100 Subjects with less extreme Lp(a) elevations (> 30 mg/dL) also show increased risk of CVD when they have comorbid LDLC elevations.¹⁰¹ However, the Copenhagen studies are composed exclusively of white subjects and the effects of Lp(a) are known to vary with race or ethnicity.

The Multi-Ethnic Study of Atherosclerosis (MESA) recruited an ethnically diverse sample of > 6,000 Americans, aged 45 to 84 years, without CVD, into an ongoing prospective cohort study. Research using subjects from this study has found consistently increased risk of CHD, heart failure, subclinical aortic valve calcification, and more severe CAVS in white subjects with elevated Lp(a).^60,102,103 Black subjects with elevated Lp(a) had increased risk of CHD and more severe CAVS and Hispanic subjects with Lp(a) elevation were at higher risk for CHD.^60,102 So far, no studies of MESA subjects have identified a relationship between Lp(a) elevation and CVD events for Asian-Americans subjects (predominantly of Chinese descent). There is a need for ongoing research to more precisely define relevant cut-off levels by race, ethnicity and sex.

The Atherosclerosis Risk in Communities (ARIC) Study was a prospective multiethnic cohort study including > 15,000 US adults, aged 45 to 64 years.¹⁰³ Lp(a) elevations in this cohort were associated with greater risks for first CVD events, heart failure, and recurrent CVD events.^61,64,105 The risk of stroke for subjects with elevated Lp(a) was greater for black and white women, and for black men.^61,106 However, a meta-analysis of case-control studies showed increased ischemic stroke risk in both men and women with elevated Lp(a).⁵⁷

A recent European meta-analysis collected blood samples and outcome data from > 50,000 subjects in 7 prospective cohort studies. Using a central laboratory to standardize Lp(a) measurements, researchers found increased risk of major coronary events and new CVD in subjects with Lp(a) > 50 mg/dL compared to those below that threshold.¹⁰⁷

Although many of these studies show modest increases in risk of CVD events with Lp(a) elevation, it should be noted that other studies do not demonstrate such consistent associations. This is particularly true in studies of women and nonwhite ethnic groups.^103,108-112 The variability of study results may be due to other confounding factors such as autoantibodies that either upregulate or downregulate atherogenicity of LDLC and potentially other lipoproteins. This is particularly relevant to women who have an increased risk for autoimmune disease.

Lp(a) has significant genetic heritability—75% in Europeans and 85% in African Americans.¹¹³ In whites, the LPA gene on chromosome 6p26- 27 with the polymorphism genetic variants rs10455872 and rs3798220 is consistently associated with elevated Lp(a) levels.^63,100,113 However, the degree of Lp(a) elevation associated with these specific genetic variants varies by ethnicity.^78,113,115

Lifestyle and Cardiovascular Health

It is noteworthy that the Lp(a) genetic risks can also be modified by lifestyle risk reduction even in the absence of significant blood level reductions. For example, Khera and colleagues constructed a genetic risk profile for CVD that included genes related to Lp(a).¹¹⁶ Subjects with high genetic risk were more likely to experience CVD events compared with subjects with low genetic risk. However, risks for CVD were attenuated by 4 healthy lifestyle factors: current nonsmoker, body mass index < 30, at least weekly physical activity, and a healthy diet. Subjects with high genetic risk and an unhealthy lifestyle (0 or 1 of the 4 healthy lifestyle factors) were the most likely to develop CVD (Hazard ratio [HR], 3.5), but that risk was lower for subjects with healthy (3 or 4 of the 4 healthy lifestyle factors) and intermediate lifestyles (2 of the 4 healthy lifestyle factors) (HR, 1.9 and 2.2, respectively), despite despite high genetic risk for CVD.

While the independent CVD risk associated with elevated Lp(a) does not appear to be responsive to lifestyle risk reduction alone, certainly elevated LDLC and traditional risk factors can increase the overall CVD risk and are worthy of preventive interventions. In particular, inflammation from any source exacerbates CVD risk. Proatherogenic diet, insufficient sleep, lack of exercise, and maladaptive stress responses are other targets for personalized CVD risk reduction. ^28,117 Studies of dietary modifications and other lifestyle factors have shown reduced risk of CVD events, despite lack of reduction in Lp(a) levels.^119,120 It is noteworthy that statin therapy (with or without ezetimibe) fails to impact CAVS progression, likely because statins either raise or have no effect on Lp(a) levels.^92,119

Until recently, there has been no evidence supporting any therapeutic intervention causing clinically meaningful reductions in Lp(a). Table 4 lists major drug classes and their effects on Lp(a) and CVD outcomes; however, a detailed discussion of each of these therapies is beyond the scope of this review. Drugs that reduce Lp(a) by 20-30% have varying effects on CVD outcomes, from no effect^122,123 to a 10% to 20% decrease in CVD events when compared with a placebo.^124,125 Because these drugs also produce substantial reductions in LDLC, it is not possible to determine how much of the beneficial effects are due to reductions in Lp(a).

Lipoprotein apheresis produces profound reductions in Lp(a) of 60 to 80% in very highrisk populations.^69,126 Within-subjects comparisons show up to 80% reductions in CVD events, relative to event rates prior to treatment initiation.^69,127 Early trials of antisense oligonucleotide against apo(a) therapies show potential to produce similar outcomes.^128,129 These treatments may be particularly effective in patients with isolated Lp(a) elevations.

Summary

Lp(a) elevation is a major contributor to cardiovascular disease risk and has been recognized as an ICD-10-CM coded clinical diagnosis, the first laboratory abnormality to be defined a clinical disease in the asymptomatic healthy young individuals. This change addresses currently under- diagnosed CVD risk independent of LDLC reduction strategies. A brief overview of recent guidelines for the clinical use of Lp(a) testing from the American Heart Association^43,151 and the National Lipid Association52 can be found in Table 5. Although drug therapies for lowering Lp(a) levels remain limited, new treatment options are actively being developed.

Many Americans with high Lp(a) have not yet been identified. Expanded one-time screening can inform these patients of their cardiovascular risk and increase their access to early, aggressive lifestyle modification and optimal lipid-lowering therapy. Given the further increased CVD risk factors for military service members and veterans, a case can be made for broader screening and enhanced surveillance of elevated Lp(a) in these presumably healthy and fit individuals as well as management focused on modifiable risk factors.

Acknowledgements

This program initiative was conducted by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. as part of the Integrative Cardiac Health Project at Walter Reed National Military Medical Center (WRNMMC), and is made possible by a cooperative agreement that was awarded and administered by the US Army Medical Research & Materiel Command (USAMRMC), at Fort Detrick under Contract Number: W81XWH-16-2-0007. It reflects literature review preparatory work for a research protocol but does not involve an actual research project. The work in this manuscript was supported by the staff of the Integrative Cardiac Health Project (ICHP) with special thanks to Claire Fuller, Elaine Walizer, Dr. Mariam Kashani and the entire health coaching team.

Cardiovascular disease (CVD) remains the leading cause of global mortality. In 2015, 41.5% of the US population had at least 1 form of CVD and CVD accounted for nearly 18 million deaths worldwide.1,2 The major disease categories represented include myocardial infarction (MI), sudden death, strokes, calcific aortic valve stenosis (CAVS), and peripheral vascular disease.^1,2 In terms of health care costs, quality of life, and caregiver burden, the overall impact of disease prevalence continues to rise.^1,3-6 There is an urgent need for more precise and earlier CVD risk assessment to guide lifestyle and therapeutic interventions for prevention of disease progression as well as potential reversal of preclinical disease. Even at a young age, visible coronary atherosclerosis has been found in up to 11% of “healthy” active individuals during autopsies for trauma fatalities.^7,8

The impact of CVD on the US and global populations is profound. In 2011, CVD prevalence was predicted to reach 40% by 2030.9 That estimate was exceeded in 2015, and it is now predicted that by 2035, 45% of the US population will suffer from some form of clinical or preclinical CVD. In 2015, the decadeslong decline in CVD mortality was reversed for the first time since 1969, showing a 1% increase in deaths from CVD.¹ Nearly 300,000 of those using US Department of Veterans Affairs (VA) services were hospitalized for CVD between 2010 and 2014.¹⁰ The annual direct and indirect costs related to CVD in the US are estimated at $329.7 billion, and these costs are predicted to top $1 trillion by 2035.¹ Heart attack, coronary atherosclerosis, and stroke accounted for 3 of the 10 most expensive conditions treated in US hospitals in 2013.¹¹ Globally, the estimate for CVD-related direct and indirect costs was $863 billion in 2010 and may exceed $1 trillion by 2030.¹²

The nature of military service adds additional risk factors, such as posttraumatic stress disorder, depression, sleep disorders and physical trauma which increase CVD morbidity/ mortality in service members, veterans, and their families.^13-16 In addition, living in lowerincome areas (countries or neighborhoods) can increase the risk of both CVD incidence and fatalities, particularly in younger individuals.^17-20 The Military Health System (MHS) and VA are responsible for the care of those individuals who have voluntarily taken on these additional risks through their time in service. This responsibility calls for rapid translation to practice tools and resources that can support interventions to minimize as many modifiable risk factors as possible and improve longterm health. This strategy aligns with the World Health Organization’s (WHO) focus on prevention of disease progression through interventions targeting modifiable risk.^3-6,21-23 The driving force behind the launch of the US Department of Health and Human Services (HHS) Million Hearts program was the goal of preventing 1 million heart attacks and strokes by 2017 with risk reduction through aspirin, blood pressure control, cholesterol management, smoking cessation, sodium reduction, and physical activity.^24,25 While some reductions in CVD events have been documented, the outcomes fell short of the goals set, highlighting both the need and value of continued and expanded efforts for CVD risk reduction.²⁶

More precise assessment of risk factors during preventative care, as well as after a diagnosis of CVD, may improve the timeliness and precision of earlier interventions (both lifestyle and therapeutic) that reduce CVD morbidity and mortality^.27 Personalized or precision medicine approaches take into account differences in socioeconomic, environmental, and lifestyle factors that are potentially reversible, as well as gender, race, and ethnicity.^28-31 Current methods of predicting CVD risk have considerable room for improvement.²⁷ About 40% of patients with newly diagnosed CVD have normal traditional cholesterol profiles, including those whose first cardiac event proves fatal.^29-33 Currently available risk scores (hundreds have been described in the literature) mischaracterize risk in minority populations and women, and have shown deficiencies in identifying preclinical atherosclerosis.^34,35 The failure to recognize preclinical CVD in military personnel during their active duty life cycle results in missed opportunities for improved health and readiness sustainment.

Most CVD risk prediction models incorporate some form of blood lipids. Total cholesterol (TC) is most commonly used in clinical practice, along with high-density lipoprotein (HDLC), low-density lipoprotein (LDLC), and triglycerides (TG).^23,27,36 High LDLC and/or TC are well established as lipid-related CVD risk factors and are incorporated into many CVD risk scoring systems/models described in the literature.²⁷ LDLC reduction is commonly recommended as CVD prevention, but even with optimal statin treatment, there is still considerable residual risk for new and recurrent CVD events.^{28,32,34,35,37-42}

Incorporating novel biomarkers and alternative lipid measurements may improve risk prediction and aid targeted treatment, ultimately reducing CVD events.²⁷ Apolipoprotein B (ApoB) is a major atherogenic component embedded in LDL and VLDL correlating to non-HDLC and may be useful in the setting of triglycerides ≥ 200 mg/d as levels > 130 mg/ dL appear to be risk-enhancing, but measurements may be unreliable.⁴³ According to the 2018 Cholesterol Guidelines, lipoprotein(a) [Lp(a)] elevation also is recognized as a risk-enhancing factor that is particularly implicated when there is a strong family history of premature atherosclerotic CVD or personal history of CVD not explained by major risk factors.⁴³

Lp(a) elevation is a largely underrecognized category of lipid disorder that impacts up to 20% to 30% of the population globally and within the US, although there is considerable variability by geographic location and ethnicity.⁴⁴ Globally, Lp(a) elevation places > 1 billion people at moderate to high risk for CVD.44 Lp(a) has a strong genetic component and is recognized as a distinct and independent risk factor for MI, sudden death, strokes and CAVS. Lp(a) has an extensive body of evidence to support its distinct role both as a causal factor in CVD and as an augmentation to traditional risk factors.^44-48

Lipoproteni(a) Elevation Use For Diagnosis

The importance of Lp(a) elevation as a clinical diagnosis rather than a laboratory abnormality alone was brought forward by the Lipoprotein(a) Foundation. Its founder, Sandra Tremulis, is a survivor of an acute coronary event that occurred when she was 39-years old, despite running marathons and having none of the traditional CVD lifestyle risk factors.⁴⁹ This experience inspired her to create the Lipoprotein(a) Foundation to give a voice to families living with or at risk for CVD due to Lp(a) elevation.

As often happens in the progress of medicine, patients and their families drive change based on their personal experiences with the gaps in standard clinical practice. It was this foundation—not a member of the medical establishment—that submitted the formal request for the addition of new ICD-10-CM diagnostic and family history codes for Lp(a) elevation during the Centers for Disease Control and Prevention (CDC) September 2017 ICD-10-CM Coordination and Maintenance Committee meeting.⁵⁰ In June 2018, the final ICD-10-CM code addenda for 2019 was released and included the new codes E78.⁴¹ (Elevated Lp[a]) and Z83.430 (Family history of elevated Lp[a]).⁵² After the new codes were approved, both the American Heart Association and the National Lipid Association added recommendations regarding Lp(a) testing to their clinical practice guidelines.^43,52

Practically, these codes standardize billing and payment for legitimate clinical work and laboratory testing. Prior to the addition of Lp(a) elevation as a clinical diagnosis, testing and treatment of Lp(a) elevation was considered experimental and not medically necessary until after a cardiovascular event had already occurred. Services for Lp(a) elevation were therefore not reimbursed by many healthcare organizations and insurance companies. The new ICD-10-CM codes encourage the assessment of Lp(a) both in individuals with early onset major CVD events and in presumably fit, healthy individuals, particularly when there is a family history of Lp(a) elevation. Given that Lp(a) levels do not change significantly over time, the current understanding is that only a single measurement is needed to define the individual risk over a lifetime.^41,42,44,45 As therapies targeting Lp(a) levels evolve, repeated measurements may be indicated to monitor response and direct changes in management. “Elevated Lipoprotein(a)” is the first laboratory testing abnormality that has achieved the status of a clinical diagnosis.

Lp(a) Measurements

There is considerable complexity to the measurement of lipoproteins in blood samples due to heterogeneity in both density and size of particles as illustrated in the Figure.⁵³

For traditional lipids measured in clinical practice, the size and density ranges from small high-density lipoprotein (HDL) through LDLC and intermediate- density lipoprotein (IDL) to the largest least dense particles in the very low-density lipoprotein (VLDL) and chylomicron remnant fractions. Standard lipid profiles consist of mass concentration measurements (mg/dL) of TC, TG, HDLC, and LDLC.⁵³ Non-HDLC (calculated as: TC−HDLC) consists of all cholesterol found in atherogenic lipoproteins, including remnant-C and Lp(a). Until recently, the cholesterol content of Lp(a), corresponding to about 30% of Lp(a) total mass, was included in the TC, non-HDLC and LDLC measurements with no separate reporting by the majority of clinical laboratories.

After > 50 years of research on the structure and biochemistry of Lp(a), the physiology and biological functions of these complex and polymorphic lipoprotein particles are not fully understood. Lp(a) is composed of a lipoprotein particle similar in composition to LDL (protein and lipid), containing 1 molecule of ApoB wrapped around a core of cholesteryl ester and triglyceride with phospholipids and unesterified cholesterol at its surface.⁴⁸ The presence of a unique hydrophilic, highly glycosylated protein referred to as apolopoprotienA (apo[a]), covalently attached to ApoB-100 by a single disulfide bridge, differentiates Lp(a) from LDL.⁴⁸ Cholesterol rich ApoB is an important component within many lipoproteins pathogenic for atherosclerosis and CVD.^45,47,53

The apo(a) contributes to the increased density of Lp(a) compared to LDLC with associated reduced binding affinity to the LDL receptor. This reduced receptor binding affinity is a presumed mechanism for the lack of Lp(a) plasma level response to statin therapies, which increase hepatic LDL receptor activity.⁴⁷ Apo(a) evolved from the plasminogen gene through duplication and remodeling and demonstrates extensive heterogeneity in protein size, with > 40 different apo(a) isoforms resulting in > 40 different Lp(a) particle sizes. Size of the apo(a) particle is determined by the number of pleated structures known as kringles. Most people (> 80%) carry 2 different-sized apo(a) isoforms. Plasma Lp(a) level is determined by the net production of apo(a) in each isoform, and the smaller apo(a) isoforms are associated with higher plasma levels of Lp(a).⁴⁵

Given the heterogeneity in Lp(a) molecular weight, which can vary even within individuals, recommendations have been made for reporting results as particle numbers or concentrations (nmol/L or mmol/L) rather than as mass concentration (mg/dL).⁵⁵ However, the majority of the large CVD morbidity and mortality outcomes studies used Lp(a) mass concentration levels in mg/ dL to characterize risk levels.^56,57 There is no standardized method to convert Lp(a) measurements from mg/dL to nmol/L.⁵⁵ Current assays using WHO standardized reagents and controls are reliable for categorizing risk levels.⁵⁸

The European Atherosclerosis Society consensus panel recommended that desirable Lp(a) levels should be below the 80th percentile (< 50 mg/dL or < 125 nmol/L) in patients with intermediate or high CVD risk.⁵⁹ Subsequent epidemiological and Mendelian randomization studies have been performed in general populations with no history of CVD and demonstrated that increased CVD risk can be detected with Lp(a) levels as low as 25 to 30 mg/dL.^56,60-63 In secondary prevention populations with prior CVD and optimal treatment (statins, antiplatelet drugs), recurrent event risk was also increased with elevated Lp(a).^63-66

Using immunoturbidometric assays, Varvel and colleagues reported the prevalence of elevated Lp(a) mass concentration levels (mg/dL) in > 500,000 US patients undergoing clinical evaluations based on data from a referral laboratory of patients.⁵⁸ The mean Lp(a) levels were 34.0 mg/dL with median (interquartile range [IQR]) levels at 17 (7-47) mg/dL and overall range of 0 to 907 mg/dL.⁵⁸ Females had higher Lp(a) levels compared to males but no ethnic or racial breakdown was provided. Lp(a) levels > 30 mg/dL and > 50 mg/dL were present in 35% and 24% of subjects, respectively. Table 1 displays the relationship between various Lp(a) level cut-offs to mean levels of LDLC, estimated LDLC corrected for Lp(a), TC, HDLC, and TG.⁵⁸ The data demonstrate that Lp(a) elevation cannot be inferred from LDLC levels nor from any of the other traditional lipoprotein measures. Patients with high risk Lp(a) levels may have normal LDLC. While Lp(a) thresholds have been identified for stratification of CVD risk, the target levels for risk reduction have not been specifically defined, particularly since therapies are not widely available for reduction of Lp(a). Table 2 provides an overview of clinical lipoprotein measurements that may be reasonable targets for therapeutic interventions and reduction of CVD risk.^44,53,55 In general, existing studies suggest that radical reduction (> 80%) is required to impact long-term outcomes, particularly in individuals with severe disease.^68,69

LDLC reduction alone leaves a residual CVD risk that is greater than the risk reduced.40 In addition, the autoimmune inflammation and lipid specific autoantibodies play an important role in increased CVD morbidity and mortality risk.^70,71 The presence of autoantibodies such as antiphospholipid antibodies (without a specific autoimmune disease diagnosis) increases the risk of subclinical atherosclerosis.^72,73 Certain autoimmune diseases such as systemic lupus erythematosus are recognized as independent risk factors for CVD.^74,75 Autoantibodies appear to mediate CVD events and mortality risk, independent of traditional therapies for risk reduction.⁷³ Further research is needed to clarify the role of autoantibodies as markers of increased or decreased CVD risk and their mechanism of action.

Autoantibodies directed at new antigens in lipoproteins within atherosclerotic lesions can modulate the impact of atherosclerosis via activation of the innate and adaptive immune system.⁷⁶ The lipid-associated neopeptides are recognized as damage-associated or danger- associated molecular patterns (DAMPs), also known as alarmins, which signal molecules that can trigger and perpetuate noninfectious inflammatory responses.^77-79 Plasma autoantibodies (immunoglobulin M and G [IgM, IgG]) modify proinflammatory oxidation-specific epitopes on oxidized phospholipids (oxPL) within lipoproteins and are linked with markers of inflammation and CVD events.^80-82 Modified LDLC and ApoB-100 immune complexes with specific autoantibodies in the IgG class are associated with increased CVD.⁷⁶ These and other risk-modulating autoantibodies may explain some of the variability in CVD outcomes by ethnicity and between individuals.

Some antibodies to oxidized LDL (ox-LDL) may have a protective role in the development of atherosclerosis.^83,84 In a cohort of > 500 women, the number of carotid atherosclerotic plaques and total carotid plaque area were inversely correlated with a specific IgM autoantibody (MDA-p210).⁸⁴ High concentrations of Lp(a)- containing circulating immune complexes and Lp(a)-specific IgM and IgG have been described in patients with coronary heart disease (CHD).⁸⁵ Like ox-LDL, oxidized Lp(a) [ox-Lp(a)] is more potent than native Lp(a) in increasing atherosclerosis risk and is increased in patients with CHD compared to healthy controls.^86-88 Ox-Lp(a) levels may represent an even stronger risk marker for CVD than ox-LDL.⁸⁵

Possible Mechanisms of Pathogenesis

While the precise quantification of Lp(a) in human plasma (or serum) has been challenging, current clinical laboratories use standardized international reference reagents and controls in their assays. Most current Lp(a) assays are based on immunological methods (eg, immunonephelometry, immunoturbidimetry, or enzyme linked immunosorbent assay [ELISA]) using antibodies against apo(a).⁸⁹ Apo(a) contains 10 subtypes of kringle IV and 1 copy of kringle V. Some assays use antibodies against kringle-IV type 2; however, it has been recommended that newer methods should use antibodies against the specific bridging kringle-IV Type 9 domain, which has a more stable bond and is present as a single copy.^48,89 Other approaches to Lp(a) measurement include ultraperformance liquid chromatography/mass spectrometry that can determine both the concentration and particle size of apo(a).^48,90 For routine clinical care, currently available assays reporting in mg/dL can be considered fairly accurate for separating low-risk from moderate-to-high-risk patients.⁴⁵

The physiologic role of Lp(a) in humans remains to be fully defined and individuals with extremely low plasma Lp(a) levels present no disease or deficiency syndromes.⁹¹ Lp(a) accumulates in endothelial injuries and binds to components of the vessel wall and subendothelial matrix, presumably due to the strong lysine binding site in apo(a).⁴⁶ Mediated by apo(a), the binding stimulates chemotactic activation of monocytes/macrophages and thereby modulating angiogenesis and inflammation.⁸⁹ Lp(a) may contribute to CVD and CAVS via its LDL-like component, with proinflammatory effects of oxidized phospholipids (OxPL) on both ApoB and apo(a) and antifibrinolytic/prothrombotic effects of apo(a).⁹² In Vitro studies have demonstrated that apo(a) modifies cellular function of cultured vascular endothelial cells (promoting stress fiber formation, endothelial contraction and vascular permeability), smooth muscles, and monocytes/ macrophages (promoting differentiation of proinflammatory M1-1 type macrophages) via complex mechanisms of cell signaling and cytokine production.89 Lp(a) is the only monogenetic risk factor for aortic valve calcification and stenosis⁹³ and is strongly linked specifically with the single nucleotide polymorphism (SNP) rs10455872 in the gene LPA encoding for apo(a).⁹⁴

CVD Risk Predictive Value

There are a large number of studies demonstrating that Lp(a) elevations are an independent predictor of adverse cardiovascular outcomes including MI, sudden death, strokes, calcific aortic valve stenosis and peripheral vascular disease (Table 3). The Copenhagen City Heart Study and Copenhagen General Population Study are well known prospective population- based cohort studies that track outcomes through national patient registries.⁹⁵ These studies demonstrate increased risk for MI, CHD, CAVS, and heart failure when subjects with very high Lp(a) levels (50-115 mg/dL) are compared with subjects with very low Lp(a) levels (< 5 mg/dL).^96-100 Subjects with less extreme Lp(a) elevations (> 30 mg/dL) also show increased risk of CVD when they have comorbid LDLC elevations.¹⁰¹ However, the Copenhagen studies are composed exclusively of white subjects and the effects of Lp(a) are known to vary with race or ethnicity.

The Multi-Ethnic Study of Atherosclerosis (MESA) recruited an ethnically diverse sample of > 6,000 Americans, aged 45 to 84 years, without CVD, into an ongoing prospective cohort study. Research using subjects from this study has found consistently increased risk of CHD, heart failure, subclinical aortic valve calcification, and more severe CAVS in white subjects with elevated Lp(a).^60,102,103 Black subjects with elevated Lp(a) had increased risk of CHD and more severe CAVS and Hispanic subjects with Lp(a) elevation were at higher risk for CHD.^60,102 So far, no studies of MESA subjects have identified a relationship between Lp(a) elevation and CVD events for Asian-Americans subjects (predominantly of Chinese descent). There is a need for ongoing research to more precisely define relevant cut-off levels by race, ethnicity and sex.

The Atherosclerosis Risk in Communities (ARIC) Study was a prospective multiethnic cohort study including > 15,000 US adults, aged 45 to 64 years.¹⁰³ Lp(a) elevations in this cohort were associated with greater risks for first CVD events, heart failure, and recurrent CVD events.^61,64,105 The risk of stroke for subjects with elevated Lp(a) was greater for black and white women, and for black men.^61,106 However, a meta-analysis of case-control studies showed increased ischemic stroke risk in both men and women with elevated Lp(a).⁵⁷

A recent European meta-analysis collected blood samples and outcome data from > 50,000 subjects in 7 prospective cohort studies. Using a central laboratory to standardize Lp(a) measurements, researchers found increased risk of major coronary events and new CVD in subjects with Lp(a) > 50 mg/dL compared to those below that threshold.¹⁰⁷

Although many of these studies show modest increases in risk of CVD events with Lp(a) elevation, it should be noted that other studies do not demonstrate such consistent associations. This is particularly true in studies of women and nonwhite ethnic groups.^103,108-112 The variability of study results may be due to other confounding factors such as autoantibodies that either upregulate or downregulate atherogenicity of LDLC and potentially other lipoproteins. This is particularly relevant to women who have an increased risk for autoimmune disease.

Lp(a) has significant genetic heritability—75% in Europeans and 85% in African Americans.¹¹³ In whites, the LPA gene on chromosome 6p26- 27 with the polymorphism genetic variants rs10455872 and rs3798220 is consistently associated with elevated Lp(a) levels.^63,100,113 However, the degree of Lp(a) elevation associated with these specific genetic variants varies by ethnicity.^78,113,115

Lifestyle and Cardiovascular Health

It is noteworthy that the Lp(a) genetic risks can also be modified by lifestyle risk reduction even in the absence of significant blood level reductions. For example, Khera and colleagues constructed a genetic risk profile for CVD that included genes related to Lp(a).¹¹⁶ Subjects with high genetic risk were more likely to experience CVD events compared with subjects with low genetic risk. However, risks for CVD were attenuated by 4 healthy lifestyle factors: current nonsmoker, body mass index < 30, at least weekly physical activity, and a healthy diet. Subjects with high genetic risk and an unhealthy lifestyle (0 or 1 of the 4 healthy lifestyle factors) were the most likely to develop CVD (Hazard ratio [HR], 3.5), but that risk was lower for subjects with healthy (3 or 4 of the 4 healthy lifestyle factors) and intermediate lifestyles (2 of the 4 healthy lifestyle factors) (HR, 1.9 and 2.2, respectively), despite despite high genetic risk for CVD.

While the independent CVD risk associated with elevated Lp(a) does not appear to be responsive to lifestyle risk reduction alone, certainly elevated LDLC and traditional risk factors can increase the overall CVD risk and are worthy of preventive interventions. In particular, inflammation from any source exacerbates CVD risk. Proatherogenic diet, insufficient sleep, lack of exercise, and maladaptive stress responses are other targets for personalized CVD risk reduction. ^28,117 Studies of dietary modifications and other lifestyle factors have shown reduced risk of CVD events, despite lack of reduction in Lp(a) levels.^119,120 It is noteworthy that statin therapy (with or without ezetimibe) fails to impact CAVS progression, likely because statins either raise or have no effect on Lp(a) levels.^92,119

Until recently, there has been no evidence supporting any therapeutic intervention causing clinically meaningful reductions in Lp(a). Table 4 lists major drug classes and their effects on Lp(a) and CVD outcomes; however, a detailed discussion of each of these therapies is beyond the scope of this review. Drugs that reduce Lp(a) by 20-30% have varying effects on CVD outcomes, from no effect^122,123 to a 10% to 20% decrease in CVD events when compared with a placebo.^124,125 Because these drugs also produce substantial reductions in LDLC, it is not possible to determine how much of the beneficial effects are due to reductions in Lp(a).

Lipoprotein apheresis produces profound reductions in Lp(a) of 60 to 80% in very highrisk populations.^69,126 Within-subjects comparisons show up to 80% reductions in CVD events, relative to event rates prior to treatment initiation.^69,127 Early trials of antisense oligonucleotide against apo(a) therapies show potential to produce similar outcomes.^128,129 These treatments may be particularly effective in patients with isolated Lp(a) elevations.

Summary

Lp(a) elevation is a major contributor to cardiovascular disease risk and has been recognized as an ICD-10-CM coded clinical diagnosis, the first laboratory abnormality to be defined a clinical disease in the asymptomatic healthy young individuals. This change addresses currently under- diagnosed CVD risk independent of LDLC reduction strategies. A brief overview of recent guidelines for the clinical use of Lp(a) testing from the American Heart Association^43,151 and the National Lipid Association52 can be found in Table 5. Although drug therapies for lowering Lp(a) levels remain limited, new treatment options are actively being developed.

Many Americans with high Lp(a) have not yet been identified. Expanded one-time screening can inform these patients of their cardiovascular risk and increase their access to early, aggressive lifestyle modification and optimal lipid-lowering therapy. Given the further increased CVD risk factors for military service members and veterans, a case can be made for broader screening and enhanced surveillance of elevated Lp(a) in these presumably healthy and fit individuals as well as management focused on modifiable risk factors.

Acknowledgements

This program initiative was conducted by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. as part of the Integrative Cardiac Health Project at Walter Reed National Military Medical Center (WRNMMC), and is made possible by a cooperative agreement that was awarded and administered by the US Army Medical Research & Materiel Command (USAMRMC), at Fort Detrick under Contract Number: W81XWH-16-2-0007. It reflects literature review preparatory work for a research protocol but does not involve an actual research project. The work in this manuscript was supported by the staff of the Integrative Cardiac Health Project (ICHP) with special thanks to Claire Fuller, Elaine Walizer, Dr. Mariam Kashani and the entire health coaching team.

Cardiovascular disease (CVD) remains the leading cause of global mortality. In 2015, 41.5% of the US population had at least 1 form of CVD and CVD accounted for nearly 18 million deaths worldwide.1,2 The major disease categories represented include myocardial infarction (MI), sudden death, strokes, calcific aortic valve stenosis (CAVS), and peripheral vascular disease.^1,2 In terms of health care costs, quality of life, and caregiver burden, the overall impact of disease prevalence continues to rise.^1,3-6 There is an urgent need for more precise and earlier CVD risk assessment to guide lifestyle and therapeutic interventions for prevention of disease progression as well as potential reversal of preclinical disease. Even at a young age, visible coronary atherosclerosis has been found in up to 11% of “healthy” active individuals during autopsies for trauma fatalities.^7,8

The impact of CVD on the US and global populations is profound. In 2011, CVD prevalence was predicted to reach 40% by 2030.9 That estimate was exceeded in 2015, and it is now predicted that by 2035, 45% of the US population will suffer from some form of clinical or preclinical CVD. In 2015, the decadeslong decline in CVD mortality was reversed for the first time since 1969, showing a 1% increase in deaths from CVD.¹ Nearly 300,000 of those using US Department of Veterans Affairs (VA) services were hospitalized for CVD between 2010 and 2014.¹⁰ The annual direct and indirect costs related to CVD in the US are estimated at $329.7 billion, and these costs are predicted to top $1 trillion by 2035.¹ Heart attack, coronary atherosclerosis, and stroke accounted for 3 of the 10 most expensive conditions treated in US hospitals in 2013.¹¹ Globally, the estimate for CVD-related direct and indirect costs was $863 billion in 2010 and may exceed $1 trillion by 2030.¹²

The nature of military service adds additional risk factors, such as posttraumatic stress disorder, depression, sleep disorders and physical trauma which increase CVD morbidity/ mortality in service members, veterans, and their families.^13-16 In addition, living in lowerincome areas (countries or neighborhoods) can increase the risk of both CVD incidence and fatalities, particularly in younger individuals.^17-20 The Military Health System (MHS) and VA are responsible for the care of those individuals who have voluntarily taken on these additional risks through their time in service. This responsibility calls for rapid translation to practice tools and resources that can support interventions to minimize as many modifiable risk factors as possible and improve longterm health. This strategy aligns with the World Health Organization’s (WHO) focus on prevention of disease progression through interventions targeting modifiable risk.^3-6,21-23 The driving force behind the launch of the US Department of Health and Human Services (HHS) Million Hearts program was the goal of preventing 1 million heart attacks and strokes by 2017 with risk reduction through aspirin, blood pressure control, cholesterol management, smoking cessation, sodium reduction, and physical activity.^24,25 While some reductions in CVD events have been documented, the outcomes fell short of the goals set, highlighting both the need and value of continued and expanded efforts for CVD risk reduction.²⁶

More precise assessment of risk factors during preventative care, as well as after a diagnosis of CVD, may improve the timeliness and precision of earlier interventions (both lifestyle and therapeutic) that reduce CVD morbidity and mortality^.27 Personalized or precision medicine approaches take into account differences in socioeconomic, environmental, and lifestyle factors that are potentially reversible, as well as gender, race, and ethnicity.^28-31 Current methods of predicting CVD risk have considerable room for improvement.²⁷ About 40% of patients with newly diagnosed CVD have normal traditional cholesterol profiles, including those whose first cardiac event proves fatal.^29-33 Currently available risk scores (hundreds have been described in the literature) mischaracterize risk in minority populations and women, and have shown deficiencies in identifying preclinical atherosclerosis.^34,35 The failure to recognize preclinical CVD in military personnel during their active duty life cycle results in missed opportunities for improved health and readiness sustainment.

Most CVD risk prediction models incorporate some form of blood lipids. Total cholesterol (TC) is most commonly used in clinical practice, along with high-density lipoprotein (HDLC), low-density lipoprotein (LDLC), and triglycerides (TG).^23,27,36 High LDLC and/or TC are well established as lipid-related CVD risk factors and are incorporated into many CVD risk scoring systems/models described in the literature.²⁷ LDLC reduction is commonly recommended as CVD prevention, but even with optimal statin treatment, there is still considerable residual risk for new and recurrent CVD events.^{28,32,34,35,37-42}

Incorporating novel biomarkers and alternative lipid measurements may improve risk prediction and aid targeted treatment, ultimately reducing CVD events.²⁷ Apolipoprotein B (ApoB) is a major atherogenic component embedded in LDL and VLDL correlating to non-HDLC and may be useful in the setting of triglycerides ≥ 200 mg/d as levels > 130 mg/ dL appear to be risk-enhancing, but measurements may be unreliable.⁴³ According to the 2018 Cholesterol Guidelines, lipoprotein(a) [Lp(a)] elevation also is recognized as a risk-enhancing factor that is particularly implicated when there is a strong family history of premature atherosclerotic CVD or personal history of CVD not explained by major risk factors.⁴³

Lp(a) elevation is a largely underrecognized category of lipid disorder that impacts up to 20% to 30% of the population globally and within the US, although there is considerable variability by geographic location and ethnicity.⁴⁴ Globally, Lp(a) elevation places > 1 billion people at moderate to high risk for CVD.44 Lp(a) has a strong genetic component and is recognized as a distinct and independent risk factor for MI, sudden death, strokes and CAVS. Lp(a) has an extensive body of evidence to support its distinct role both as a causal factor in CVD and as an augmentation to traditional risk factors.^44-48

Lipoproteni(a) Elevation Use For Diagnosis

The importance of Lp(a) elevation as a clinical diagnosis rather than a laboratory abnormality alone was brought forward by the Lipoprotein(a) Foundation. Its founder, Sandra Tremulis, is a survivor of an acute coronary event that occurred when she was 39-years old, despite running marathons and having none of the traditional CVD lifestyle risk factors.⁴⁹ This experience inspired her to create the Lipoprotein(a) Foundation to give a voice to families living with or at risk for CVD due to Lp(a) elevation.

As often happens in the progress of medicine, patients and their families drive change based on their personal experiences with the gaps in standard clinical practice. It was this foundation—not a member of the medical establishment—that submitted the formal request for the addition of new ICD-10-CM diagnostic and family history codes for Lp(a) elevation during the Centers for Disease Control and Prevention (CDC) September 2017 ICD-10-CM Coordination and Maintenance Committee meeting.⁵⁰ In June 2018, the final ICD-10-CM code addenda for 2019 was released and included the new codes E78.⁴¹ (Elevated Lp[a]) and Z83.430 (Family history of elevated Lp[a]).⁵² After the new codes were approved, both the American Heart Association and the National Lipid Association added recommendations regarding Lp(a) testing to their clinical practice guidelines.^43,52

Practically, these codes standardize billing and payment for legitimate clinical work and laboratory testing. Prior to the addition of Lp(a) elevation as a clinical diagnosis, testing and treatment of Lp(a) elevation was considered experimental and not medically necessary until after a cardiovascular event had already occurred. Services for Lp(a) elevation were therefore not reimbursed by many healthcare organizations and insurance companies. The new ICD-10-CM codes encourage the assessment of Lp(a) both in individuals with early onset major CVD events and in presumably fit, healthy individuals, particularly when there is a family history of Lp(a) elevation. Given that Lp(a) levels do not change significantly over time, the current understanding is that only a single measurement is needed to define the individual risk over a lifetime.^41,42,44,45 As therapies targeting Lp(a) levels evolve, repeated measurements may be indicated to monitor response and direct changes in management. “Elevated Lipoprotein(a)” is the first laboratory testing abnormality that has achieved the status of a clinical diagnosis.

Lp(a) Measurements

There is considerable complexity to the measurement of lipoproteins in blood samples due to heterogeneity in both density and size of particles as illustrated in the Figure.⁵³

For traditional lipids measured in clinical practice, the size and density ranges from small high-density lipoprotein (HDL) through LDLC and intermediate- density lipoprotein (IDL) to the largest least dense particles in the very low-density lipoprotein (VLDL) and chylomicron remnant fractions. Standard lipid profiles consist of mass concentration measurements (mg/dL) of TC, TG, HDLC, and LDLC.⁵³ Non-HDLC (calculated as: TC−HDLC) consists of all cholesterol found in atherogenic lipoproteins, including remnant-C and Lp(a). Until recently, the cholesterol content of Lp(a), corresponding to about 30% of Lp(a) total mass, was included in the TC, non-HDLC and LDLC measurements with no separate reporting by the majority of clinical laboratories.

After > 50 years of research on the structure and biochemistry of Lp(a), the physiology and biological functions of these complex and polymorphic lipoprotein particles are not fully understood. Lp(a) is composed of a lipoprotein particle similar in composition to LDL (protein and lipid), containing 1 molecule of ApoB wrapped around a core of cholesteryl ester and triglyceride with phospholipids and unesterified cholesterol at its surface.⁴⁸ The presence of a unique hydrophilic, highly glycosylated protein referred to as apolopoprotienA (apo[a]), covalently attached to ApoB-100 by a single disulfide bridge, differentiates Lp(a) from LDL.⁴⁸ Cholesterol rich ApoB is an important component within many lipoproteins pathogenic for atherosclerosis and CVD.^45,47,53

The apo(a) contributes to the increased density of Lp(a) compared to LDLC with associated reduced binding affinity to the LDL receptor. This reduced receptor binding affinity is a presumed mechanism for the lack of Lp(a) plasma level response to statin therapies, which increase hepatic LDL receptor activity.⁴⁷ Apo(a) evolved from the plasminogen gene through duplication and remodeling and demonstrates extensive heterogeneity in protein size, with > 40 different apo(a) isoforms resulting in > 40 different Lp(a) particle sizes. Size of the apo(a) particle is determined by the number of pleated structures known as kringles. Most people (> 80%) carry 2 different-sized apo(a) isoforms. Plasma Lp(a) level is determined by the net production of apo(a) in each isoform, and the smaller apo(a) isoforms are associated with higher plasma levels of Lp(a).⁴⁵

Given the heterogeneity in Lp(a) molecular weight, which can vary even within individuals, recommendations have been made for reporting results as particle numbers or concentrations (nmol/L or mmol/L) rather than as mass concentration (mg/dL).⁵⁵ However, the majority of the large CVD morbidity and mortality outcomes studies used Lp(a) mass concentration levels in mg/ dL to characterize risk levels.^56,57 There is no standardized method to convert Lp(a) measurements from mg/dL to nmol/L.⁵⁵ Current assays using WHO standardized reagents and controls are reliable for categorizing risk levels.⁵⁸

The European Atherosclerosis Society consensus panel recommended that desirable Lp(a) levels should be below the 80th percentile (< 50 mg/dL or < 125 nmol/L) in patients with intermediate or high CVD risk.⁵⁹ Subsequent epidemiological and Mendelian randomization studies have been performed in general populations with no history of CVD and demonstrated that increased CVD risk can be detected with Lp(a) levels as low as 25 to 30 mg/dL.^56,60-63 In secondary prevention populations with prior CVD and optimal treatment (statins, antiplatelet drugs), recurrent event risk was also increased with elevated Lp(a).^63-66

Using immunoturbidometric assays, Varvel and colleagues reported the prevalence of elevated Lp(a) mass concentration levels (mg/dL) in > 500,000 US patients undergoing clinical evaluations based on data from a referral laboratory of patients.⁵⁸ The mean Lp(a) levels were 34.0 mg/dL with median (interquartile range [IQR]) levels at 17 (7-47) mg/dL and overall range of 0 to 907 mg/dL.⁵⁸ Females had higher Lp(a) levels compared to males but no ethnic or racial breakdown was provided. Lp(a) levels > 30 mg/dL and > 50 mg/dL were present in 35% and 24% of subjects, respectively. Table 1 displays the relationship between various Lp(a) level cut-offs to mean levels of LDLC, estimated LDLC corrected for Lp(a), TC, HDLC, and TG.⁵⁸ The data demonstrate that Lp(a) elevation cannot be inferred from LDLC levels nor from any of the other traditional lipoprotein measures. Patients with high risk Lp(a) levels may have normal LDLC. While Lp(a) thresholds have been identified for stratification of CVD risk, the target levels for risk reduction have not been specifically defined, particularly since therapies are not widely available for reduction of Lp(a). Table 2 provides an overview of clinical lipoprotein measurements that may be reasonable targets for therapeutic interventions and reduction of CVD risk.^44,53,55 In general, existing studies suggest that radical reduction (> 80%) is required to impact long-term outcomes, particularly in individuals with severe disease.^68,69

LDLC reduction alone leaves a residual CVD risk that is greater than the risk reduced.40 In addition, the autoimmune inflammation and lipid specific autoantibodies play an important role in increased CVD morbidity and mortality risk.^70,71 The presence of autoantibodies such as antiphospholipid antibodies (without a specific autoimmune disease diagnosis) increases the risk of subclinical atherosclerosis.^72,73 Certain autoimmune diseases such as systemic lupus erythematosus are recognized as independent risk factors for CVD.^74,75 Autoantibodies appear to mediate CVD events and mortality risk, independent of traditional therapies for risk reduction.⁷³ Further research is needed to clarify the role of autoantibodies as markers of increased or decreased CVD risk and their mechanism of action.

Autoantibodies directed at new antigens in lipoproteins within atherosclerotic lesions can modulate the impact of atherosclerosis via activation of the innate and adaptive immune system.⁷⁶ The lipid-associated neopeptides are recognized as damage-associated or danger- associated molecular patterns (DAMPs), also known as alarmins, which signal molecules that can trigger and perpetuate noninfectious inflammatory responses.^77-79 Plasma autoantibodies (immunoglobulin M and G [IgM, IgG]) modify proinflammatory oxidation-specific epitopes on oxidized phospholipids (oxPL) within lipoproteins and are linked with markers of inflammation and CVD events.^80-82 Modified LDLC and ApoB-100 immune complexes with specific autoantibodies in the IgG class are associated with increased CVD.⁷⁶ These and other risk-modulating autoantibodies may explain some of the variability in CVD outcomes by ethnicity and between individuals.

Some antibodies to oxidized LDL (ox-LDL) may have a protective role in the development of atherosclerosis.^83,84 In a cohort of > 500 women, the number of carotid atherosclerotic plaques and total carotid plaque area were inversely correlated with a specific IgM autoantibody (MDA-p210).⁸⁴ High concentrations of Lp(a)- containing circulating immune complexes and Lp(a)-specific IgM and IgG have been described in patients with coronary heart disease (CHD).⁸⁵ Like ox-LDL, oxidized Lp(a) [ox-Lp(a)] is more potent than native Lp(a) in increasing atherosclerosis risk and is increased in patients with CHD compared to healthy controls.^86-88 Ox-Lp(a) levels may represent an even stronger risk marker for CVD than ox-LDL.⁸⁵

Possible Mechanisms of Pathogenesis

While the precise quantification of Lp(a) in human plasma (or serum) has been challenging, current clinical laboratories use standardized international reference reagents and controls in their assays. Most current Lp(a) assays are based on immunological methods (eg, immunonephelometry, immunoturbidimetry, or enzyme linked immunosorbent assay [ELISA]) using antibodies against apo(a).⁸⁹ Apo(a) contains 10 subtypes of kringle IV and 1 copy of kringle V. Some assays use antibodies against kringle-IV type 2; however, it has been recommended that newer methods should use antibodies against the specific bridging kringle-IV Type 9 domain, which has a more stable bond and is present as a single copy.^48,89 Other approaches to Lp(a) measurement include ultraperformance liquid chromatography/mass spectrometry that can determine both the concentration and particle size of apo(a).^48,90 For routine clinical care, currently available assays reporting in mg/dL can be considered fairly accurate for separating low-risk from moderate-to-high-risk patients.⁴⁵

The physiologic role of Lp(a) in humans remains to be fully defined and individuals with extremely low plasma Lp(a) levels present no disease or deficiency syndromes.⁹¹ Lp(a) accumulates in endothelial injuries and binds to components of the vessel wall and subendothelial matrix, presumably due to the strong lysine binding site in apo(a).⁴⁶ Mediated by apo(a), the binding stimulates chemotactic activation of monocytes/macrophages and thereby modulating angiogenesis and inflammation.⁸⁹ Lp(a) may contribute to CVD and CAVS via its LDL-like component, with proinflammatory effects of oxidized phospholipids (OxPL) on both ApoB and apo(a) and antifibrinolytic/prothrombotic effects of apo(a).⁹² In Vitro studies have demonstrated that apo(a) modifies cellular function of cultured vascular endothelial cells (promoting stress fiber formation, endothelial contraction and vascular permeability), smooth muscles, and monocytes/ macrophages (promoting differentiation of proinflammatory M1-1 type macrophages) via complex mechanisms of cell signaling and cytokine production.89 Lp(a) is the only monogenetic risk factor for aortic valve calcification and stenosis⁹³ and is strongly linked specifically with the single nucleotide polymorphism (SNP) rs10455872 in the gene LPA encoding for apo(a).⁹⁴

CVD Risk Predictive Value

There are a large number of studies demonstrating that Lp(a) elevations are an independent predictor of adverse cardiovascular outcomes including MI, sudden death, strokes, calcific aortic valve stenosis and peripheral vascular disease (Table 3). The Copenhagen City Heart Study and Copenhagen General Population Study are well known prospective population- based cohort studies that track outcomes through national patient registries.⁹⁵ These studies demonstrate increased risk for MI, CHD, CAVS, and heart failure when subjects with very high Lp(a) levels (50-115 mg/dL) are compared with subjects with very low Lp(a) levels (< 5 mg/dL).^96-100 Subjects with less extreme Lp(a) elevations (> 30 mg/dL) also show increased risk of CVD when they have comorbid LDLC elevations.¹⁰¹ However, the Copenhagen studies are composed exclusively of white subjects and the effects of Lp(a) are known to vary with race or ethnicity.

The Multi-Ethnic Study of Atherosclerosis (MESA) recruited an ethnically diverse sample of > 6,000 Americans, aged 45 to 84 years, without CVD, into an ongoing prospective cohort study. Research using subjects from this study has found consistently increased risk of CHD, heart failure, subclinical aortic valve calcification, and more severe CAVS in white subjects with elevated Lp(a).^60,102,103 Black subjects with elevated Lp(a) had increased risk of CHD and more severe CAVS and Hispanic subjects with Lp(a) elevation were at higher risk for CHD.^60,102 So far, no studies of MESA subjects have identified a relationship between Lp(a) elevation and CVD events for Asian-Americans subjects (predominantly of Chinese descent). There is a need for ongoing research to more precisely define relevant cut-off levels by race, ethnicity and sex.

The Atherosclerosis Risk in Communities (ARIC) Study was a prospective multiethnic cohort study including > 15,000 US adults, aged 45 to 64 years.¹⁰³ Lp(a) elevations in this cohort were associated with greater risks for first CVD events, heart failure, and recurrent CVD events.^61,64,105 The risk of stroke for subjects with elevated Lp(a) was greater for black and white women, and for black men.^61,106 However, a meta-analysis of case-control studies showed increased ischemic stroke risk in both men and women with elevated Lp(a).⁵⁷

A recent European meta-analysis collected blood samples and outcome data from > 50,000 subjects in 7 prospective cohort studies. Using a central laboratory to standardize Lp(a) measurements, researchers found increased risk of major coronary events and new CVD in subjects with Lp(a) > 50 mg/dL compared to those below that threshold.¹⁰⁷

Although many of these studies show modest increases in risk of CVD events with Lp(a) elevation, it should be noted that other studies do not demonstrate such consistent associations. This is particularly true in studies of women and nonwhite ethnic groups.^103,108-112 The variability of study results may be due to other confounding factors such as autoantibodies that either upregulate or downregulate atherogenicity of LDLC and potentially other lipoproteins. This is particularly relevant to women who have an increased risk for autoimmune disease.

Lp(a) has significant genetic heritability—75% in Europeans and 85% in African Americans.¹¹³ In whites, the LPA gene on chromosome 6p26- 27 with the polymorphism genetic variants rs10455872 and rs3798220 is consistently associated with elevated Lp(a) levels.^63,100,113 However, the degree of Lp(a) elevation associated with these specific genetic variants varies by ethnicity.^78,113,115

Lifestyle and Cardiovascular Health

It is noteworthy that the Lp(a) genetic risks can also be modified by lifestyle risk reduction even in the absence of significant blood level reductions. For example, Khera and colleagues constructed a genetic risk profile for CVD that included genes related to Lp(a).¹¹⁶ Subjects with high genetic risk were more likely to experience CVD events compared with subjects with low genetic risk. However, risks for CVD were attenuated by 4 healthy lifestyle factors: current nonsmoker, body mass index < 30, at least weekly physical activity, and a healthy diet. Subjects with high genetic risk and an unhealthy lifestyle (0 or 1 of the 4 healthy lifestyle factors) were the most likely to develop CVD (Hazard ratio [HR], 3.5), but that risk was lower for subjects with healthy (3 or 4 of the 4 healthy lifestyle factors) and intermediate lifestyles (2 of the 4 healthy lifestyle factors) (HR, 1.9 and 2.2, respectively), despite despite high genetic risk for CVD.

While the independent CVD risk associated with elevated Lp(a) does not appear to be responsive to lifestyle risk reduction alone, certainly elevated LDLC and traditional risk factors can increase the overall CVD risk and are worthy of preventive interventions. In particular, inflammation from any source exacerbates CVD risk. Proatherogenic diet, insufficient sleep, lack of exercise, and maladaptive stress responses are other targets for personalized CVD risk reduction. ^28,117 Studies of dietary modifications and other lifestyle factors have shown reduced risk of CVD events, despite lack of reduction in Lp(a) levels.^119,120 It is noteworthy that statin therapy (with or without ezetimibe) fails to impact CAVS progression, likely because statins either raise or have no effect on Lp(a) levels.^92,119

Until recently, there has been no evidence supporting any therapeutic intervention causing clinically meaningful reductions in Lp(a). Table 4 lists major drug classes and their effects on Lp(a) and CVD outcomes; however, a detailed discussion of each of these therapies is beyond the scope of this review. Drugs that reduce Lp(a) by 20-30% have varying effects on CVD outcomes, from no effect^122,123 to a 10% to 20% decrease in CVD events when compared with a placebo.^124,125 Because these drugs also produce substantial reductions in LDLC, it is not possible to determine how much of the beneficial effects are due to reductions in Lp(a).

Lipoprotein apheresis produces profound reductions in Lp(a) of 60 to 80% in very highrisk populations.^69,126 Within-subjects comparisons show up to 80% reductions in CVD events, relative to event rates prior to treatment initiation.^69,127 Early trials of antisense oligonucleotide against apo(a) therapies show potential to produce similar outcomes.^128,129 These treatments may be particularly effective in patients with isolated Lp(a) elevations.

Summary

Lp(a) elevation is a major contributor to cardiovascular disease risk and has been recognized as an ICD-10-CM coded clinical diagnosis, the first laboratory abnormality to be defined a clinical disease in the asymptomatic healthy young individuals. This change addresses currently under- diagnosed CVD risk independent of LDLC reduction strategies. A brief overview of recent guidelines for the clinical use of Lp(a) testing from the American Heart Association^43,151 and the National Lipid Association52 can be found in Table 5. Although drug therapies for lowering Lp(a) levels remain limited, new treatment options are actively being developed.

Many Americans with high Lp(a) have not yet been identified. Expanded one-time screening can inform these patients of their cardiovascular risk and increase their access to early, aggressive lifestyle modification and optimal lipid-lowering therapy. Given the further increased CVD risk factors for military service members and veterans, a case can be made for broader screening and enhanced surveillance of elevated Lp(a) in these presumably healthy and fit individuals as well as management focused on modifiable risk factors.

Acknowledgements

This program initiative was conducted by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. as part of the Integrative Cardiac Health Project at Walter Reed National Military Medical Center (WRNMMC), and is made possible by a cooperative agreement that was awarded and administered by the US Army Medical Research & Materiel Command (USAMRMC), at Fort Detrick under Contract Number: W81XWH-16-2-0007. It reflects literature review preparatory work for a research protocol but does not involve an actual research project. The work in this manuscript was supported by the staff of the Integrative Cardiac Health Project (ICHP) with special thanks to Claire Fuller, Elaine Walizer, Dr. Mariam Kashani and the entire health coaching team.

Dermatologists are increasingly called on to evaluate patients with complex medical problems who are often taking many medications. Over the last several decades, many new drugs that target molecular pathways in carcinogenesis and the inflammatory immune system have been developed. Increased skin cancer risk has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, Janus kinase (JAK) inhibitors, and phosphodiesterase 5 (PDE-5) inhibitors. We review the literature and data regarding the significance and strength of these associations and the molecular pathways by which these medications promote cutaneous tumorigenesis. The association of skin cancer with drugs that either induce photosensitivity—nonsteroidal anti-inflammatory drugs, antibiotics (eg, tetracyclines, fluoroquinolones, trimethoprim-sulfamethoxazole), voriconazole, thiazides—or suppress the immune system—certain biologics (eg, anti–tumor necrosis factor agents), calcineurin inhibitors, thiopurines, methotrexate, cyclosporine—is well known and is therefore not reviewed in this discussion.

BRAF Inhibitors

The mitogen-activated protein kinase (MAPK) pathway (also known as the RAS/RAF/MAPK signaling pathway) is important in growth factor–receptor signaling and plays a key role in cell differentiation, survival, and proliferation. Activating mutations in this pathway allow cells to grow and proliferate in a growth factor–independent manner. Twenty percent of human cancers harbor a mutation in the RAS oncogene, an upstream mediator of the pathway.¹ Activating mutations in BRAF, a serine/threonine kinase, predominate in cutaneous melanoma and also have been found in 40% to 70% of papillary thyroid malignancies, 10% to 20% of cholangiocarcinomas, and 5% to 20% of colorectal carcinomas. The most common BRAF mutation in cutaneous melanoma is V600E, which involves a glutamic acid for valine substitution at codon 600. This mutation activates BRAF 500-fold and is present in approximately 50% of melanomas.^1,2

Vemurafenib, a selective BRAF inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in the United States in 2011. Phase 3 trial data demonstrated that vemurafenib resulted in improved survival and decreased risk for disease progression compared to dacarbazine, the former best treatment.³ During phase 1 testing, it became apparent that vemurafenib treatment was associated with a 31% increased risk for squamous cell carcinoma (SCC), most commonly well-differentiated SCC, and keratoacanthomas (KAs).⁴ This association was confirmed in phase 2 and 3 studies, though the incidence was lower. McArthur et al⁵ reported a 19% incidence of cutaneous SCC with extended follow-up analysis of the phase 3 trial. Dabrafenib, another BRAF inhibitor, has been similarly associated with increasing the risk for SCC and KA.

In one study, the mean time to development of SCC after initiating vemurafenib therapy was 10 weeks, with lesions reported as early as 3 weeks. Most patients had clinical signs of chronically sun damaged skin; however, a history of SCC was present in only 17%. Most lesions (63%) were characterized as KAs.⁶

The mechanism for BRAF inhibitor–induced squamoproliferative growth is due to paradoxical activation of the MAPK pathway in cells with wild-type BRAF that harbor upstream-activating mutations in RAS or tyrosine kinase receptors.⁷ In the presence of a BRAF inhibitor, inactivated BRAF forms heterodimers with wild-type CRAF (a BRAF-CRAF heterodimer). The heterodimer forms a complex with the mutant RAS that leads to transactivation of the CRAF molecule,^8,9 resulting in a paradoxical increase in MAPK signaling and consequent ERK phosphorylation and activation through CRAF signaling. RAS, particularly HRAS, mutations have been found in 60% of all vemurafenib-associated SCCs and KAs. For this reason, it is thought that vemurafenib potentiates tumorigenesis in subclinical lesions harboring upstream MAPK pathway mutations as opposed to inducing de novo lesions.⁶

Because BRAF inhibitors are remarkably efficacious in the treatment of metastatic melanomas harboring the V600E BRAF mutation, there are no restrictions on their use, despite the known increased risk for SCC. Squamous cell carcinomas tend to be low grade, and all tumors that developed in phase 1 to 3 trials were treated with simple excision. The development of SCC did not necessitate interruption of treatment. Furthermore, the addition of MEK inhibition to BRAF inhibitor therapy reduces the risk for SCC from 19% to 7%.^7,10,11

In addition to SCC, second primary melanomas (SPMs) have been reported in patients treated with BRAF inhibitors. It has been shown that these melanomas occur in melanocytes with wild-type BRAF. It has been postulated that some of these tumors occur in cells that harbor upstream mutations in RAS, whereas others might result from alternate signaling through non-RAF oncogenic pathways.^9,12

Zimmer et al¹ reported 12 SPMs in 11 patients treated with BRAF inhibitor therapy. They reported a median delay of 8 weeks (range, 4–27 weeks) for SPM development. Tumors were detected in early stages; 1 tumor harbored an NRAS mutation.¹

Dalle et al¹³ reported 25 SPMs in 120 vemurafenib-treated patients. Median delay in SPM development was 14 weeks (range, 4–42 weeks). All tumors were thin, ranging from in situ to 0.45-mm thick. Wild-type BRAF was detected in the 21 melanomas sampled; 1 lesion showed mutated NRAS.¹³

The exact incidence of SPM in the setting of BRAF inhibition is thought to be at least 10-fold less than SCC and KA.² Patients on BRAF inhibitor therapy should have routine full-body skin examinations, given the increased risk for SPM and SCC.

Another drug belonging to the tyrosine kinase inhibitor family, sorafenib, is used in the treatment of solid tumors, particularly hepatocellular and renal cell carcinomas, and also has been associated with development of cutaneous SCC and KAs.¹⁴ Sorafenib is a multiple tyrosine kinase inhibitor that also inhibits the RAF serine/threonine kinases. Similar to vemurafenib and dabrafenib, SCCs and KAs associated with sorafenib tend to arise in patients with chronic actinic damage during the first 2 months of treatment. It has been hypothesized that inhibition of RAF kinases is pathogenic in inducing SCCs because these lesions have not been reported with sunitinib, another multiple tyrosine kinase inhibitor that lacks the ability to inhibit serine/threonine kinases.^15,16 Although SCCs and KAs associated with sorafenib tend to be low grade, it is reasonable to consider sunitinib or an alternative tyrosine kinase inhibitor in patients who develop multiple SCCs while taking sorafenib.¹⁶

Sonic Hedgehog–Inhibiting Agents

Vismodegib, the first small molecule inhibitor of the signaling protein smoothened, gained FDA approval for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in 2012. A second agent with an identical mechanism of action, sonidegib, was approved by the FDA for locally advanced BCC in 2015. Approximately 90% of BCCs contain mutations in the sonic hedgehog pathway, which lead to constitutive smoothened activation and uncontrolled cell proliferation.¹⁷ The development of smoothened inhibitors introduced a much-needed treatment for inoperable or metastatic BCC,^17,18 though long-term utility is limited by drug resistance with extended use in this patient population.^19,20 Several case reports have documented the emergence of KA²¹ and cutaneous SCC following vismodegib treatment of advanced or metastatic BCC.^22-24 A larger case-control study by Mohan et al²⁵ showed that patients with BCC treated with vismodegib had an increased risk for non-BCC malignancy (hazard ratio [HR]=6.37), most of which were cutaneous SCC (HR=8.12).

The mechanism by which selective inhibition of smoothened leads to cutaneous SCC is unclear. A study found that patients on vismodegib who developed SCC within the original BCC site had elevated ERK levels within tumor tissue, suggesting that the RAS/RAF/MAPK pathway can become upregulated during hedgehog inhibition.²⁶ Other studies looking at hedgehog inhibition in medulloblastoma models also have shown activated RAS/RAF/MAPK pathways.²⁵ These findings suggest that tumors under smoothened inhibition might be able to bypass the sonic hedgehog pathway and continue to grow by upregulating alternative growth pathways, such as RAS/RAF/MAPK.^25,26

The incidence of cutaneous SCC following vismodegib treatment is unknown. Chang and Oro²⁷ examined BCC tumor regrowth from secondary (acquired) resistance to vismodegib and noted that lesions recurred within 1 cm of the original tumor 21% of the time. Although none of the 12 patients whose tumors regrew during treatment were reported to have developed SCC, several demonstrated different BCC subtypes than the pretreatment specimen. The authors proposed that regrowth of BCC was due to upregulated alternative pathways allowing tumors to bypass smoothened inhibition, which is similar to the proposed mechanism for SCC development in vismodegib patients.²⁷

Prospective studies are needed to confirm the link between vismodegib and cutaneous SCC; establish the incidence of SCC development; and identify any pretreatment factors, tumor characteristics, or treatment details (eg, dosage, duration) that might contribute to SCC development. Furthermore, because Mohan et al²⁵ observed that vismodegib-treated patients were less likely to develop SCC in situ than controls, it is unknown if these tumors are more aggressive than traditional SCC. At this point, careful surveillance and regular full-body skin examinations are advised for patients on vismodegib for treatment of advanced BCC.

JAK Inhibitors

Another class of medications potentially associated with increased development of nonmelanoma skin cancer (NMSC) is the JAK inhibitors (also known as jakinibs). Many proinflammatory signaling pathways converge on the JAK family of enzymes—JAK1, JAK2, JAK3, and TYK2. These enzymes operate in cytokine signal transduction by phosphorylating activated cytokine receptors, which allows for recruitment and activation by means of phosphorylation of transcription factors collectively known as signal transducers and activators of transcription (STATs). Phosphorylated STATs dimerize and translocate to the nucleus, acting as direct transcription promoters. Janus kinase inhibitors modulate the immune response by reducing the effect of interleukin and interferon signaling.

Ruxolitinib, a JAK1/JAK2 inhibitor, was the first JAK inhibitor approved by the FDA and is indicated for the treatment of myelofibrosis and polycythemia vera. Additionally, oral and topical JAK inhibitors have shown efficacy in the treatment of psoriasis, rheumatoid arthritis, alopecia areata, vitiligo, and pruritus from atopic dermatitis.²⁸

The JAK-STAT pathway is complex, and the biological activity of the pathway is both proinflammatory and pro–cell survival and proliferation. Because signaling through the pathway can increase angiogenesis and inhibit apoptosis, inhibition of this pathway has been exploited for the treatment of some tumors. However, inhibition of interferon and proinflammatory interleukin signaling also can potentially promote tumor growth by means of inhibition of downstream cytotoxic T-cell signaling, theoretically increasing the risk for NMSC. A study examining the 5-year efficacy of ruxolitinib in myelofibrosis patients (COMFORT-II trial) found that 17.1% of patients developed NMSC compared to only 2.7% of those on the best available therapy. After adjustment by patient exposure, the NMSC rate was still doubled for ruxolitinib-treated patients compared to controls (6.1/100 patient-years and 3.0/100 patient-years, respectively).²⁹ Eighty-week follow-up of the phase 3 clinical trial of ruxolitinib for the treatment of polycythemia vera also noted an increased incidence of NMSC, albeit a more conservative increase. Patients randomized to the ruxolitinib treatment group developed NMSC at a rate of 4.4/100 patient-years, whereas the rate for controls treated with best available therapy was 2.7/100 patient-years.³⁰ In contrast, 5-year follow-up of the COMFORT-I trial, also examining the efficacy of ruxolitinib in myelofibrosis, showed no increased risk for NMSC between ruxolitinib-treated patients and placebo (2.7/100 patient-years and 3.9/100 patient-years, respectively).³¹

A 2017 case series described 5 patients with myelofibrosis who developed multiple skin cancers with aggressive features while receiving ruxolitinib.³² Duration of ruxolitinib therapy ranged from 4 months to 4 years; 3 patients had a history of hydroxyurea exposure, and only 1 patient had a history of NMSC. High-risk cutaneous SCC, undifferentiated pleomorphic sarcoma, and lentigo maligna melanoma (Breslow thickness, 0.45 mm) were among the tumors reported in this series. Although no definitive conclusion can be made regarding the causality of JAK inhibitors in promoting these tumors, the association warrants further investigation. Clinicians should be aware that ruxolitinib might amplify the risk for NMSC in patients with pre-existing genetic or exposure-related susceptibility. Interruption of drug therapy may be necessary in managing patients who develop an aggressive tumor.³²

In contrast, tofacitinib, which specifically inhibits JAK3, carries very low risk, if any, for NMSC when used for the treatment of psoriasis and rheumatoid arthritis. Results from 2 phase 3 trials analyzing the efficacy of tofacitinib in psoriasis demonstrated that only 2 of 1486 patients treated developed NMSC compared to none in the control group.³³ Furthermore, analysis of NMSC across the tofacitinib rheumatoid arthritis clinical program, which included a total of 15,103 patient-years of exposure, demonstrated that the overall NMSC incidence was 0.55 for every 100 patient-years. Of note, the risk in patients receiving high-dose treatment (10 mg vs 5 mg) was nearly doubled in long-term follow-up studies (0.79/100 patient-years and 0.41/100 patient-years, respectively). Overall, the study concluded that treatment with tofacitinib presents no greater increased risk for NMSC than treatment with tumor necrosis factor inhibitors.³³

PDE-5 Inhibitors

Phosphodiesterase 5 inhibitors, such as sildenafil citrate, have been widely prescribed for the treatment of erectile dysfunction. Studies have shown that BRAF-activated melanomas, which occur in approximately 50% to 70% of melanomas, also result in reduced PDE-5 expression.^34-36 In these melanomas, downregulation of PDE-5 results in increased intracellular calcium,³⁶ which has been shown to induce melanoma invasion.^36,37 Given this similarity in molecular pathway between BRAF-activated melanomas and PDE-5 inhibitors, there has been increased concern that PDE-5 inhibitors might be associated with an increased risk for melanoma.

In 2014, Li et al³⁸ published a retrospective analysis suggesting an association with sildenafil and an increased risk for melanoma. Their study utilized the Health Professionals Follow-up Study to identify a statistically significant elevation in the risk for invasive melanoma with both recent sildenafil use (multivariate-adjusted HR=2.24) and use at any time (HR=1.92). These results controlled for confounding variables, such as presence of major chronic disease, use of other erectile dysfunction treatments, family history of melanoma, history of sun exposure, and UV index of the patient’s residence. Notably, the study also found that sildenafil did not affect the incidence of BCC or SCC.³⁸

In 2015, Loeb et al³⁹ also examined the potential association between PDE-5 inhibitors and melanoma. Review of several Swedish drug and cancer registries allowed for analysis of melanoma risk and PDE-5 inhibitor use, based on number of prescriptions filled and type of PDE-5 inhibitor prescribed. Their analysis showed that men developing melanoma were more likely than nonmelanoma controls to have taken a PDE-5 inhibitor (11% vs 8%). In a subgroup analysis, however, statistical significance was shown for men with only a single prescription filled (34% of cases; P<.05), whereas the difference for men with multiple filled prescriptions did not meet statistical significance. Furthermore, the study did not find increased risk with longer-acting tadalafil and vardenafil (odds ratio [OR]=1.16) compared to sildenafil (OR=1.14). Last, use of PDE-5 inhibitors was only associated with stage 0 (OR=1.49) and stage I (OR=1.21) tumors, not with stages II to IV (OR=0.83) tumors. Although there was a statistically significant association between PDE-5 inhibitors and malignant melanoma (P<.05), the subgroup analysis findings pointed away from a causal relationship and likely toward a confounding of variable(s).³⁹

A 2016 study by Lian et al⁴⁰ looked at the risk for melanoma in a cohort of patients diagnosed with erectile dysfunction. No association between PDE-5 inhibitors and melanoma risk was shown when comparing patients who received a PDE-5 inhibitor and those who did not receive a PDE-5 inhibitor. However, secondary analysis did show that melanoma risk was increased among patients receiving more pills (34%) and prescriptions (30%). The authors concluded that there was no association between PDE-5 inhibitor use and overall increased risk for melanoma, and the increased risk associated with a greater number of pills and prescriptions would require further study.⁴⁰

In contrast, a 2017 meta-analysis by Tang et al⁴¹ of 5 studies (3 of which were the aforementioned trials^38-40) concluded that use of PDE-5 inhibitors was associated with a small but significantly increased risk for melanoma (OR=1.12) and BCC (OR=1.14) but not SCC. Furthermore, the study found no evidence of dosage-dependent association between PDE-5 inhibitor use and melanoma risk.⁴¹

Overall, clinical studies have been inconclusive in determining the risk for melanoma in the setting of PDE-5 inhibitor use. Studies showing an increased rate of melanoma within patient cohorts receiving PDE-5 inhibitors are limited; results might be affected by confounding variables. However, given the similarity in mechanism between PDE-5 inhibitors and HRAS-activated melanomas, it is reasonable to continue research into this potential association.

Conclusion

Since the turn of the century, drugs targeting cell-signaling pathways have been developed to treat inflammatory, oncologic, and immune conditions. The role of immunosuppressants in promoting skin cancer is well established and supported by a vast literature base. However, associations are less clear with newer immunomodulatory and antineoplastic medications. Skin cancer has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, JAK inhibitors, and PDE-5 inhibitors. In the case of JAK and PDE-5 inhibitors, the increased risk for melanoma and NMSC is somewhat inconclusive; risk is more firmly established for BRAF inhibitors and smoothened inhibitors. For the antineoplastic agents reviewed, the therapeutic effect of cancer regression is well documented, and benefits of continued therapy outweigh the increased risk for skin cancer promotion in nearly all cases. The value of early detection has been well documented for skin malignancy; therefore, increased skin surveillance and prompt management of suspicious lesions should be a priority for physicians treating patients undergoing therapy with these medications

Dermatologists are increasingly called on to evaluate patients with complex medical problems who are often taking many medications. Over the last several decades, many new drugs that target molecular pathways in carcinogenesis and the inflammatory immune system have been developed. Increased skin cancer risk has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, Janus kinase (JAK) inhibitors, and phosphodiesterase 5 (PDE-5) inhibitors. We review the literature and data regarding the significance and strength of these associations and the molecular pathways by which these medications promote cutaneous tumorigenesis. The association of skin cancer with drugs that either induce photosensitivity—nonsteroidal anti-inflammatory drugs, antibiotics (eg, tetracyclines, fluoroquinolones, trimethoprim-sulfamethoxazole), voriconazole, thiazides—or suppress the immune system—certain biologics (eg, anti–tumor necrosis factor agents), calcineurin inhibitors, thiopurines, methotrexate, cyclosporine—is well known and is therefore not reviewed in this discussion.

BRAF Inhibitors

The mitogen-activated protein kinase (MAPK) pathway (also known as the RAS/RAF/MAPK signaling pathway) is important in growth factor–receptor signaling and plays a key role in cell differentiation, survival, and proliferation. Activating mutations in this pathway allow cells to grow and proliferate in a growth factor–independent manner. Twenty percent of human cancers harbor a mutation in the RAS oncogene, an upstream mediator of the pathway.¹ Activating mutations in BRAF, a serine/threonine kinase, predominate in cutaneous melanoma and also have been found in 40% to 70% of papillary thyroid malignancies, 10% to 20% of cholangiocarcinomas, and 5% to 20% of colorectal carcinomas. The most common BRAF mutation in cutaneous melanoma is V600E, which involves a glutamic acid for valine substitution at codon 600. This mutation activates BRAF 500-fold and is present in approximately 50% of melanomas.^1,2

Vemurafenib, a selective BRAF inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in the United States in 2011. Phase 3 trial data demonstrated that vemurafenib resulted in improved survival and decreased risk for disease progression compared to dacarbazine, the former best treatment.³ During phase 1 testing, it became apparent that vemurafenib treatment was associated with a 31% increased risk for squamous cell carcinoma (SCC), most commonly well-differentiated SCC, and keratoacanthomas (KAs).⁴ This association was confirmed in phase 2 and 3 studies, though the incidence was lower. McArthur et al⁵ reported a 19% incidence of cutaneous SCC with extended follow-up analysis of the phase 3 trial. Dabrafenib, another BRAF inhibitor, has been similarly associated with increasing the risk for SCC and KA.

In one study, the mean time to development of SCC after initiating vemurafenib therapy was 10 weeks, with lesions reported as early as 3 weeks. Most patients had clinical signs of chronically sun damaged skin; however, a history of SCC was present in only 17%. Most lesions (63%) were characterized as KAs.⁶

The mechanism for BRAF inhibitor–induced squamoproliferative growth is due to paradoxical activation of the MAPK pathway in cells with wild-type BRAF that harbor upstream-activating mutations in RAS or tyrosine kinase receptors.⁷ In the presence of a BRAF inhibitor, inactivated BRAF forms heterodimers with wild-type CRAF (a BRAF-CRAF heterodimer). The heterodimer forms a complex with the mutant RAS that leads to transactivation of the CRAF molecule,^8,9 resulting in a paradoxical increase in MAPK signaling and consequent ERK phosphorylation and activation through CRAF signaling. RAS, particularly HRAS, mutations have been found in 60% of all vemurafenib-associated SCCs and KAs. For this reason, it is thought that vemurafenib potentiates tumorigenesis in subclinical lesions harboring upstream MAPK pathway mutations as opposed to inducing de novo lesions.⁶

Because BRAF inhibitors are remarkably efficacious in the treatment of metastatic melanomas harboring the V600E BRAF mutation, there are no restrictions on their use, despite the known increased risk for SCC. Squamous cell carcinomas tend to be low grade, and all tumors that developed in phase 1 to 3 trials were treated with simple excision. The development of SCC did not necessitate interruption of treatment. Furthermore, the addition of MEK inhibition to BRAF inhibitor therapy reduces the risk for SCC from 19% to 7%.^7,10,11

In addition to SCC, second primary melanomas (SPMs) have been reported in patients treated with BRAF inhibitors. It has been shown that these melanomas occur in melanocytes with wild-type BRAF. It has been postulated that some of these tumors occur in cells that harbor upstream mutations in RAS, whereas others might result from alternate signaling through non-RAF oncogenic pathways.^9,12

Zimmer et al¹ reported 12 SPMs in 11 patients treated with BRAF inhibitor therapy. They reported a median delay of 8 weeks (range, 4–27 weeks) for SPM development. Tumors were detected in early stages; 1 tumor harbored an NRAS mutation.¹

Dalle et al¹³ reported 25 SPMs in 120 vemurafenib-treated patients. Median delay in SPM development was 14 weeks (range, 4–42 weeks). All tumors were thin, ranging from in situ to 0.45-mm thick. Wild-type BRAF was detected in the 21 melanomas sampled; 1 lesion showed mutated NRAS.¹³

The exact incidence of SPM in the setting of BRAF inhibition is thought to be at least 10-fold less than SCC and KA.² Patients on BRAF inhibitor therapy should have routine full-body skin examinations, given the increased risk for SPM and SCC.

Another drug belonging to the tyrosine kinase inhibitor family, sorafenib, is used in the treatment of solid tumors, particularly hepatocellular and renal cell carcinomas, and also has been associated with development of cutaneous SCC and KAs.¹⁴ Sorafenib is a multiple tyrosine kinase inhibitor that also inhibits the RAF serine/threonine kinases. Similar to vemurafenib and dabrafenib, SCCs and KAs associated with sorafenib tend to arise in patients with chronic actinic damage during the first 2 months of treatment. It has been hypothesized that inhibition of RAF kinases is pathogenic in inducing SCCs because these lesions have not been reported with sunitinib, another multiple tyrosine kinase inhibitor that lacks the ability to inhibit serine/threonine kinases.^15,16 Although SCCs and KAs associated with sorafenib tend to be low grade, it is reasonable to consider sunitinib or an alternative tyrosine kinase inhibitor in patients who develop multiple SCCs while taking sorafenib.¹⁶

Sonic Hedgehog–Inhibiting Agents

Vismodegib, the first small molecule inhibitor of the signaling protein smoothened, gained FDA approval for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in 2012. A second agent with an identical mechanism of action, sonidegib, was approved by the FDA for locally advanced BCC in 2015. Approximately 90% of BCCs contain mutations in the sonic hedgehog pathway, which lead to constitutive smoothened activation and uncontrolled cell proliferation.¹⁷ The development of smoothened inhibitors introduced a much-needed treatment for inoperable or metastatic BCC,^17,18 though long-term utility is limited by drug resistance with extended use in this patient population.^19,20 Several case reports have documented the emergence of KA²¹ and cutaneous SCC following vismodegib treatment of advanced or metastatic BCC.^22-24 A larger case-control study by Mohan et al²⁵ showed that patients with BCC treated with vismodegib had an increased risk for non-BCC malignancy (hazard ratio [HR]=6.37), most of which were cutaneous SCC (HR=8.12).

The mechanism by which selective inhibition of smoothened leads to cutaneous SCC is unclear. A study found that patients on vismodegib who developed SCC within the original BCC site had elevated ERK levels within tumor tissue, suggesting that the RAS/RAF/MAPK pathway can become upregulated during hedgehog inhibition.²⁶ Other studies looking at hedgehog inhibition in medulloblastoma models also have shown activated RAS/RAF/MAPK pathways.²⁵ These findings suggest that tumors under smoothened inhibition might be able to bypass the sonic hedgehog pathway and continue to grow by upregulating alternative growth pathways, such as RAS/RAF/MAPK.^25,26

The incidence of cutaneous SCC following vismodegib treatment is unknown. Chang and Oro²⁷ examined BCC tumor regrowth from secondary (acquired) resistance to vismodegib and noted that lesions recurred within 1 cm of the original tumor 21% of the time. Although none of the 12 patients whose tumors regrew during treatment were reported to have developed SCC, several demonstrated different BCC subtypes than the pretreatment specimen. The authors proposed that regrowth of BCC was due to upregulated alternative pathways allowing tumors to bypass smoothened inhibition, which is similar to the proposed mechanism for SCC development in vismodegib patients.²⁷

Prospective studies are needed to confirm the link between vismodegib and cutaneous SCC; establish the incidence of SCC development; and identify any pretreatment factors, tumor characteristics, or treatment details (eg, dosage, duration) that might contribute to SCC development. Furthermore, because Mohan et al²⁵ observed that vismodegib-treated patients were less likely to develop SCC in situ than controls, it is unknown if these tumors are more aggressive than traditional SCC. At this point, careful surveillance and regular full-body skin examinations are advised for patients on vismodegib for treatment of advanced BCC.

JAK Inhibitors

Another class of medications potentially associated with increased development of nonmelanoma skin cancer (NMSC) is the JAK inhibitors (also known as jakinibs). Many proinflammatory signaling pathways converge on the JAK family of enzymes—JAK1, JAK2, JAK3, and TYK2. These enzymes operate in cytokine signal transduction by phosphorylating activated cytokine receptors, which allows for recruitment and activation by means of phosphorylation of transcription factors collectively known as signal transducers and activators of transcription (STATs). Phosphorylated STATs dimerize and translocate to the nucleus, acting as direct transcription promoters. Janus kinase inhibitors modulate the immune response by reducing the effect of interleukin and interferon signaling.

Ruxolitinib, a JAK1/JAK2 inhibitor, was the first JAK inhibitor approved by the FDA and is indicated for the treatment of myelofibrosis and polycythemia vera. Additionally, oral and topical JAK inhibitors have shown efficacy in the treatment of psoriasis, rheumatoid arthritis, alopecia areata, vitiligo, and pruritus from atopic dermatitis.²⁸

The JAK-STAT pathway is complex, and the biological activity of the pathway is both proinflammatory and pro–cell survival and proliferation. Because signaling through the pathway can increase angiogenesis and inhibit apoptosis, inhibition of this pathway has been exploited for the treatment of some tumors. However, inhibition of interferon and proinflammatory interleukin signaling also can potentially promote tumor growth by means of inhibition of downstream cytotoxic T-cell signaling, theoretically increasing the risk for NMSC. A study examining the 5-year efficacy of ruxolitinib in myelofibrosis patients (COMFORT-II trial) found that 17.1% of patients developed NMSC compared to only 2.7% of those on the best available therapy. After adjustment by patient exposure, the NMSC rate was still doubled for ruxolitinib-treated patients compared to controls (6.1/100 patient-years and 3.0/100 patient-years, respectively).²⁹ Eighty-week follow-up of the phase 3 clinical trial of ruxolitinib for the treatment of polycythemia vera also noted an increased incidence of NMSC, albeit a more conservative increase. Patients randomized to the ruxolitinib treatment group developed NMSC at a rate of 4.4/100 patient-years, whereas the rate for controls treated with best available therapy was 2.7/100 patient-years.³⁰ In contrast, 5-year follow-up of the COMFORT-I trial, also examining the efficacy of ruxolitinib in myelofibrosis, showed no increased risk for NMSC between ruxolitinib-treated patients and placebo (2.7/100 patient-years and 3.9/100 patient-years, respectively).³¹

A 2017 case series described 5 patients with myelofibrosis who developed multiple skin cancers with aggressive features while receiving ruxolitinib.³² Duration of ruxolitinib therapy ranged from 4 months to 4 years; 3 patients had a history of hydroxyurea exposure, and only 1 patient had a history of NMSC. High-risk cutaneous SCC, undifferentiated pleomorphic sarcoma, and lentigo maligna melanoma (Breslow thickness, 0.45 mm) were among the tumors reported in this series. Although no definitive conclusion can be made regarding the causality of JAK inhibitors in promoting these tumors, the association warrants further investigation. Clinicians should be aware that ruxolitinib might amplify the risk for NMSC in patients with pre-existing genetic or exposure-related susceptibility. Interruption of drug therapy may be necessary in managing patients who develop an aggressive tumor.³²

In contrast, tofacitinib, which specifically inhibits JAK3, carries very low risk, if any, for NMSC when used for the treatment of psoriasis and rheumatoid arthritis. Results from 2 phase 3 trials analyzing the efficacy of tofacitinib in psoriasis demonstrated that only 2 of 1486 patients treated developed NMSC compared to none in the control group.³³ Furthermore, analysis of NMSC across the tofacitinib rheumatoid arthritis clinical program, which included a total of 15,103 patient-years of exposure, demonstrated that the overall NMSC incidence was 0.55 for every 100 patient-years. Of note, the risk in patients receiving high-dose treatment (10 mg vs 5 mg) was nearly doubled in long-term follow-up studies (0.79/100 patient-years and 0.41/100 patient-years, respectively). Overall, the study concluded that treatment with tofacitinib presents no greater increased risk for NMSC than treatment with tumor necrosis factor inhibitors.³³

PDE-5 Inhibitors

Phosphodiesterase 5 inhibitors, such as sildenafil citrate, have been widely prescribed for the treatment of erectile dysfunction. Studies have shown that BRAF-activated melanomas, which occur in approximately 50% to 70% of melanomas, also result in reduced PDE-5 expression.^34-36 In these melanomas, downregulation of PDE-5 results in increased intracellular calcium,³⁶ which has been shown to induce melanoma invasion.^36,37 Given this similarity in molecular pathway between BRAF-activated melanomas and PDE-5 inhibitors, there has been increased concern that PDE-5 inhibitors might be associated with an increased risk for melanoma.

In 2014, Li et al³⁸ published a retrospective analysis suggesting an association with sildenafil and an increased risk for melanoma. Their study utilized the Health Professionals Follow-up Study to identify a statistically significant elevation in the risk for invasive melanoma with both recent sildenafil use (multivariate-adjusted HR=2.24) and use at any time (HR=1.92). These results controlled for confounding variables, such as presence of major chronic disease, use of other erectile dysfunction treatments, family history of melanoma, history of sun exposure, and UV index of the patient’s residence. Notably, the study also found that sildenafil did not affect the incidence of BCC or SCC.³⁸

In 2015, Loeb et al³⁹ also examined the potential association between PDE-5 inhibitors and melanoma. Review of several Swedish drug and cancer registries allowed for analysis of melanoma risk and PDE-5 inhibitor use, based on number of prescriptions filled and type of PDE-5 inhibitor prescribed. Their analysis showed that men developing melanoma were more likely than nonmelanoma controls to have taken a PDE-5 inhibitor (11% vs 8%). In a subgroup analysis, however, statistical significance was shown for men with only a single prescription filled (34% of cases; P<.05), whereas the difference for men with multiple filled prescriptions did not meet statistical significance. Furthermore, the study did not find increased risk with longer-acting tadalafil and vardenafil (odds ratio [OR]=1.16) compared to sildenafil (OR=1.14). Last, use of PDE-5 inhibitors was only associated with stage 0 (OR=1.49) and stage I (OR=1.21) tumors, not with stages II to IV (OR=0.83) tumors. Although there was a statistically significant association between PDE-5 inhibitors and malignant melanoma (P<.05), the subgroup analysis findings pointed away from a causal relationship and likely toward a confounding of variable(s).³⁹

A 2016 study by Lian et al⁴⁰ looked at the risk for melanoma in a cohort of patients diagnosed with erectile dysfunction. No association between PDE-5 inhibitors and melanoma risk was shown when comparing patients who received a PDE-5 inhibitor and those who did not receive a PDE-5 inhibitor. However, secondary analysis did show that melanoma risk was increased among patients receiving more pills (34%) and prescriptions (30%). The authors concluded that there was no association between PDE-5 inhibitor use and overall increased risk for melanoma, and the increased risk associated with a greater number of pills and prescriptions would require further study.⁴⁰

In contrast, a 2017 meta-analysis by Tang et al⁴¹ of 5 studies (3 of which were the aforementioned trials^38-40) concluded that use of PDE-5 inhibitors was associated with a small but significantly increased risk for melanoma (OR=1.12) and BCC (OR=1.14) but not SCC. Furthermore, the study found no evidence of dosage-dependent association between PDE-5 inhibitor use and melanoma risk.⁴¹

Overall, clinical studies have been inconclusive in determining the risk for melanoma in the setting of PDE-5 inhibitor use. Studies showing an increased rate of melanoma within patient cohorts receiving PDE-5 inhibitors are limited; results might be affected by confounding variables. However, given the similarity in mechanism between PDE-5 inhibitors and HRAS-activated melanomas, it is reasonable to continue research into this potential association.

Conclusion

Since the turn of the century, drugs targeting cell-signaling pathways have been developed to treat inflammatory, oncologic, and immune conditions. The role of immunosuppressants in promoting skin cancer is well established and supported by a vast literature base. However, associations are less clear with newer immunomodulatory and antineoplastic medications. Skin cancer has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, JAK inhibitors, and PDE-5 inhibitors. In the case of JAK and PDE-5 inhibitors, the increased risk for melanoma and NMSC is somewhat inconclusive; risk is more firmly established for BRAF inhibitors and smoothened inhibitors. For the antineoplastic agents reviewed, the therapeutic effect of cancer regression is well documented, and benefits of continued therapy outweigh the increased risk for skin cancer promotion in nearly all cases. The value of early detection has been well documented for skin malignancy; therefore, increased skin surveillance and prompt management of suspicious lesions should be a priority for physicians treating patients undergoing therapy with these medications

Dermatologists are increasingly called on to evaluate patients with complex medical problems who are often taking many medications. Over the last several decades, many new drugs that target molecular pathways in carcinogenesis and the inflammatory immune system have been developed. Increased skin cancer risk has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, Janus kinase (JAK) inhibitors, and phosphodiesterase 5 (PDE-5) inhibitors. We review the literature and data regarding the significance and strength of these associations and the molecular pathways by which these medications promote cutaneous tumorigenesis. The association of skin cancer with drugs that either induce photosensitivity—nonsteroidal anti-inflammatory drugs, antibiotics (eg, tetracyclines, fluoroquinolones, trimethoprim-sulfamethoxazole), voriconazole, thiazides—or suppress the immune system—certain biologics (eg, anti–tumor necrosis factor agents), calcineurin inhibitors, thiopurines, methotrexate, cyclosporine—is well known and is therefore not reviewed in this discussion.

BRAF Inhibitors

The mitogen-activated protein kinase (MAPK) pathway (also known as the RAS/RAF/MAPK signaling pathway) is important in growth factor–receptor signaling and plays a key role in cell differentiation, survival, and proliferation. Activating mutations in this pathway allow cells to grow and proliferate in a growth factor–independent manner. Twenty percent of human cancers harbor a mutation in the RAS oncogene, an upstream mediator of the pathway.¹ Activating mutations in BRAF, a serine/threonine kinase, predominate in cutaneous melanoma and also have been found in 40% to 70% of papillary thyroid malignancies, 10% to 20% of cholangiocarcinomas, and 5% to 20% of colorectal carcinomas. The most common BRAF mutation in cutaneous melanoma is V600E, which involves a glutamic acid for valine substitution at codon 600. This mutation activates BRAF 500-fold and is present in approximately 50% of melanomas.^1,2

Vemurafenib, a selective BRAF inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in the United States in 2011. Phase 3 trial data demonstrated that vemurafenib resulted in improved survival and decreased risk for disease progression compared to dacarbazine, the former best treatment.³ During phase 1 testing, it became apparent that vemurafenib treatment was associated with a 31% increased risk for squamous cell carcinoma (SCC), most commonly well-differentiated SCC, and keratoacanthomas (KAs).⁴ This association was confirmed in phase 2 and 3 studies, though the incidence was lower. McArthur et al⁵ reported a 19% incidence of cutaneous SCC with extended follow-up analysis of the phase 3 trial. Dabrafenib, another BRAF inhibitor, has been similarly associated with increasing the risk for SCC and KA.

In one study, the mean time to development of SCC after initiating vemurafenib therapy was 10 weeks, with lesions reported as early as 3 weeks. Most patients had clinical signs of chronically sun damaged skin; however, a history of SCC was present in only 17%. Most lesions (63%) were characterized as KAs.⁶

The mechanism for BRAF inhibitor–induced squamoproliferative growth is due to paradoxical activation of the MAPK pathway in cells with wild-type BRAF that harbor upstream-activating mutations in RAS or tyrosine kinase receptors.⁷ In the presence of a BRAF inhibitor, inactivated BRAF forms heterodimers with wild-type CRAF (a BRAF-CRAF heterodimer). The heterodimer forms a complex with the mutant RAS that leads to transactivation of the CRAF molecule,^8,9 resulting in a paradoxical increase in MAPK signaling and consequent ERK phosphorylation and activation through CRAF signaling. RAS, particularly HRAS, mutations have been found in 60% of all vemurafenib-associated SCCs and KAs. For this reason, it is thought that vemurafenib potentiates tumorigenesis in subclinical lesions harboring upstream MAPK pathway mutations as opposed to inducing de novo lesions.⁶

Because BRAF inhibitors are remarkably efficacious in the treatment of metastatic melanomas harboring the V600E BRAF mutation, there are no restrictions on their use, despite the known increased risk for SCC. Squamous cell carcinomas tend to be low grade, and all tumors that developed in phase 1 to 3 trials were treated with simple excision. The development of SCC did not necessitate interruption of treatment. Furthermore, the addition of MEK inhibition to BRAF inhibitor therapy reduces the risk for SCC from 19% to 7%.^7,10,11

In addition to SCC, second primary melanomas (SPMs) have been reported in patients treated with BRAF inhibitors. It has been shown that these melanomas occur in melanocytes with wild-type BRAF. It has been postulated that some of these tumors occur in cells that harbor upstream mutations in RAS, whereas others might result from alternate signaling through non-RAF oncogenic pathways.^9,12