Kevin Gendreau, MD, a weight loss doctor at Southcoast Health in Fall River, Maine, lets patients know that he was once obese. He says this knowledge inspires and motivates them to lose weight.

Courtesy Dr. Kevin Gendreau

After dropping 125 pounds over 18 months, “I can relate to their binges, hardships, and plateaus on a very personal level,” he says.

Peminda Cabandugama, MD, an endocrinologist and obesity medicine specialist at Truman Medical Center at the University of Missouri-Kansas City, has weighed between 180 and 240 pounds in the past decade. He now weighs 225 pounds and has a healthy lifestyle.

“I have had patients come to me saying, ‘I used to see a different weight loss doctor who was not heavy. But how can he understand what I’m going through?’” he says.

Dr. Cabandugama shares his weight loss struggles with patients “to dispel this myth that weight management is as simple as just eating too much and not exercising. It involves a smorgasbord of emotions and hormones, some within and outside of our control. I hope that sharing this allows me to connect more with my patients so that they know that even their health care professional goes through the same challenges that they do.”

“Patients are more likely to make behavior changes when doctors are supportive and have had similar experiences and talk about their stories,” says Wendy Bennett, MD, an obesity researcher and associate professor of medicine at Johns Hopkins University in Baltimore.

Do patients respect overweight doctors?

While Dr. Gendreau and Dr. Cabandugama have lost weight, some doctors who would like to shed unwanted pounds have been unable to do so. What impact does this have on patients?  

Doctors sometimes have biased attitudes toward overweight patients, but few studies have looked at whether patients have biases towards overweight doctors. The results vary and may depend on whether or not the patients are overweight. 

A random online survey of 358 participants suggested that regardless of their own weight, people had biases about doctor weight gain. They viewed the overweight or obese doctors as less trustworthy and credible, which could lead the participants to reject their medical advice and change doctors. 

“Patients expect doctors who are providing health care to be doing everything they can to take care of their own health and well-being,” says Pamela Peeke, MD, an assistant clinical professor of medicine at the University of Maryland in Baltimore.

“I am a physician who believes you have to walk the talk — that the best teachers are those who live it,” she says.

Still, “I don’t think based on this one experimental study that we can conclude that overweight physicians are harming patients’ efforts to change their behavior,” notes Dr. Bennett, who was not involved in the study.

“I think that patients do often want to connect with their physicians on more personal levels, but without the story behind where the advice is coming from, patients may struggle to trust a provider who seems to be contradicting the messages,” she says.

A study that Dr. Bennett helped lead suggests that patients are not biased against overweight doctors if they themselves need to lose weight. A national survey of 600 overweight patients showed that 87% trusted diet advice from overweight primary care doctors, compared to 77% who trusted diet advice from doctors who had a healthy weight.

“This shows that patients were more trusting of physicians who are more like them, which can lead to better relationships. We know from the studies on race that patients are often more trusting of physicians from the same race as them,” says Dr. Bennett.

Dr. Gendreau says that when he was severely obese, some patients questioned whether to trust his weight loss advice.

“It was very awkward when they turned to me and  said, ‘What about you?’ I would respond that it’s my job to inform them about the risks to their health,” he says.

Nearly half (48%) of doctors said they are trying to lose weight, according to the 2021 Medscape Physician Lifestyle and Happiness Report. As a result, many doctors may end up in the position of seemingly advising to “do what I say, not what I do.”

Nearly three in five Americans are trying to lose weight, according to Gelesis poll results released in December 2020.

Should doctors pay more attention to wellness?

Doctors have an ethical duty to maintain their own health and wellness so they can provide safe and effective medical care. If they don’t have a healthy lifestyle, they need to make adjustments, the American Medical Association Code of Ethics advises.

Dr. Peeke agrees with the AMA. “We signed on to do this — we have to go out of our way to carve out time, even if it’s just 15 minutes where we hide away and eat that healthy lunch that we brought with us,” she says.

Dr. Gendreau suggests busy doctors do what he did.

“I started by bringing healthy snacks — small Ziploc bags filled with mixed nuts and berries — and expanded from there. This way, if I got hungry or stressed between patients, I would have easy access to something nutritious,” he says.

He and Dr. Peeke also suggest making protein shakes or berry smoothies that are low in sugar.

“These can keep you full for hours as you sip them between patients,” says Dr. Gendreau.

Convincing busy doctors to make lifestyle changes may be challenging. Sixty-five percent of those who responded to the Physician Lifestyle and Happiness Report say that they sometimes, rarely, or never focus on their health and wellness. Only 45% said they are eating healthy, and 65% said they exercise.  

“Self-care isn’t a priority for most physicians because we are taught to take care of others and to put them first,” says Dr. Gendreau. “Like many doctors, I had so many other priorities — family, friends, career. Also, my last year of medical school was so difficult that my priority was finishing. I pushed my health to the side and told myself that I could fix this later.”

Only about one in five medical schools require students to take a nutrition course, according to David Eisenberg, MD, an adjunct associate professor of nutrition at the Harvard T.H. Chan School of Public Health, Boston.

“I didn’t get one ounce of nutrition training, which is the reason I became a Pew Foundation scholar in nutrition and metabolism. I had to go outside of my traditional training,” says Dr. Peeke.

“Physicians are not adequately trained to do the behavioral counseling and motivational interviewing that is needed,” says Dr. Bennett. “We do a good job of diagnosing obesity based on body mass index and understanding the relationship with future health conditions. But most doctors struggle with both a lack of time and the skill set to make significant behavior changes.”

“Medical school curriculum is focused so heavily on the pathology and pathophysiology of obesity, rather than how to prevent it with the appropriate diet and exercise regimen,” Dr. Gendreau says. “My physician patients often tell me that their own education in the field of nutrition is lacking, which can affect their weight loss journey and what they teach their patients.”

Dr. Gendreau, crediting his own weight loss journey as well as his obesity medicine fellowship, says his confidence in discussing weight loss with patients has soared.

Reframing obesity as a chronic disease

Rather than criticizing overweight people, including doctors, for their personal health choices, a better approach is to think of weight or obesity as a chronic illness, says Dr. Bennett.

“If we understand that obesity is a chronic health condition that people are struggling with, we can empathize with them,” she says, recommending that more providers share their weight loss journeys with patients they give lifestyle advice to, which may help address and repair potential biases.


A version of this article first appeared on WebMD.com.

Kevin Gendreau, MD, a weight loss doctor at Southcoast Health in Fall River, Maine, lets patients know that he was once obese. He says this knowledge inspires and motivates them to lose weight.

Courtesy Dr. Kevin Gendreau

After dropping 125 pounds over 18 months, “I can relate to their binges, hardships, and plateaus on a very personal level,” he says.

Peminda Cabandugama, MD, an endocrinologist and obesity medicine specialist at Truman Medical Center at the University of Missouri-Kansas City, has weighed between 180 and 240 pounds in the past decade. He now weighs 225 pounds and has a healthy lifestyle.

“I have had patients come to me saying, ‘I used to see a different weight loss doctor who was not heavy. But how can he understand what I’m going through?’” he says.

Dr. Cabandugama shares his weight loss struggles with patients “to dispel this myth that weight management is as simple as just eating too much and not exercising. It involves a smorgasbord of emotions and hormones, some within and outside of our control. I hope that sharing this allows me to connect more with my patients so that they know that even their health care professional goes through the same challenges that they do.”

“Patients are more likely to make behavior changes when doctors are supportive and have had similar experiences and talk about their stories,” says Wendy Bennett, MD, an obesity researcher and associate professor of medicine at Johns Hopkins University in Baltimore.

Do patients respect overweight doctors?

While Dr. Gendreau and Dr. Cabandugama have lost weight, some doctors who would like to shed unwanted pounds have been unable to do so. What impact does this have on patients?  

Doctors sometimes have biased attitudes toward overweight patients, but few studies have looked at whether patients have biases towards overweight doctors. The results vary and may depend on whether or not the patients are overweight. 

A random online survey of 358 participants suggested that regardless of their own weight, people had biases about doctor weight gain. They viewed the overweight or obese doctors as less trustworthy and credible, which could lead the participants to reject their medical advice and change doctors. 

“Patients expect doctors who are providing health care to be doing everything they can to take care of their own health and well-being,” says Pamela Peeke, MD, an assistant clinical professor of medicine at the University of Maryland in Baltimore.

“I am a physician who believes you have to walk the talk — that the best teachers are those who live it,” she says.

Still, “I don’t think based on this one experimental study that we can conclude that overweight physicians are harming patients’ efforts to change their behavior,” notes Dr. Bennett, who was not involved in the study.

“I think that patients do often want to connect with their physicians on more personal levels, but without the story behind where the advice is coming from, patients may struggle to trust a provider who seems to be contradicting the messages,” she says.

A study that Dr. Bennett helped lead suggests that patients are not biased against overweight doctors if they themselves need to lose weight. A national survey of 600 overweight patients showed that 87% trusted diet advice from overweight primary care doctors, compared to 77% who trusted diet advice from doctors who had a healthy weight.

“This shows that patients were more trusting of physicians who are more like them, which can lead to better relationships. We know from the studies on race that patients are often more trusting of physicians from the same race as them,” says Dr. Bennett.

Dr. Gendreau says that when he was severely obese, some patients questioned whether to trust his weight loss advice.

“It was very awkward when they turned to me and  said, ‘What about you?’ I would respond that it’s my job to inform them about the risks to their health,” he says.

Nearly half (48%) of doctors said they are trying to lose weight, according to the 2021 Medscape Physician Lifestyle and Happiness Report. As a result, many doctors may end up in the position of seemingly advising to “do what I say, not what I do.”

Nearly three in five Americans are trying to lose weight, according to Gelesis poll results released in December 2020.

Should doctors pay more attention to wellness?

Doctors have an ethical duty to maintain their own health and wellness so they can provide safe and effective medical care. If they don’t have a healthy lifestyle, they need to make adjustments, the American Medical Association Code of Ethics advises.

Dr. Peeke agrees with the AMA. “We signed on to do this — we have to go out of our way to carve out time, even if it’s just 15 minutes where we hide away and eat that healthy lunch that we brought with us,” she says.

Dr. Gendreau suggests busy doctors do what he did.

“I started by bringing healthy snacks — small Ziploc bags filled with mixed nuts and berries — and expanded from there. This way, if I got hungry or stressed between patients, I would have easy access to something nutritious,” he says.

He and Dr. Peeke also suggest making protein shakes or berry smoothies that are low in sugar.

“These can keep you full for hours as you sip them between patients,” says Dr. Gendreau.

Convincing busy doctors to make lifestyle changes may be challenging. Sixty-five percent of those who responded to the Physician Lifestyle and Happiness Report say that they sometimes, rarely, or never focus on their health and wellness. Only 45% said they are eating healthy, and 65% said they exercise.  

“Self-care isn’t a priority for most physicians because we are taught to take care of others and to put them first,” says Dr. Gendreau. “Like many doctors, I had so many other priorities — family, friends, career. Also, my last year of medical school was so difficult that my priority was finishing. I pushed my health to the side and told myself that I could fix this later.”

Only about one in five medical schools require students to take a nutrition course, according to David Eisenberg, MD, an adjunct associate professor of nutrition at the Harvard T.H. Chan School of Public Health, Boston.

“I didn’t get one ounce of nutrition training, which is the reason I became a Pew Foundation scholar in nutrition and metabolism. I had to go outside of my traditional training,” says Dr. Peeke.

“Physicians are not adequately trained to do the behavioral counseling and motivational interviewing that is needed,” says Dr. Bennett. “We do a good job of diagnosing obesity based on body mass index and understanding the relationship with future health conditions. But most doctors struggle with both a lack of time and the skill set to make significant behavior changes.”

“Medical school curriculum is focused so heavily on the pathology and pathophysiology of obesity, rather than how to prevent it with the appropriate diet and exercise regimen,” Dr. Gendreau says. “My physician patients often tell me that their own education in the field of nutrition is lacking, which can affect their weight loss journey and what they teach their patients.”

Dr. Gendreau, crediting his own weight loss journey as well as his obesity medicine fellowship, says his confidence in discussing weight loss with patients has soared.

Reframing obesity as a chronic disease

Rather than criticizing overweight people, including doctors, for their personal health choices, a better approach is to think of weight or obesity as a chronic illness, says Dr. Bennett.

“If we understand that obesity is a chronic health condition that people are struggling with, we can empathize with them,” she says, recommending that more providers share their weight loss journeys with patients they give lifestyle advice to, which may help address and repair potential biases.


A version of this article first appeared on WebMD.com.

Kevin Gendreau, MD, a weight loss doctor at Southcoast Health in Fall River, Maine, lets patients know that he was once obese. He says this knowledge inspires and motivates them to lose weight.

Courtesy Dr. Kevin Gendreau

After dropping 125 pounds over 18 months, “I can relate to their binges, hardships, and plateaus on a very personal level,” he says.

Peminda Cabandugama, MD, an endocrinologist and obesity medicine specialist at Truman Medical Center at the University of Missouri-Kansas City, has weighed between 180 and 240 pounds in the past decade. He now weighs 225 pounds and has a healthy lifestyle.

“I have had patients come to me saying, ‘I used to see a different weight loss doctor who was not heavy. But how can he understand what I’m going through?’” he says.

Dr. Cabandugama shares his weight loss struggles with patients “to dispel this myth that weight management is as simple as just eating too much and not exercising. It involves a smorgasbord of emotions and hormones, some within and outside of our control. I hope that sharing this allows me to connect more with my patients so that they know that even their health care professional goes through the same challenges that they do.”

“Patients are more likely to make behavior changes when doctors are supportive and have had similar experiences and talk about their stories,” says Wendy Bennett, MD, an obesity researcher and associate professor of medicine at Johns Hopkins University in Baltimore.

Do patients respect overweight doctors?

While Dr. Gendreau and Dr. Cabandugama have lost weight, some doctors who would like to shed unwanted pounds have been unable to do so. What impact does this have on patients?  

Doctors sometimes have biased attitudes toward overweight patients, but few studies have looked at whether patients have biases towards overweight doctors. The results vary and may depend on whether or not the patients are overweight. 

A random online survey of 358 participants suggested that regardless of their own weight, people had biases about doctor weight gain. They viewed the overweight or obese doctors as less trustworthy and credible, which could lead the participants to reject their medical advice and change doctors. 

“Patients expect doctors who are providing health care to be doing everything they can to take care of their own health and well-being,” says Pamela Peeke, MD, an assistant clinical professor of medicine at the University of Maryland in Baltimore.

“I am a physician who believes you have to walk the talk — that the best teachers are those who live it,” she says.

Still, “I don’t think based on this one experimental study that we can conclude that overweight physicians are harming patients’ efforts to change their behavior,” notes Dr. Bennett, who was not involved in the study.

“I think that patients do often want to connect with their physicians on more personal levels, but without the story behind where the advice is coming from, patients may struggle to trust a provider who seems to be contradicting the messages,” she says.

A study that Dr. Bennett helped lead suggests that patients are not biased against overweight doctors if they themselves need to lose weight. A national survey of 600 overweight patients showed that 87% trusted diet advice from overweight primary care doctors, compared to 77% who trusted diet advice from doctors who had a healthy weight.

“This shows that patients were more trusting of physicians who are more like them, which can lead to better relationships. We know from the studies on race that patients are often more trusting of physicians from the same race as them,” says Dr. Bennett.

Dr. Gendreau says that when he was severely obese, some patients questioned whether to trust his weight loss advice.

“It was very awkward when they turned to me and  said, ‘What about you?’ I would respond that it’s my job to inform them about the risks to their health,” he says.

Nearly half (48%) of doctors said they are trying to lose weight, according to the 2021 Medscape Physician Lifestyle and Happiness Report. As a result, many doctors may end up in the position of seemingly advising to “do what I say, not what I do.”

Nearly three in five Americans are trying to lose weight, according to Gelesis poll results released in December 2020.

Should doctors pay more attention to wellness?

Doctors have an ethical duty to maintain their own health and wellness so they can provide safe and effective medical care. If they don’t have a healthy lifestyle, they need to make adjustments, the American Medical Association Code of Ethics advises.

Dr. Peeke agrees with the AMA. “We signed on to do this — we have to go out of our way to carve out time, even if it’s just 15 minutes where we hide away and eat that healthy lunch that we brought with us,” she says.

Dr. Gendreau suggests busy doctors do what he did.

“I started by bringing healthy snacks — small Ziploc bags filled with mixed nuts and berries — and expanded from there. This way, if I got hungry or stressed between patients, I would have easy access to something nutritious,” he says.

He and Dr. Peeke also suggest making protein shakes or berry smoothies that are low in sugar.

“These can keep you full for hours as you sip them between patients,” says Dr. Gendreau.

Convincing busy doctors to make lifestyle changes may be challenging. Sixty-five percent of those who responded to the Physician Lifestyle and Happiness Report say that they sometimes, rarely, or never focus on their health and wellness. Only 45% said they are eating healthy, and 65% said they exercise.  

“Self-care isn’t a priority for most physicians because we are taught to take care of others and to put them first,” says Dr. Gendreau. “Like many doctors, I had so many other priorities — family, friends, career. Also, my last year of medical school was so difficult that my priority was finishing. I pushed my health to the side and told myself that I could fix this later.”

Only about one in five medical schools require students to take a nutrition course, according to David Eisenberg, MD, an adjunct associate professor of nutrition at the Harvard T.H. Chan School of Public Health, Boston.

“I didn’t get one ounce of nutrition training, which is the reason I became a Pew Foundation scholar in nutrition and metabolism. I had to go outside of my traditional training,” says Dr. Peeke.

“Physicians are not adequately trained to do the behavioral counseling and motivational interviewing that is needed,” says Dr. Bennett. “We do a good job of diagnosing obesity based on body mass index and understanding the relationship with future health conditions. But most doctors struggle with both a lack of time and the skill set to make significant behavior changes.”

“Medical school curriculum is focused so heavily on the pathology and pathophysiology of obesity, rather than how to prevent it with the appropriate diet and exercise regimen,” Dr. Gendreau says. “My physician patients often tell me that their own education in the field of nutrition is lacking, which can affect their weight loss journey and what they teach their patients.”

Dr. Gendreau, crediting his own weight loss journey as well as his obesity medicine fellowship, says his confidence in discussing weight loss with patients has soared.

Reframing obesity as a chronic disease

Rather than criticizing overweight people, including doctors, for their personal health choices, a better approach is to think of weight or obesity as a chronic illness, says Dr. Bennett.

“If we understand that obesity is a chronic health condition that people are struggling with, we can empathize with them,” she says, recommending that more providers share their weight loss journeys with patients they give lifestyle advice to, which may help address and repair potential biases.


A version of this article first appeared on WebMD.com.

After several weeks of outcry and heated debate over the Food and Drug Administration’s controversial approval of the Alzheimer’s drug aducanumab (Aduhelm), the head of the agency is now calling for a federal investigation into its own approval proceedings.

Janet Woodcock, MD, the FDA’s acting commissioner, sent a letter to the Office of the Inspector General on July 9, she announced in a tweet.

Dr. Woodcock is asking for an investigation into questionable meetings and other interactions between Biogen and FDA staff members prior to the drug’s approval that “may have occurred outside of the formal correspondence process.”

The letter explains that concerns around these issues “could undermine the public’s confidence in the FDA’s decision.” Therefore, an independent investigation is needed to determine whether anything occurred that was “inconsistent with FDA policies and procedures.”

Dr. Woodcock noted that she has “tremendous confidence in the integrity of the staff and leadership of the Center for Drug Evaluation and Research” involved in the review process.

However, “FDA is dedicated to scientific integrity, to reviewing data without bias, and to basing its regulatory decisions on data,” she wrote. “You have my personal commitment that the Agency will fully cooperate should your office undertake a review.”

Dr. Woodcock concluded by urging that a review be conducted as soon as possible, noting that “should such a review result in actionable items, you also have my commitment to addressing these issues.”

A version of this article first appeared on Medscape.com.

After several weeks of outcry and heated debate over the Food and Drug Administration’s controversial approval of the Alzheimer’s drug aducanumab (Aduhelm), the head of the agency is now calling for a federal investigation into its own approval proceedings.

Janet Woodcock, MD, the FDA’s acting commissioner, sent a letter to the Office of the Inspector General on July 9, she announced in a tweet.

Dr. Woodcock is asking for an investigation into questionable meetings and other interactions between Biogen and FDA staff members prior to the drug’s approval that “may have occurred outside of the formal correspondence process.”

The letter explains that concerns around these issues “could undermine the public’s confidence in the FDA’s decision.” Therefore, an independent investigation is needed to determine whether anything occurred that was “inconsistent with FDA policies and procedures.”

Dr. Woodcock noted that she has “tremendous confidence in the integrity of the staff and leadership of the Center for Drug Evaluation and Research” involved in the review process.

However, “FDA is dedicated to scientific integrity, to reviewing data without bias, and to basing its regulatory decisions on data,” she wrote. “You have my personal commitment that the Agency will fully cooperate should your office undertake a review.”

Dr. Woodcock concluded by urging that a review be conducted as soon as possible, noting that “should such a review result in actionable items, you also have my commitment to addressing these issues.”

A version of this article first appeared on Medscape.com.

After several weeks of outcry and heated debate over the Food and Drug Administration’s controversial approval of the Alzheimer’s drug aducanumab (Aduhelm), the head of the agency is now calling for a federal investigation into its own approval proceedings.

Janet Woodcock, MD, the FDA’s acting commissioner, sent a letter to the Office of the Inspector General on July 9, she announced in a tweet.

Dr. Woodcock is asking for an investigation into questionable meetings and other interactions between Biogen and FDA staff members prior to the drug’s approval that “may have occurred outside of the formal correspondence process.”

The letter explains that concerns around these issues “could undermine the public’s confidence in the FDA’s decision.” Therefore, an independent investigation is needed to determine whether anything occurred that was “inconsistent with FDA policies and procedures.”

Dr. Woodcock noted that she has “tremendous confidence in the integrity of the staff and leadership of the Center for Drug Evaluation and Research” involved in the review process.

However, “FDA is dedicated to scientific integrity, to reviewing data without bias, and to basing its regulatory decisions on data,” she wrote. “You have my personal commitment that the Agency will fully cooperate should your office undertake a review.”

Dr. Woodcock concluded by urging that a review be conducted as soon as possible, noting that “should such a review result in actionable items, you also have my commitment to addressing these issues.”

A version of this article first appeared on Medscape.com.

Some children are more susceptible to viral and bacterial respiratory infections in the first few years of life than others. However, the factors contributing to this susceptibility are incompletely understood. The pathogenesis, development, severity, and clinical outcomes of respiratory infections are largely dependent on the resident composition of the nasopharyngeal microbiome and immune defense.¹

Respiratory infections caused by bacteria and/or viruses are a leading cause of death in children in the United States and worldwide. The well-recognized, predominant causative bacteria are Streptococcus pneumoniae (pneumococcus), nontypeable Haemophilus influenzae (Hflu), and Moraxella catarrhalis (Mcat). Respiratory infections caused by these pathogens result in considerable morbidity, mortality, and account for high health care costs. The clinical and laboratory group that I lead in Rochester, N.Y., has been studying acute otitis media (AOM) etiology, epidemiology, pathogenesis, prevention, and treatment for over 3 decades. Our research findings are likely applicable and generalizable to understanding the pathogenesis and immune response to other infectious diseases induced by pneumococcus, Hflu, and Mcat since they are also key pathogens causing sinusitis and lung infections.

Previous immunologic analysis of children with AOM by our group provided clarity in differences between infection-prone children manifest as otitis prone (OP; often referred to in our publications as stringently defined OP because of the stringent diagnostic requirement of tympanocentesis-proven etiology of infection) and non-OP children. We showed that about 90% of OP children have deficient immune responses following nasopharyngeal colonization and AOM, demonstrated by inadequate innate responses and adaptive immune responses.² Many of these children also showed an increased propensity to viral upper respiratory infection and 30% fail to produce protective antibody responses after injection of routine pediatric vaccines.^3,4

In this column, I want to share new information regarding differences in the nasopharyngeal microbiome of children who are respiratory infection prone versus those who are non–respiratory infection prone and children with asthma versus those who do not exhibit that clinical phenotype. We performed a retrospective analysis of clinical samples collected from 358 children, aged 6 months to 5 years, from our prospectively enrolled cohort in Rochester, N.Y., to determine associations between AOM and other childhood respiratory illnesses and nasopharyngeal microbiota. In order to define subgroups of children within the cohort, we used a statistical method called unsupervised clustering analysis to see if relatively unique groups of children could be discerned. The overall cohort successfully clustered into two groups, showing marked differences in the prevalence of respiratory infections and asthma.⁵ We termed the two clinical phenotypes infection and asthma prone (n = 99, 28% of the children) and non–infection and asthma prone (n = 259, 72% of the children). Infection- and asthma-prone children were significantly more likely to experience recurrent AOM, influenza, sinusitis, pneumonia, asthma, and allergic rhinitis, compared with non–infection- and asthma-prone children (Figure).

The two groups did not experience significantly different rates of eczema, food allergy, skin infections, urinary tract infections, or acute gastroenteritis, suggesting a common thread involving the respiratory tract that did not cross over to the gastrointestinal, skin, or urinary tract. We found that age at first nasopharyngeal colonization with any of the three bacterial respiratory pathogens (pneumococcus, Hflu, or Mcat) was significantly associated with the respiratory infection– and asthma-prone clinical phenotype. Specifically, respiratory infection– and asthma-prone children experienced colonization at a significantly earlier age than nonprone children did for all three bacteria. In an analysis of individual conditions, early Mcat colonization significantly associated with pneumonia, sinusitis, and asthma susceptibility; Hflu with pneumonia, sinusitis, influenza, and allergic rhinitis; and pneumococcus with sinusitis.

Since early colonization with the three bacterial respiratory pathogens was strongly associated with respiratory illnesses and asthma, nasopharyngeal microbiome analysis was performed on an available subset of samples. Bacterial diversity trended lower in infection- and asthma-prone children, consistent with dysbiosis in the respiratory infection– and asthma-prone clinical phenotype. Nine different bacteria genera were found to be differentially abundant when comparing respiratory infection– and asthma-prone and nonprone children, pointing the way to possible interventions to make the respiratory infection– and asthma-prone child nasopharyngeal microbiome more like the nonprone child.

As I have written previously in this column, recent accumulating data have shed light on the importance of the human microbiome in modulating immune homeostasis and disease susceptibility.⁶ My group is working toward generating new knowledge for the long-term goal of identifying new therapeutic strategies to facilitate a protective, diverse nasopharyngeal microbiome (with appropriately tuned intranasal probiotics) to prevent respiratory pathogen colonization and/or subsequent progression to respiratory infection and asthma. Also, vaccines directed against colonization-enhancing members of the microbiome may provide a means to indirectly control respiratory pathogen nasopharyngeal colonization.

Dr. Pichichero is a specialist in pediatric infectious diseases and director of the Research Institute at Rochester (N.Y.) General Hospital. He has no conflicts to declare. Contact him at [email protected]

References

1. Man WH et al. Nat Rev Microbiol. 2017;15(5):259-70.

2. Pichichero ME. J Infect. 2020;80(6):614-22.

3. Ren D et al. Clin Infect Dis. 2019;68(9):1566-74.

4. Pichichero ME et al. Pediatr Infect Dis J. 2013;32(11):1163-8.

5. Chapman T et al. PLoS One. 2020 Dec 11;15(12).

6. Blaser MJ. The microbiome revolution. J Clin Invest. 2014;124:4162-5.

Some children are more susceptible to viral and bacterial respiratory infections in the first few years of life than others. However, the factors contributing to this susceptibility are incompletely understood. The pathogenesis, development, severity, and clinical outcomes of respiratory infections are largely dependent on the resident composition of the nasopharyngeal microbiome and immune defense.¹

Respiratory infections caused by bacteria and/or viruses are a leading cause of death in children in the United States and worldwide. The well-recognized, predominant causative bacteria are Streptococcus pneumoniae (pneumococcus), nontypeable Haemophilus influenzae (Hflu), and Moraxella catarrhalis (Mcat). Respiratory infections caused by these pathogens result in considerable morbidity, mortality, and account for high health care costs. The clinical and laboratory group that I lead in Rochester, N.Y., has been studying acute otitis media (AOM) etiology, epidemiology, pathogenesis, prevention, and treatment for over 3 decades. Our research findings are likely applicable and generalizable to understanding the pathogenesis and immune response to other infectious diseases induced by pneumococcus, Hflu, and Mcat since they are also key pathogens causing sinusitis and lung infections.

Previous immunologic analysis of children with AOM by our group provided clarity in differences between infection-prone children manifest as otitis prone (OP; often referred to in our publications as stringently defined OP because of the stringent diagnostic requirement of tympanocentesis-proven etiology of infection) and non-OP children. We showed that about 90% of OP children have deficient immune responses following nasopharyngeal colonization and AOM, demonstrated by inadequate innate responses and adaptive immune responses.² Many of these children also showed an increased propensity to viral upper respiratory infection and 30% fail to produce protective antibody responses after injection of routine pediatric vaccines.^3,4

In this column, I want to share new information regarding differences in the nasopharyngeal microbiome of children who are respiratory infection prone versus those who are non–respiratory infection prone and children with asthma versus those who do not exhibit that clinical phenotype. We performed a retrospective analysis of clinical samples collected from 358 children, aged 6 months to 5 years, from our prospectively enrolled cohort in Rochester, N.Y., to determine associations between AOM and other childhood respiratory illnesses and nasopharyngeal microbiota. In order to define subgroups of children within the cohort, we used a statistical method called unsupervised clustering analysis to see if relatively unique groups of children could be discerned. The overall cohort successfully clustered into two groups, showing marked differences in the prevalence of respiratory infections and asthma.⁵ We termed the two clinical phenotypes infection and asthma prone (n = 99, 28% of the children) and non–infection and asthma prone (n = 259, 72% of the children). Infection- and asthma-prone children were significantly more likely to experience recurrent AOM, influenza, sinusitis, pneumonia, asthma, and allergic rhinitis, compared with non–infection- and asthma-prone children (Figure).

The two groups did not experience significantly different rates of eczema, food allergy, skin infections, urinary tract infections, or acute gastroenteritis, suggesting a common thread involving the respiratory tract that did not cross over to the gastrointestinal, skin, or urinary tract. We found that age at first nasopharyngeal colonization with any of the three bacterial respiratory pathogens (pneumococcus, Hflu, or Mcat) was significantly associated with the respiratory infection– and asthma-prone clinical phenotype. Specifically, respiratory infection– and asthma-prone children experienced colonization at a significantly earlier age than nonprone children did for all three bacteria. In an analysis of individual conditions, early Mcat colonization significantly associated with pneumonia, sinusitis, and asthma susceptibility; Hflu with pneumonia, sinusitis, influenza, and allergic rhinitis; and pneumococcus with sinusitis.

Since early colonization with the three bacterial respiratory pathogens was strongly associated with respiratory illnesses and asthma, nasopharyngeal microbiome analysis was performed on an available subset of samples. Bacterial diversity trended lower in infection- and asthma-prone children, consistent with dysbiosis in the respiratory infection– and asthma-prone clinical phenotype. Nine different bacteria genera were found to be differentially abundant when comparing respiratory infection– and asthma-prone and nonprone children, pointing the way to possible interventions to make the respiratory infection– and asthma-prone child nasopharyngeal microbiome more like the nonprone child.

As I have written previously in this column, recent accumulating data have shed light on the importance of the human microbiome in modulating immune homeostasis and disease susceptibility.⁶ My group is working toward generating new knowledge for the long-term goal of identifying new therapeutic strategies to facilitate a protective, diverse nasopharyngeal microbiome (with appropriately tuned intranasal probiotics) to prevent respiratory pathogen colonization and/or subsequent progression to respiratory infection and asthma. Also, vaccines directed against colonization-enhancing members of the microbiome may provide a means to indirectly control respiratory pathogen nasopharyngeal colonization.

Dr. Pichichero is a specialist in pediatric infectious diseases and director of the Research Institute at Rochester (N.Y.) General Hospital. He has no conflicts to declare. Contact him at [email protected]

References

1. Man WH et al. Nat Rev Microbiol. 2017;15(5):259-70.

2. Pichichero ME. J Infect. 2020;80(6):614-22.

3. Ren D et al. Clin Infect Dis. 2019;68(9):1566-74.

4. Pichichero ME et al. Pediatr Infect Dis J. 2013;32(11):1163-8.

5. Chapman T et al. PLoS One. 2020 Dec 11;15(12).

6. Blaser MJ. The microbiome revolution. J Clin Invest. 2014;124:4162-5.

Some children are more susceptible to viral and bacterial respiratory infections in the first few years of life than others. However, the factors contributing to this susceptibility are incompletely understood. The pathogenesis, development, severity, and clinical outcomes of respiratory infections are largely dependent on the resident composition of the nasopharyngeal microbiome and immune defense.¹

Respiratory infections caused by bacteria and/or viruses are a leading cause of death in children in the United States and worldwide. The well-recognized, predominant causative bacteria are Streptococcus pneumoniae (pneumococcus), nontypeable Haemophilus influenzae (Hflu), and Moraxella catarrhalis (Mcat). Respiratory infections caused by these pathogens result in considerable morbidity, mortality, and account for high health care costs. The clinical and laboratory group that I lead in Rochester, N.Y., has been studying acute otitis media (AOM) etiology, epidemiology, pathogenesis, prevention, and treatment for over 3 decades. Our research findings are likely applicable and generalizable to understanding the pathogenesis and immune response to other infectious diseases induced by pneumococcus, Hflu, and Mcat since they are also key pathogens causing sinusitis and lung infections.

Previous immunologic analysis of children with AOM by our group provided clarity in differences between infection-prone children manifest as otitis prone (OP; often referred to in our publications as stringently defined OP because of the stringent diagnostic requirement of tympanocentesis-proven etiology of infection) and non-OP children. We showed that about 90% of OP children have deficient immune responses following nasopharyngeal colonization and AOM, demonstrated by inadequate innate responses and adaptive immune responses.² Many of these children also showed an increased propensity to viral upper respiratory infection and 30% fail to produce protective antibody responses after injection of routine pediatric vaccines.^3,4

In this column, I want to share new information regarding differences in the nasopharyngeal microbiome of children who are respiratory infection prone versus those who are non–respiratory infection prone and children with asthma versus those who do not exhibit that clinical phenotype. We performed a retrospective analysis of clinical samples collected from 358 children, aged 6 months to 5 years, from our prospectively enrolled cohort in Rochester, N.Y., to determine associations between AOM and other childhood respiratory illnesses and nasopharyngeal microbiota. In order to define subgroups of children within the cohort, we used a statistical method called unsupervised clustering analysis to see if relatively unique groups of children could be discerned. The overall cohort successfully clustered into two groups, showing marked differences in the prevalence of respiratory infections and asthma.⁵ We termed the two clinical phenotypes infection and asthma prone (n = 99, 28% of the children) and non–infection and asthma prone (n = 259, 72% of the children). Infection- and asthma-prone children were significantly more likely to experience recurrent AOM, influenza, sinusitis, pneumonia, asthma, and allergic rhinitis, compared with non–infection- and asthma-prone children (Figure).

The two groups did not experience significantly different rates of eczema, food allergy, skin infections, urinary tract infections, or acute gastroenteritis, suggesting a common thread involving the respiratory tract that did not cross over to the gastrointestinal, skin, or urinary tract. We found that age at first nasopharyngeal colonization with any of the three bacterial respiratory pathogens (pneumococcus, Hflu, or Mcat) was significantly associated with the respiratory infection– and asthma-prone clinical phenotype. Specifically, respiratory infection– and asthma-prone children experienced colonization at a significantly earlier age than nonprone children did for all three bacteria. In an analysis of individual conditions, early Mcat colonization significantly associated with pneumonia, sinusitis, and asthma susceptibility; Hflu with pneumonia, sinusitis, influenza, and allergic rhinitis; and pneumococcus with sinusitis.

Since early colonization with the three bacterial respiratory pathogens was strongly associated with respiratory illnesses and asthma, nasopharyngeal microbiome analysis was performed on an available subset of samples. Bacterial diversity trended lower in infection- and asthma-prone children, consistent with dysbiosis in the respiratory infection– and asthma-prone clinical phenotype. Nine different bacteria genera were found to be differentially abundant when comparing respiratory infection– and asthma-prone and nonprone children, pointing the way to possible interventions to make the respiratory infection– and asthma-prone child nasopharyngeal microbiome more like the nonprone child.

As I have written previously in this column, recent accumulating data have shed light on the importance of the human microbiome in modulating immune homeostasis and disease susceptibility.⁶ My group is working toward generating new knowledge for the long-term goal of identifying new therapeutic strategies to facilitate a protective, diverse nasopharyngeal microbiome (with appropriately tuned intranasal probiotics) to prevent respiratory pathogen colonization and/or subsequent progression to respiratory infection and asthma. Also, vaccines directed against colonization-enhancing members of the microbiome may provide a means to indirectly control respiratory pathogen nasopharyngeal colonization.

Dr. Pichichero is a specialist in pediatric infectious diseases and director of the Research Institute at Rochester (N.Y.) General Hospital. He has no conflicts to declare. Contact him at [email protected]

References

1. Man WH et al. Nat Rev Microbiol. 2017;15(5):259-70.

2. Pichichero ME. J Infect. 2020;80(6):614-22.

3. Ren D et al. Clin Infect Dis. 2019;68(9):1566-74.

4. Pichichero ME et al. Pediatr Infect Dis J. 2013;32(11):1163-8.

5. Chapman T et al. PLoS One. 2020 Dec 11;15(12).

6. Blaser MJ. The microbiome revolution. J Clin Invest. 2014;124:4162-5.

Some people recovering from COVID-19 fare worse than current or previous cancer patients when referred to outpatient rehabilitation services, a new study from the CDC demonstrates.

People experiencing ongoing or “long-haul” symptoms after COVID-19 illness were more likely to report pain, challenges with physical activities, and “substantially worse health,” compared with people needing rehabilitation because of cancer, lead author Jessica Rogers-Brown, PhD, and colleagues report.

The study was published online July 9 in Morbidity and Mortality Weekly Report (MMWR).

The CDC investigators compared the self-reported physical and mental health symptoms, physical endurance, and use of health services of 1,295 outpatients recovering from COVID-19 and a control group of another 2,395 outpatients rehabilitating from a previous or current cancer diagnosis who had not experienced COVID-19.

Researchers used electronic health record data from January 2020 to March 2021 in the Select Medical network of outpatient clinics. The study included patients from 36 states and the District of Columbia.

Compared with people referred for cancer rehabilitation, those with COVID-19 symptoms lasting beyond 4 weeks were 2.3 times more likely to report pain, 1.8 times more likely to report worse physical health, and 1.6 times more likely to report difficulty with physical activities, an adjusted odds ratio analysis reveals.

The COVID-19 rehabilitation group also performed significantly worse on a 6-minute walk test, suggesting less physical endurance than people recovering from cancer (P < .001). They also used more rehabilitation services overall than the control group.

The researchers suggest services tailored to the unique physical and mental health rehabilitation needs of the post–COVID-19 patient population could be warranted.

The study does not suggest all people recovering with COVID-19 will fare worse than people recovering from cancer, the authors caution. They note that “these results should not be interpreted to mean that post–COVID-19 patients overall had poorer physical and mental health than patients with cancer.”

“Instead, results indicate that post–COVID-19 patients specifically referred to a large physical rehabilitation network had poorer health measures than those referred for cancer, which indicates that some patients recovering from COVID-19 had substantial rehabilitation needs.”

A version of this article first appeared on Medscape.com.

Some people recovering from COVID-19 fare worse than current or previous cancer patients when referred to outpatient rehabilitation services, a new study from the CDC demonstrates.

People experiencing ongoing or “long-haul” symptoms after COVID-19 illness were more likely to report pain, challenges with physical activities, and “substantially worse health,” compared with people needing rehabilitation because of cancer, lead author Jessica Rogers-Brown, PhD, and colleagues report.

The study was published online July 9 in Morbidity and Mortality Weekly Report (MMWR).

The CDC investigators compared the self-reported physical and mental health symptoms, physical endurance, and use of health services of 1,295 outpatients recovering from COVID-19 and a control group of another 2,395 outpatients rehabilitating from a previous or current cancer diagnosis who had not experienced COVID-19.

Researchers used electronic health record data from January 2020 to March 2021 in the Select Medical network of outpatient clinics. The study included patients from 36 states and the District of Columbia.

Compared with people referred for cancer rehabilitation, those with COVID-19 symptoms lasting beyond 4 weeks were 2.3 times more likely to report pain, 1.8 times more likely to report worse physical health, and 1.6 times more likely to report difficulty with physical activities, an adjusted odds ratio analysis reveals.

The COVID-19 rehabilitation group also performed significantly worse on a 6-minute walk test, suggesting less physical endurance than people recovering from cancer (P < .001). They also used more rehabilitation services overall than the control group.

The researchers suggest services tailored to the unique physical and mental health rehabilitation needs of the post–COVID-19 patient population could be warranted.

The study does not suggest all people recovering with COVID-19 will fare worse than people recovering from cancer, the authors caution. They note that “these results should not be interpreted to mean that post–COVID-19 patients overall had poorer physical and mental health than patients with cancer.”

“Instead, results indicate that post–COVID-19 patients specifically referred to a large physical rehabilitation network had poorer health measures than those referred for cancer, which indicates that some patients recovering from COVID-19 had substantial rehabilitation needs.”

A version of this article first appeared on Medscape.com.

Some people recovering from COVID-19 fare worse than current or previous cancer patients when referred to outpatient rehabilitation services, a new study from the CDC demonstrates.

People experiencing ongoing or “long-haul” symptoms after COVID-19 illness were more likely to report pain, challenges with physical activities, and “substantially worse health,” compared with people needing rehabilitation because of cancer, lead author Jessica Rogers-Brown, PhD, and colleagues report.

The study was published online July 9 in Morbidity and Mortality Weekly Report (MMWR).

The CDC investigators compared the self-reported physical and mental health symptoms, physical endurance, and use of health services of 1,295 outpatients recovering from COVID-19 and a control group of another 2,395 outpatients rehabilitating from a previous or current cancer diagnosis who had not experienced COVID-19.

Researchers used electronic health record data from January 2020 to March 2021 in the Select Medical network of outpatient clinics. The study included patients from 36 states and the District of Columbia.

Compared with people referred for cancer rehabilitation, those with COVID-19 symptoms lasting beyond 4 weeks were 2.3 times more likely to report pain, 1.8 times more likely to report worse physical health, and 1.6 times more likely to report difficulty with physical activities, an adjusted odds ratio analysis reveals.

The COVID-19 rehabilitation group also performed significantly worse on a 6-minute walk test, suggesting less physical endurance than people recovering from cancer (P < .001). They also used more rehabilitation services overall than the control group.

The researchers suggest services tailored to the unique physical and mental health rehabilitation needs of the post–COVID-19 patient population could be warranted.

The study does not suggest all people recovering with COVID-19 will fare worse than people recovering from cancer, the authors caution. They note that “these results should not be interpreted to mean that post–COVID-19 patients overall had poorer physical and mental health than patients with cancer.”

“Instead, results indicate that post–COVID-19 patients specifically referred to a large physical rehabilitation network had poorer health measures than those referred for cancer, which indicates that some patients recovering from COVID-19 had substantial rehabilitation needs.”

A version of this article first appeared on Medscape.com.

Individuals of South Asian ancestry face twice the risk of heart disease, compared with individuals of European descent, yet existing risk calculators fail to account for this disparity, according to the results of a new study.

These findings confirm previous reports and practice guidelines that identify South Asian ancestry as a risk enhancer for atherosclerotic cardiovascular disease (ASCVD), suggesting that earlier heart disease screening and prevention is warranted in this patient population, lead author Aniruddh P. Patel, MD, research fellow at the Center for Genomic Medicine, Massachusetts General Hospital, Boston, and colleagues said.

“Previous studies in multiple countries have estimated a 1.7- to 4-fold higher risk of ASCVD among South Asian individuals, compared with other ancestries, but have important potential limitations,” Dr. Patel and colleagues wrote in the paper on their prospective cohort study, published in Circulation.

The INTERHEART case-control study, for example, which assessed risk factors for acute myocardial infarction among more than 15,000 cases from 52 countries, is now 2 decades old, and “may not reflect recent advances in cardiovascular disease prevention,” the investigators wrote.

Most studies in the area have been small and retrospective, they added, and have not adequately assessed emerging risk factors, such as prediabetes, which appear to play a relatively greater role in the development of heart disease among South Asians.
 

Methods and results

To address this knowledge gap, Dr. Patel and colleagues analyzed data from the UK Biobank prospective cohort study, including 449,349 middle-aged participants of European ancestry and 8,124 similarly aged participants of South Asian descent who did not have heart disease upon enrollment. Respective rates of incident ASCVD (i.e., MI, ischemic stroke, or coronary revascularization) were analyzed in the context of a variety of lifestyle, anthropometric, and clinical factors.

After a median follow-up of 11.1 years, individuals of South Asian descent had an incident ASCVD rate of 6.8%, compared with 4.4% for individuals of European descent, representing twice the relative risk (adjusted hazard ratio, 2.03; 95% CI, 1.86-2.22; P < .001). Even after accounting for all covariates, risk of ASCVD remained 45% higher for South Asian individuals (aHR, 1.45; 95% CI, 1.28-1.65; P < .001). This elevation in risk was not captured by existing risk calculators, including the American College of Cardiology/American Heart Association Pooled Cohort Equations, or the QRISK3 equations.

The findings were “largely consistent across a range of age, sex, and clinical subgroups,” and “confirm and extend previous reports that hypertension, diabetes, and central adiposity are the leading associations in this observed disparity,” the investigators wrote.
 

Two diabetes subtypes are more prevalent in South Asians

Hypertension, diabetes, and central adiposity do not fully explain South Asians’ higher risk for ASCVD, wrote Namratha R. Kandula, MD, of Northwestern University Medical Center, Chicago, and Alka M. Kanaya, MD, of the University of California, San Francisco, in an accompanying editorial published in Circulation.

Some of the undetected risk may stem from unique diabetes disease factors, Dr. Kandula and Dr. Kanaya added.

“Newer data have demonstrated distinct subtypes of type 2 diabetes, with South Asians having a higher prevalence of both a severe insulin resistant with obesity subtype and a less recognized severe insulin deficient subtype,” they wrote. “Importantly, both of these more prevalent diabetes subtypes in South Asians were associated with a higher incidence of coronary artery calcium, a marker of subclinical atherosclerosis and strong predictor of future ASCVD, compared to other diabetes subtypes.”
 

Diabetes rate is higher for South Asians in the U.S.

Although the present study was conducted in the United Kingdom, the findings likely apply to individuals of South Asian ancestry living in the United States, according to principal author Amit V. Khera, MD, associate director of the precision medicine unit at the Center for Genomic Medicine, Massachusetts General Hospital.

“There are already more than 5 million individuals of South Asian ancestry in the U.S. and this represents one of the fastest-growing ethnic subgroups,” Dr. Khera said in an interview. “As in our study of individuals in the U.K., South Asians in the U.S. suffer from diabetes at much higher rates – 23% versus 12% – and this often occurs even in the absence of obesity.”

Dr. Khera noted that the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease identify South Asian ancestry as a risk-enhancing factor, calling this a “stopgap measure.” More work is needed, he said, in the research arena and in the clinic.
 

Zero South Asians included in studies used to develop risk estimator

“I think the first step is to simply acknowledge that the risk estimators we use in clinical practice have important limitations when it comes to diverse patient populations,” Dr. Khera said in an interview. “We saw this in our study, where – despite a more than doubling of risk – the predicted risk based on the equations used in primary care showed no difference. This risk estimator was developed based on legacy cohort studies, in [which] zero South Asians were included. Despite important differences across race/ethnicity, the current state-of-the-art in the U.S. is to use one equation for Black individuals and another for all other ethnicities.”

Experts suggest steps for reducing heart disease risk

While risk modeling remains suboptimal, Dr. Khera suggested that clinicians can take immediate steps to reduce the risk of heart disease among individuals with South Asian ancestry.

“Despite all of the uncertainty – we still don’t have a complete understanding of why the risk is so high – there are still several things primary care doctors can do for their patients,” Dr. Khera said.

Foremost, he recommended lifestyle and dietary counseling.

“Dietary counseling is particularly effective if put in the context of cultural norms,” Dr. Khera said. “Many South Asians consider fruit juices or white rice to be healthy, when they lead to rapid spikes in blood sugar.”

Dr. Khera also advised earlier heart disease screening, such as coronary calcium scanning “sometime between age 40-50 years,” noting that positive test results may motivate patients to start or adhere to medications, such as cholesterol-lowering therapies. If necessary, clinicians can also refer to heart centers for South Asian patients, which are becoming increasingly common.

According to Cheryl A.M. Anderson, PhD, chair of the AHA’s Council on Epidemiology and Prevention, and professor and dean of the Herbert Wertheim School of Public Health and Human Longevity Science at the University of California, San Diego, the current study suggests that heart disease management strategies for South Asian patients may be lacking.

“We have had a tradition of preventing or trying to treat heart disease in a fashion that doesn’t yet account for the increased risk that might be prevalent in those of South Asian ancestry,” Dr. Anderson said in an interview.

She suggested that improving associated risk-analysis tools could be beneficial, although the tools themselves, in the context of race or ethnicity, may present their own risks.

“We want to be mindful of potential adverse implications from having everything linked to one’s ancestry, which I think this tool doesn’t do,” Dr. Anderson said, referring to the AHA/ACC Pooled Cohort Equations. “But in sort of the bigger picture of things, we always want to expand and refine our toolkit.”

According to Rajesh Dash, MD, PhD, associate professor, cardiologist, and director of the South Asian Translational Heart Initiative (SSATHI) Prevention Clinic and CardioClick Telemedicine Clinic at Stanford (Calif.) HealthCare, the science supports more active risk mitigation strategies for South Asian patients, and the AHA and the ACC “are the two entities that need to lead the way.”

“Certainly the American Heart Association and the American College of Cardiology should be taking a more active leadership role in this,” Dr. Dash said in an interview.

In 2018, the AHA issued a scientific statement about the elevated risk of ASCVD among South Asian individuals, “but it did not rise to the level of specific recommendations, and did not necessarily go as far as to incorporate new screening parameters for that population,” Dr. Dash said. He also noted that the most recent AHA/ACC guideline identifies South Asian ancestry as a risk-enhancing feature, a statement similarly lacking in actionable value.

“That does not definitively lead someone like a primary care physician to a decision to start a statin, or to be more aggressive with a diagnostic workup, like a stress test, for instance, for a patient who they otherwise would not have done one in had they not been South Asian,” Dr. Dash said.

The steps taken by the AHA and the ACC are “a healthy step forward,” he noted, “but not nearly the degree of attention or vigilance that is required, as well as the level of action that is required to change the narrative for the population.”

At the SSATHI Prevention Clinic, Dr. Dash and colleagues aren’t waiting for the narrative to change, and are already taking a more aggressive approach.

The clinic has an average patient age of 41 years, “easily 15 years younger than the average age in most cardiology clinics,” Dr. Dash said, based on the fact that approximately two-thirds of heart attacks in South Asian individuals occur under the age of 55. “We have to look earlier.”

The SSATHI Prevention Clinic screens for both traditional and emerging risk factors, and Dr. Dash suggested that primary care doctors should do the same.

“If you have a South Asian patient as a primary care physician, you should be aggressively looking for risk factors, traditional ones to start, like elevated cholesterol, hypertension, diabetes, or – and I would argue strongly – prediabetes or insulin resistance.”

Dr. Dash also recommended looking into family history, and considering screening for inflammatory biomarkers, the latter of which are commonly elevated at an earlier age among South Asian individuals, and may have a relatively greater prognostic impact.

To encourage broader implementation of this kind of approach, Dr. Dash called for more large-scale studies. Ideally, these would be randomized clinical trials, but, realistically, real-world datasets may be the answer.

The study was supported by the National Heart, Lung, and Blood Institute; the Broad Institute at MIT and Harvard; the National Human Genome Research Institute; and others. The investigators disclosed relationships with IBM Research, Sanofi, Amgen, and others. Dr. Dash disclosed relationships with HealthPals and AstraZeneca. Dr. Anderson reported no relevant conflicts of interest.

Individuals of South Asian ancestry face twice the risk of heart disease, compared with individuals of European descent, yet existing risk calculators fail to account for this disparity, according to the results of a new study.

These findings confirm previous reports and practice guidelines that identify South Asian ancestry as a risk enhancer for atherosclerotic cardiovascular disease (ASCVD), suggesting that earlier heart disease screening and prevention is warranted in this patient population, lead author Aniruddh P. Patel, MD, research fellow at the Center for Genomic Medicine, Massachusetts General Hospital, Boston, and colleagues said.

“Previous studies in multiple countries have estimated a 1.7- to 4-fold higher risk of ASCVD among South Asian individuals, compared with other ancestries, but have important potential limitations,” Dr. Patel and colleagues wrote in the paper on their prospective cohort study, published in Circulation.

The INTERHEART case-control study, for example, which assessed risk factors for acute myocardial infarction among more than 15,000 cases from 52 countries, is now 2 decades old, and “may not reflect recent advances in cardiovascular disease prevention,” the investigators wrote.

Most studies in the area have been small and retrospective, they added, and have not adequately assessed emerging risk factors, such as prediabetes, which appear to play a relatively greater role in the development of heart disease among South Asians.
 

Methods and results

To address this knowledge gap, Dr. Patel and colleagues analyzed data from the UK Biobank prospective cohort study, including 449,349 middle-aged participants of European ancestry and 8,124 similarly aged participants of South Asian descent who did not have heart disease upon enrollment. Respective rates of incident ASCVD (i.e., MI, ischemic stroke, or coronary revascularization) were analyzed in the context of a variety of lifestyle, anthropometric, and clinical factors.

After a median follow-up of 11.1 years, individuals of South Asian descent had an incident ASCVD rate of 6.8%, compared with 4.4% for individuals of European descent, representing twice the relative risk (adjusted hazard ratio, 2.03; 95% CI, 1.86-2.22; P < .001). Even after accounting for all covariates, risk of ASCVD remained 45% higher for South Asian individuals (aHR, 1.45; 95% CI, 1.28-1.65; P < .001). This elevation in risk was not captured by existing risk calculators, including the American College of Cardiology/American Heart Association Pooled Cohort Equations, or the QRISK3 equations.

The findings were “largely consistent across a range of age, sex, and clinical subgroups,” and “confirm and extend previous reports that hypertension, diabetes, and central adiposity are the leading associations in this observed disparity,” the investigators wrote.
 

Two diabetes subtypes are more prevalent in South Asians

Hypertension, diabetes, and central adiposity do not fully explain South Asians’ higher risk for ASCVD, wrote Namratha R. Kandula, MD, of Northwestern University Medical Center, Chicago, and Alka M. Kanaya, MD, of the University of California, San Francisco, in an accompanying editorial published in Circulation.

Some of the undetected risk may stem from unique diabetes disease factors, Dr. Kandula and Dr. Kanaya added.

“Newer data have demonstrated distinct subtypes of type 2 diabetes, with South Asians having a higher prevalence of both a severe insulin resistant with obesity subtype and a less recognized severe insulin deficient subtype,” they wrote. “Importantly, both of these more prevalent diabetes subtypes in South Asians were associated with a higher incidence of coronary artery calcium, a marker of subclinical atherosclerosis and strong predictor of future ASCVD, compared to other diabetes subtypes.”
 

Diabetes rate is higher for South Asians in the U.S.

Although the present study was conducted in the United Kingdom, the findings likely apply to individuals of South Asian ancestry living in the United States, according to principal author Amit V. Khera, MD, associate director of the precision medicine unit at the Center for Genomic Medicine, Massachusetts General Hospital.

“There are already more than 5 million individuals of South Asian ancestry in the U.S. and this represents one of the fastest-growing ethnic subgroups,” Dr. Khera said in an interview. “As in our study of individuals in the U.K., South Asians in the U.S. suffer from diabetes at much higher rates – 23% versus 12% – and this often occurs even in the absence of obesity.”

Dr. Khera noted that the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease identify South Asian ancestry as a risk-enhancing factor, calling this a “stopgap measure.” More work is needed, he said, in the research arena and in the clinic.
 

Zero South Asians included in studies used to develop risk estimator

“I think the first step is to simply acknowledge that the risk estimators we use in clinical practice have important limitations when it comes to diverse patient populations,” Dr. Khera said in an interview. “We saw this in our study, where – despite a more than doubling of risk – the predicted risk based on the equations used in primary care showed no difference. This risk estimator was developed based on legacy cohort studies, in [which] zero South Asians were included. Despite important differences across race/ethnicity, the current state-of-the-art in the U.S. is to use one equation for Black individuals and another for all other ethnicities.”

Experts suggest steps for reducing heart disease risk

While risk modeling remains suboptimal, Dr. Khera suggested that clinicians can take immediate steps to reduce the risk of heart disease among individuals with South Asian ancestry.

“Despite all of the uncertainty – we still don’t have a complete understanding of why the risk is so high – there are still several things primary care doctors can do for their patients,” Dr. Khera said.

Foremost, he recommended lifestyle and dietary counseling.

“Dietary counseling is particularly effective if put in the context of cultural norms,” Dr. Khera said. “Many South Asians consider fruit juices or white rice to be healthy, when they lead to rapid spikes in blood sugar.”

Dr. Khera also advised earlier heart disease screening, such as coronary calcium scanning “sometime between age 40-50 years,” noting that positive test results may motivate patients to start or adhere to medications, such as cholesterol-lowering therapies. If necessary, clinicians can also refer to heart centers for South Asian patients, which are becoming increasingly common.

According to Cheryl A.M. Anderson, PhD, chair of the AHA’s Council on Epidemiology and Prevention, and professor and dean of the Herbert Wertheim School of Public Health and Human Longevity Science at the University of California, San Diego, the current study suggests that heart disease management strategies for South Asian patients may be lacking.

“We have had a tradition of preventing or trying to treat heart disease in a fashion that doesn’t yet account for the increased risk that might be prevalent in those of South Asian ancestry,” Dr. Anderson said in an interview.

She suggested that improving associated risk-analysis tools could be beneficial, although the tools themselves, in the context of race or ethnicity, may present their own risks.

“We want to be mindful of potential adverse implications from having everything linked to one’s ancestry, which I think this tool doesn’t do,” Dr. Anderson said, referring to the AHA/ACC Pooled Cohort Equations. “But in sort of the bigger picture of things, we always want to expand and refine our toolkit.”

According to Rajesh Dash, MD, PhD, associate professor, cardiologist, and director of the South Asian Translational Heart Initiative (SSATHI) Prevention Clinic and CardioClick Telemedicine Clinic at Stanford (Calif.) HealthCare, the science supports more active risk mitigation strategies for South Asian patients, and the AHA and the ACC “are the two entities that need to lead the way.”

“Certainly the American Heart Association and the American College of Cardiology should be taking a more active leadership role in this,” Dr. Dash said in an interview.

In 2018, the AHA issued a scientific statement about the elevated risk of ASCVD among South Asian individuals, “but it did not rise to the level of specific recommendations, and did not necessarily go as far as to incorporate new screening parameters for that population,” Dr. Dash said. He also noted that the most recent AHA/ACC guideline identifies South Asian ancestry as a risk-enhancing feature, a statement similarly lacking in actionable value.

“That does not definitively lead someone like a primary care physician to a decision to start a statin, or to be more aggressive with a diagnostic workup, like a stress test, for instance, for a patient who they otherwise would not have done one in had they not been South Asian,” Dr. Dash said.

The steps taken by the AHA and the ACC are “a healthy step forward,” he noted, “but not nearly the degree of attention or vigilance that is required, as well as the level of action that is required to change the narrative for the population.”

At the SSATHI Prevention Clinic, Dr. Dash and colleagues aren’t waiting for the narrative to change, and are already taking a more aggressive approach.

The clinic has an average patient age of 41 years, “easily 15 years younger than the average age in most cardiology clinics,” Dr. Dash said, based on the fact that approximately two-thirds of heart attacks in South Asian individuals occur under the age of 55. “We have to look earlier.”

The SSATHI Prevention Clinic screens for both traditional and emerging risk factors, and Dr. Dash suggested that primary care doctors should do the same.

“If you have a South Asian patient as a primary care physician, you should be aggressively looking for risk factors, traditional ones to start, like elevated cholesterol, hypertension, diabetes, or – and I would argue strongly – prediabetes or insulin resistance.”

Dr. Dash also recommended looking into family history, and considering screening for inflammatory biomarkers, the latter of which are commonly elevated at an earlier age among South Asian individuals, and may have a relatively greater prognostic impact.

To encourage broader implementation of this kind of approach, Dr. Dash called for more large-scale studies. Ideally, these would be randomized clinical trials, but, realistically, real-world datasets may be the answer.

The study was supported by the National Heart, Lung, and Blood Institute; the Broad Institute at MIT and Harvard; the National Human Genome Research Institute; and others. The investigators disclosed relationships with IBM Research, Sanofi, Amgen, and others. Dr. Dash disclosed relationships with HealthPals and AstraZeneca. Dr. Anderson reported no relevant conflicts of interest.

Individuals of South Asian ancestry face twice the risk of heart disease, compared with individuals of European descent, yet existing risk calculators fail to account for this disparity, according to the results of a new study.

These findings confirm previous reports and practice guidelines that identify South Asian ancestry as a risk enhancer for atherosclerotic cardiovascular disease (ASCVD), suggesting that earlier heart disease screening and prevention is warranted in this patient population, lead author Aniruddh P. Patel, MD, research fellow at the Center for Genomic Medicine, Massachusetts General Hospital, Boston, and colleagues said.

“Previous studies in multiple countries have estimated a 1.7- to 4-fold higher risk of ASCVD among South Asian individuals, compared with other ancestries, but have important potential limitations,” Dr. Patel and colleagues wrote in the paper on their prospective cohort study, published in Circulation.

The INTERHEART case-control study, for example, which assessed risk factors for acute myocardial infarction among more than 15,000 cases from 52 countries, is now 2 decades old, and “may not reflect recent advances in cardiovascular disease prevention,” the investigators wrote.

Most studies in the area have been small and retrospective, they added, and have not adequately assessed emerging risk factors, such as prediabetes, which appear to play a relatively greater role in the development of heart disease among South Asians.
 

Methods and results

To address this knowledge gap, Dr. Patel and colleagues analyzed data from the UK Biobank prospective cohort study, including 449,349 middle-aged participants of European ancestry and 8,124 similarly aged participants of South Asian descent who did not have heart disease upon enrollment. Respective rates of incident ASCVD (i.e., MI, ischemic stroke, or coronary revascularization) were analyzed in the context of a variety of lifestyle, anthropometric, and clinical factors.

After a median follow-up of 11.1 years, individuals of South Asian descent had an incident ASCVD rate of 6.8%, compared with 4.4% for individuals of European descent, representing twice the relative risk (adjusted hazard ratio, 2.03; 95% CI, 1.86-2.22; P < .001). Even after accounting for all covariates, risk of ASCVD remained 45% higher for South Asian individuals (aHR, 1.45; 95% CI, 1.28-1.65; P < .001). This elevation in risk was not captured by existing risk calculators, including the American College of Cardiology/American Heart Association Pooled Cohort Equations, or the QRISK3 equations.

The findings were “largely consistent across a range of age, sex, and clinical subgroups,” and “confirm and extend previous reports that hypertension, diabetes, and central adiposity are the leading associations in this observed disparity,” the investigators wrote.
 

Two diabetes subtypes are more prevalent in South Asians

Hypertension, diabetes, and central adiposity do not fully explain South Asians’ higher risk for ASCVD, wrote Namratha R. Kandula, MD, of Northwestern University Medical Center, Chicago, and Alka M. Kanaya, MD, of the University of California, San Francisco, in an accompanying editorial published in Circulation.

Some of the undetected risk may stem from unique diabetes disease factors, Dr. Kandula and Dr. Kanaya added.

“Newer data have demonstrated distinct subtypes of type 2 diabetes, with South Asians having a higher prevalence of both a severe insulin resistant with obesity subtype and a less recognized severe insulin deficient subtype,” they wrote. “Importantly, both of these more prevalent diabetes subtypes in South Asians were associated with a higher incidence of coronary artery calcium, a marker of subclinical atherosclerosis and strong predictor of future ASCVD, compared to other diabetes subtypes.”
 

Diabetes rate is higher for South Asians in the U.S.

Although the present study was conducted in the United Kingdom, the findings likely apply to individuals of South Asian ancestry living in the United States, according to principal author Amit V. Khera, MD, associate director of the precision medicine unit at the Center for Genomic Medicine, Massachusetts General Hospital.

“There are already more than 5 million individuals of South Asian ancestry in the U.S. and this represents one of the fastest-growing ethnic subgroups,” Dr. Khera said in an interview. “As in our study of individuals in the U.K., South Asians in the U.S. suffer from diabetes at much higher rates – 23% versus 12% – and this often occurs even in the absence of obesity.”

Dr. Khera noted that the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease identify South Asian ancestry as a risk-enhancing factor, calling this a “stopgap measure.” More work is needed, he said, in the research arena and in the clinic.
 

Zero South Asians included in studies used to develop risk estimator

“I think the first step is to simply acknowledge that the risk estimators we use in clinical practice have important limitations when it comes to diverse patient populations,” Dr. Khera said in an interview. “We saw this in our study, where – despite a more than doubling of risk – the predicted risk based on the equations used in primary care showed no difference. This risk estimator was developed based on legacy cohort studies, in [which] zero South Asians were included. Despite important differences across race/ethnicity, the current state-of-the-art in the U.S. is to use one equation for Black individuals and another for all other ethnicities.”

Experts suggest steps for reducing heart disease risk

While risk modeling remains suboptimal, Dr. Khera suggested that clinicians can take immediate steps to reduce the risk of heart disease among individuals with South Asian ancestry.

“Despite all of the uncertainty – we still don’t have a complete understanding of why the risk is so high – there are still several things primary care doctors can do for their patients,” Dr. Khera said.

Foremost, he recommended lifestyle and dietary counseling.

“Dietary counseling is particularly effective if put in the context of cultural norms,” Dr. Khera said. “Many South Asians consider fruit juices or white rice to be healthy, when they lead to rapid spikes in blood sugar.”

Dr. Khera also advised earlier heart disease screening, such as coronary calcium scanning “sometime between age 40-50 years,” noting that positive test results may motivate patients to start or adhere to medications, such as cholesterol-lowering therapies. If necessary, clinicians can also refer to heart centers for South Asian patients, which are becoming increasingly common.

According to Cheryl A.M. Anderson, PhD, chair of the AHA’s Council on Epidemiology and Prevention, and professor and dean of the Herbert Wertheim School of Public Health and Human Longevity Science at the University of California, San Diego, the current study suggests that heart disease management strategies for South Asian patients may be lacking.

“We have had a tradition of preventing or trying to treat heart disease in a fashion that doesn’t yet account for the increased risk that might be prevalent in those of South Asian ancestry,” Dr. Anderson said in an interview.

She suggested that improving associated risk-analysis tools could be beneficial, although the tools themselves, in the context of race or ethnicity, may present their own risks.

“We want to be mindful of potential adverse implications from having everything linked to one’s ancestry, which I think this tool doesn’t do,” Dr. Anderson said, referring to the AHA/ACC Pooled Cohort Equations. “But in sort of the bigger picture of things, we always want to expand and refine our toolkit.”

According to Rajesh Dash, MD, PhD, associate professor, cardiologist, and director of the South Asian Translational Heart Initiative (SSATHI) Prevention Clinic and CardioClick Telemedicine Clinic at Stanford (Calif.) HealthCare, the science supports more active risk mitigation strategies for South Asian patients, and the AHA and the ACC “are the two entities that need to lead the way.”

“Certainly the American Heart Association and the American College of Cardiology should be taking a more active leadership role in this,” Dr. Dash said in an interview.

In 2018, the AHA issued a scientific statement about the elevated risk of ASCVD among South Asian individuals, “but it did not rise to the level of specific recommendations, and did not necessarily go as far as to incorporate new screening parameters for that population,” Dr. Dash said. He also noted that the most recent AHA/ACC guideline identifies South Asian ancestry as a risk-enhancing feature, a statement similarly lacking in actionable value.

“That does not definitively lead someone like a primary care physician to a decision to start a statin, or to be more aggressive with a diagnostic workup, like a stress test, for instance, for a patient who they otherwise would not have done one in had they not been South Asian,” Dr. Dash said.

The steps taken by the AHA and the ACC are “a healthy step forward,” he noted, “but not nearly the degree of attention or vigilance that is required, as well as the level of action that is required to change the narrative for the population.”

At the SSATHI Prevention Clinic, Dr. Dash and colleagues aren’t waiting for the narrative to change, and are already taking a more aggressive approach.

The clinic has an average patient age of 41 years, “easily 15 years younger than the average age in most cardiology clinics,” Dr. Dash said, based on the fact that approximately two-thirds of heart attacks in South Asian individuals occur under the age of 55. “We have to look earlier.”

The SSATHI Prevention Clinic screens for both traditional and emerging risk factors, and Dr. Dash suggested that primary care doctors should do the same.

“If you have a South Asian patient as a primary care physician, you should be aggressively looking for risk factors, traditional ones to start, like elevated cholesterol, hypertension, diabetes, or – and I would argue strongly – prediabetes or insulin resistance.”

Dr. Dash also recommended looking into family history, and considering screening for inflammatory biomarkers, the latter of which are commonly elevated at an earlier age among South Asian individuals, and may have a relatively greater prognostic impact.

To encourage broader implementation of this kind of approach, Dr. Dash called for more large-scale studies. Ideally, these would be randomized clinical trials, but, realistically, real-world datasets may be the answer.

The study was supported by the National Heart, Lung, and Blood Institute; the Broad Institute at MIT and Harvard; the National Human Genome Research Institute; and others. The investigators disclosed relationships with IBM Research, Sanofi, Amgen, and others. Dr. Dash disclosed relationships with HealthPals and AstraZeneca. Dr. Anderson reported no relevant conflicts of interest.

Support for a cardiovascular benefit of omega-3 fatty acids, particularly eicosapentaenoic acid (EPA), has come from a new systematic review and meta-analysis of randomized trials.

The meta-analysis of 38 randomized controlled trials found that omega-3 fatty acids improved cardiovascular outcomes, with a greater reduction in cardiovascular risk in studies of EPA alone rather than of combined eicosapentaenoic plus docosahexaenoic acid (DHA) supplements.

The paper was published online in EClinicalMedicine.

Senior author Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, was also lead investigator of the REDUCE-IT trial, which is included in the analysis and showed a 25% relative risk reduction in major cardiovascular events with a high-dose EPA product.

But the REDUCE-IT trial has been mired in controversy, with suggestions that the benefit seen might have been exaggerated because of the use of a harmful placebo. In addition, a second large trial of high-dose omega-3 fatty acids, STRENGTH (which tested a combination EPA/DHA product) showed no benefit on cardiovascular outcomes.

Dr. Bhatt said the new meta-analysis provides “a totality of evidence” that “supports a robust and consistent benefit of EPA.”

In the review, the authors concluded: “In this systematic review and meta-analysis, we noted moderate certainty of evidence favoring omega-3 fatty acids for reducing cardiovascular mortality and outcomes. ... The magnitude of relative reductions was robust in EPA trials versus those of EPA+DHA, suggesting differential effects of EPA and DHA in cardiovascular risk reduction.”
 

Controversy continues

But commenting on the publication for an interview, Steven Nissen, MD, Cleveland Clinic, who led the STRENGTH trial, pointed out that 85% of the EPA data in the new meta-analysis came from REDUCE-IT, so the results were a “foregone conclusion.”

“The purpose of a meta-analysis is to answer scientific questions when existing studies are too small to yield statistically robust results. That is not the case here,” Dr. Nissen stated.

He added: “There are only two major trials of EPA and both have important flaws. REDUCE-IT used a questionable placebo (mineral oil) and JELIS was an open-label trial that studied patients with baseline LDL [cholesterol] of 180 mg/dL that was not appropriately treated. A meta-analysis is only as good as the studies that it includes. The other EPA plus DHA studies were essentially neutral.”

Dr. Bhatt responded that, “to date, every randomized trial of EPA only has been positive. Some have been placebo controlled, some have been open label. This meta-analysis corroborates the results of each of those trials in a statistically robust way.”

He added: “Of course, REDUCE-IT is the most rigorous, contemporary trial of EPA. However, in our meta-analysis, even when excluding REDUCE-IT (or for that matter, JELIS), the EPA trials still significantly reduced cardiovascular events.”

Dr. Bhatt also pointed out that two randomized imaging studies, CHERRY and EVAPORATE, have shown benefits of EPA.

“Beyond the clinical trial data, there is a growing amount of evidence supporting the unique biological actions of different omega-3 fatty acids. EPA, in particular, appears to have the strongest basic science evidence supporting cardiovascular benefits. Overall, it is a remarkably consistent scientific story in support of EPA’s beneficial effects on cardiovascular health,” he stated.
 

38 trials included

For the current paper, Dr. Bhatt and coauthors performed a comprehensive literature search for randomized trials comparing omega-3 fatty acids with control (placebo, no supplementation, or lower dose of omega-3 fatty acids) in adults, with a follow-up of at least 12 months, and mortality and cardiovascular outcomes as endpoints.

Ultimately, 38 trials encompassing 149,051 patients were included. Of these, four trials compared EPA with control, 34 trials compared EPA+DHA with control, and 22 trials were in primary prevention. The dose of omega-3 fatty acids ranged from 0.4 g/day to 5.5 g/day.

A total of 25 trials with 143,514 individuals reported 5,550 events of cardiovascular mortality, and 24 trials with 140,983 individuals reported 10,795 events of all-cause mortality.

Omega-3 fatty acids were associated with reduced cardiovascular mortality (rate ratio, 0.93; P = .01), but not all-cause mortality (RR, 0.97; P = .27). The meta-analysis showed reduction in cardiovascular mortality with EPA monotherapy (RR, 0.82; P = .04) and EPA+DHA combination (RR, 0.94; P = .02).

A total of 20 trials with 125,611 individuals reported 2,989 nonfatal myocardial infarction events, and 29 trials with 144,384 individuals reported 9,153 coronary heart disease (CHD) events.

Omega-3 fatty acids were associated with reducing nonfatal MI (RR, 0.87; P = .0001) and CHD (RR, 0.91; P = .0002). The meta-analysis showed higher risk reductions in nonfatal MI with EPA monotherapy (RR, 0.72; P = .00002) than with EPA+DHA combination (RR, 0.92; P = .05), and also for CHD events with EPA monotherapy (RR, 0.73; P = .00004) than with EPA+DHA combination (RR, 0.94; P = .01).

A total of 17 trials (n = 135,019) reported 13,234 events of MACE, and 13 trials (n = 117,890) reported 7,416 events of revascularization.

Omega-3 fatty acids were associated with reducing MACE (RR, 0.95; P = .002) and revascularization (RR, 0.91; P = .0001). The meta-analysis showed higher risk reductions in MACE with EPA monotherapy (RR, 0.78; P = .00000001), whereas EPA+DHA combination did not reduce MACE (RR, 0.99; P = .48). This effect was consistent for revascularization.

A total of eight trials with 65,404 individuals reported 935 nonfatal strokes, and eight trials with 51,336 individuals reported 1,572 events of atrial fibrillation (AFib).

Omega-3 fatty acids did not significantly reduce nonfatal stroke (RR, 1.04; P = .55), but EPA monotherapy was associated with a reduction of nonfatal stroke, compared with control (RR: 0.71; P = .01).

Conversely, omega-3 fatty acids were associated with increased risk for AFib (RR, 1.26; P = .004), with a higher risk with EPA monotherapy than with control (RR, 1.35; P = .004).

Overall, omega-3 fatty acids did not prevent sudden cardiac death or increase gastrointestinal-related adverse events, total bleeding, or major or minor bleeding; however, the meta-analysis showed a higher risk of total bleeding with EPA monotherapy than with control (RR, 1.49; P = .006).

An influence analysis with stepwise exclusion of one trial at a time, including REDUCE-IT, did not alter the overall summary estimates. “Despite the exclusion of REDUCE-IT, EPA monotherapy reduced MACE by 23%, compared with the control,” the authors reported.

They said these new findings also have important implications for clinical practice and treatment guidelines.

“After REDUCE-IT, several national and international guidelines endorsed EPA in their therapeutic recommendations. However, the publication of two recent negative trials of EPA + DHA has created some confusion in the scientific community about the value of omega-3 FAs in preventing atherosclerotic cardiovascular disease [ASCVD],” they stated.

“This meta-analysis provides reassurance about the role of omega-3 fatty acids, specifically EPA, in the current treatment framework of ASCVD residual cardiovascular risk reduction and encourages investigators to explore further the cardiovascular effects of EPA across different clinical settings,” they added.

REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for the work Dr. Bhatt did as the trial chair and as the international principal investigator. The present analysis was unfunded.

A version of this article first appeared on Medscape.com.

Support for a cardiovascular benefit of omega-3 fatty acids, particularly eicosapentaenoic acid (EPA), has come from a new systematic review and meta-analysis of randomized trials.

The meta-analysis of 38 randomized controlled trials found that omega-3 fatty acids improved cardiovascular outcomes, with a greater reduction in cardiovascular risk in studies of EPA alone rather than of combined eicosapentaenoic plus docosahexaenoic acid (DHA) supplements.

The paper was published online in EClinicalMedicine.

Senior author Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, was also lead investigator of the REDUCE-IT trial, which is included in the analysis and showed a 25% relative risk reduction in major cardiovascular events with a high-dose EPA product.

But the REDUCE-IT trial has been mired in controversy, with suggestions that the benefit seen might have been exaggerated because of the use of a harmful placebo. In addition, a second large trial of high-dose omega-3 fatty acids, STRENGTH (which tested a combination EPA/DHA product) showed no benefit on cardiovascular outcomes.

Dr. Bhatt said the new meta-analysis provides “a totality of evidence” that “supports a robust and consistent benefit of EPA.”

In the review, the authors concluded: “In this systematic review and meta-analysis, we noted moderate certainty of evidence favoring omega-3 fatty acids for reducing cardiovascular mortality and outcomes. ... The magnitude of relative reductions was robust in EPA trials versus those of EPA+DHA, suggesting differential effects of EPA and DHA in cardiovascular risk reduction.”
 

Controversy continues

But commenting on the publication for an interview, Steven Nissen, MD, Cleveland Clinic, who led the STRENGTH trial, pointed out that 85% of the EPA data in the new meta-analysis came from REDUCE-IT, so the results were a “foregone conclusion.”

“The purpose of a meta-analysis is to answer scientific questions when existing studies are too small to yield statistically robust results. That is not the case here,” Dr. Nissen stated.

He added: “There are only two major trials of EPA and both have important flaws. REDUCE-IT used a questionable placebo (mineral oil) and JELIS was an open-label trial that studied patients with baseline LDL [cholesterol] of 180 mg/dL that was not appropriately treated. A meta-analysis is only as good as the studies that it includes. The other EPA plus DHA studies were essentially neutral.”

Dr. Bhatt responded that, “to date, every randomized trial of EPA only has been positive. Some have been placebo controlled, some have been open label. This meta-analysis corroborates the results of each of those trials in a statistically robust way.”

He added: “Of course, REDUCE-IT is the most rigorous, contemporary trial of EPA. However, in our meta-analysis, even when excluding REDUCE-IT (or for that matter, JELIS), the EPA trials still significantly reduced cardiovascular events.”

Dr. Bhatt also pointed out that two randomized imaging studies, CHERRY and EVAPORATE, have shown benefits of EPA.

“Beyond the clinical trial data, there is a growing amount of evidence supporting the unique biological actions of different omega-3 fatty acids. EPA, in particular, appears to have the strongest basic science evidence supporting cardiovascular benefits. Overall, it is a remarkably consistent scientific story in support of EPA’s beneficial effects on cardiovascular health,” he stated.
 

38 trials included

For the current paper, Dr. Bhatt and coauthors performed a comprehensive literature search for randomized trials comparing omega-3 fatty acids with control (placebo, no supplementation, or lower dose of omega-3 fatty acids) in adults, with a follow-up of at least 12 months, and mortality and cardiovascular outcomes as endpoints.

Ultimately, 38 trials encompassing 149,051 patients were included. Of these, four trials compared EPA with control, 34 trials compared EPA+DHA with control, and 22 trials were in primary prevention. The dose of omega-3 fatty acids ranged from 0.4 g/day to 5.5 g/day.

A total of 25 trials with 143,514 individuals reported 5,550 events of cardiovascular mortality, and 24 trials with 140,983 individuals reported 10,795 events of all-cause mortality.

Omega-3 fatty acids were associated with reduced cardiovascular mortality (rate ratio, 0.93; P = .01), but not all-cause mortality (RR, 0.97; P = .27). The meta-analysis showed reduction in cardiovascular mortality with EPA monotherapy (RR, 0.82; P = .04) and EPA+DHA combination (RR, 0.94; P = .02).

A total of 20 trials with 125,611 individuals reported 2,989 nonfatal myocardial infarction events, and 29 trials with 144,384 individuals reported 9,153 coronary heart disease (CHD) events.

Omega-3 fatty acids were associated with reducing nonfatal MI (RR, 0.87; P = .0001) and CHD (RR, 0.91; P = .0002). The meta-analysis showed higher risk reductions in nonfatal MI with EPA monotherapy (RR, 0.72; P = .00002) than with EPA+DHA combination (RR, 0.92; P = .05), and also for CHD events with EPA monotherapy (RR, 0.73; P = .00004) than with EPA+DHA combination (RR, 0.94; P = .01).

A total of 17 trials (n = 135,019) reported 13,234 events of MACE, and 13 trials (n = 117,890) reported 7,416 events of revascularization.

Omega-3 fatty acids were associated with reducing MACE (RR, 0.95; P = .002) and revascularization (RR, 0.91; P = .0001). The meta-analysis showed higher risk reductions in MACE with EPA monotherapy (RR, 0.78; P = .00000001), whereas EPA+DHA combination did not reduce MACE (RR, 0.99; P = .48). This effect was consistent for revascularization.

A total of eight trials with 65,404 individuals reported 935 nonfatal strokes, and eight trials with 51,336 individuals reported 1,572 events of atrial fibrillation (AFib).

Omega-3 fatty acids did not significantly reduce nonfatal stroke (RR, 1.04; P = .55), but EPA monotherapy was associated with a reduction of nonfatal stroke, compared with control (RR: 0.71; P = .01).

Conversely, omega-3 fatty acids were associated with increased risk for AFib (RR, 1.26; P = .004), with a higher risk with EPA monotherapy than with control (RR, 1.35; P = .004).

Overall, omega-3 fatty acids did not prevent sudden cardiac death or increase gastrointestinal-related adverse events, total bleeding, or major or minor bleeding; however, the meta-analysis showed a higher risk of total bleeding with EPA monotherapy than with control (RR, 1.49; P = .006).

An influence analysis with stepwise exclusion of one trial at a time, including REDUCE-IT, did not alter the overall summary estimates. “Despite the exclusion of REDUCE-IT, EPA monotherapy reduced MACE by 23%, compared with the control,” the authors reported.

They said these new findings also have important implications for clinical practice and treatment guidelines.

“After REDUCE-IT, several national and international guidelines endorsed EPA in their therapeutic recommendations. However, the publication of two recent negative trials of EPA + DHA has created some confusion in the scientific community about the value of omega-3 FAs in preventing atherosclerotic cardiovascular disease [ASCVD],” they stated.

“This meta-analysis provides reassurance about the role of omega-3 fatty acids, specifically EPA, in the current treatment framework of ASCVD residual cardiovascular risk reduction and encourages investigators to explore further the cardiovascular effects of EPA across different clinical settings,” they added.

REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for the work Dr. Bhatt did as the trial chair and as the international principal investigator. The present analysis was unfunded.

A version of this article first appeared on Medscape.com.

Support for a cardiovascular benefit of omega-3 fatty acids, particularly eicosapentaenoic acid (EPA), has come from a new systematic review and meta-analysis of randomized trials.

The meta-analysis of 38 randomized controlled trials found that omega-3 fatty acids improved cardiovascular outcomes, with a greater reduction in cardiovascular risk in studies of EPA alone rather than of combined eicosapentaenoic plus docosahexaenoic acid (DHA) supplements.

The paper was published online in EClinicalMedicine.

Senior author Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, was also lead investigator of the REDUCE-IT trial, which is included in the analysis and showed a 25% relative risk reduction in major cardiovascular events with a high-dose EPA product.

But the REDUCE-IT trial has been mired in controversy, with suggestions that the benefit seen might have been exaggerated because of the use of a harmful placebo. In addition, a second large trial of high-dose omega-3 fatty acids, STRENGTH (which tested a combination EPA/DHA product) showed no benefit on cardiovascular outcomes.

Dr. Bhatt said the new meta-analysis provides “a totality of evidence” that “supports a robust and consistent benefit of EPA.”

In the review, the authors concluded: “In this systematic review and meta-analysis, we noted moderate certainty of evidence favoring omega-3 fatty acids for reducing cardiovascular mortality and outcomes. ... The magnitude of relative reductions was robust in EPA trials versus those of EPA+DHA, suggesting differential effects of EPA and DHA in cardiovascular risk reduction.”
 

Controversy continues

But commenting on the publication for an interview, Steven Nissen, MD, Cleveland Clinic, who led the STRENGTH trial, pointed out that 85% of the EPA data in the new meta-analysis came from REDUCE-IT, so the results were a “foregone conclusion.”

“The purpose of a meta-analysis is to answer scientific questions when existing studies are too small to yield statistically robust results. That is not the case here,” Dr. Nissen stated.

He added: “There are only two major trials of EPA and both have important flaws. REDUCE-IT used a questionable placebo (mineral oil) and JELIS was an open-label trial that studied patients with baseline LDL [cholesterol] of 180 mg/dL that was not appropriately treated. A meta-analysis is only as good as the studies that it includes. The other EPA plus DHA studies were essentially neutral.”

Dr. Bhatt responded that, “to date, every randomized trial of EPA only has been positive. Some have been placebo controlled, some have been open label. This meta-analysis corroborates the results of each of those trials in a statistically robust way.”

He added: “Of course, REDUCE-IT is the most rigorous, contemporary trial of EPA. However, in our meta-analysis, even when excluding REDUCE-IT (or for that matter, JELIS), the EPA trials still significantly reduced cardiovascular events.”

Dr. Bhatt also pointed out that two randomized imaging studies, CHERRY and EVAPORATE, have shown benefits of EPA.

“Beyond the clinical trial data, there is a growing amount of evidence supporting the unique biological actions of different omega-3 fatty acids. EPA, in particular, appears to have the strongest basic science evidence supporting cardiovascular benefits. Overall, it is a remarkably consistent scientific story in support of EPA’s beneficial effects on cardiovascular health,” he stated.
 

38 trials included

For the current paper, Dr. Bhatt and coauthors performed a comprehensive literature search for randomized trials comparing omega-3 fatty acids with control (placebo, no supplementation, or lower dose of omega-3 fatty acids) in adults, with a follow-up of at least 12 months, and mortality and cardiovascular outcomes as endpoints.

Ultimately, 38 trials encompassing 149,051 patients were included. Of these, four trials compared EPA with control, 34 trials compared EPA+DHA with control, and 22 trials were in primary prevention. The dose of omega-3 fatty acids ranged from 0.4 g/day to 5.5 g/day.

A total of 25 trials with 143,514 individuals reported 5,550 events of cardiovascular mortality, and 24 trials with 140,983 individuals reported 10,795 events of all-cause mortality.

Omega-3 fatty acids were associated with reduced cardiovascular mortality (rate ratio, 0.93; P = .01), but not all-cause mortality (RR, 0.97; P = .27). The meta-analysis showed reduction in cardiovascular mortality with EPA monotherapy (RR, 0.82; P = .04) and EPA+DHA combination (RR, 0.94; P = .02).

A total of 20 trials with 125,611 individuals reported 2,989 nonfatal myocardial infarction events, and 29 trials with 144,384 individuals reported 9,153 coronary heart disease (CHD) events.

Omega-3 fatty acids were associated with reducing nonfatal MI (RR, 0.87; P = .0001) and CHD (RR, 0.91; P = .0002). The meta-analysis showed higher risk reductions in nonfatal MI with EPA monotherapy (RR, 0.72; P = .00002) than with EPA+DHA combination (RR, 0.92; P = .05), and also for CHD events with EPA monotherapy (RR, 0.73; P = .00004) than with EPA+DHA combination (RR, 0.94; P = .01).

A total of 17 trials (n = 135,019) reported 13,234 events of MACE, and 13 trials (n = 117,890) reported 7,416 events of revascularization.

Omega-3 fatty acids were associated with reducing MACE (RR, 0.95; P = .002) and revascularization (RR, 0.91; P = .0001). The meta-analysis showed higher risk reductions in MACE with EPA monotherapy (RR, 0.78; P = .00000001), whereas EPA+DHA combination did not reduce MACE (RR, 0.99; P = .48). This effect was consistent for revascularization.

A total of eight trials with 65,404 individuals reported 935 nonfatal strokes, and eight trials with 51,336 individuals reported 1,572 events of atrial fibrillation (AFib).

Omega-3 fatty acids did not significantly reduce nonfatal stroke (RR, 1.04; P = .55), but EPA monotherapy was associated with a reduction of nonfatal stroke, compared with control (RR: 0.71; P = .01).

Conversely, omega-3 fatty acids were associated with increased risk for AFib (RR, 1.26; P = .004), with a higher risk with EPA monotherapy than with control (RR, 1.35; P = .004).

Overall, omega-3 fatty acids did not prevent sudden cardiac death or increase gastrointestinal-related adverse events, total bleeding, or major or minor bleeding; however, the meta-analysis showed a higher risk of total bleeding with EPA monotherapy than with control (RR, 1.49; P = .006).

An influence analysis with stepwise exclusion of one trial at a time, including REDUCE-IT, did not alter the overall summary estimates. “Despite the exclusion of REDUCE-IT, EPA monotherapy reduced MACE by 23%, compared with the control,” the authors reported.

They said these new findings also have important implications for clinical practice and treatment guidelines.

“After REDUCE-IT, several national and international guidelines endorsed EPA in their therapeutic recommendations. However, the publication of two recent negative trials of EPA + DHA has created some confusion in the scientific community about the value of omega-3 FAs in preventing atherosclerotic cardiovascular disease [ASCVD],” they stated.

“This meta-analysis provides reassurance about the role of omega-3 fatty acids, specifically EPA, in the current treatment framework of ASCVD residual cardiovascular risk reduction and encourages investigators to explore further the cardiovascular effects of EPA across different clinical settings,” they added.

REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for the work Dr. Bhatt did as the trial chair and as the international principal investigator. The present analysis was unfunded.

A version of this article first appeared on Medscape.com.

A mechanistic link between red meat consumption and colorectal cancer (CRC) has been identified in the form of an alkylating mutational signature, according to investigators.

This is the first time a colorectal mutational signature has been associated with a component of diet, which demonstrates the value of large-scale molecular epidemiologic studies and suggests potential for early, precision dietary intervention, reported lead author Carino Gurjao, MSc, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, and colleagues.

“Red meat consumption has been consistently linked to the incidence of colorectal cancer,” the investigators wrote in Cancer Discovery. “The suggested mechanism is mutagenesis through alkylating damage induced by N-nitroso-compounds (NOCs), which are metabolic products of blood heme iron or meat nitrites/nitrates. Nevertheless, this mutational damage is yet to be observed directly in patients’ tumors.”

To this end, the investigators turned to three long-term, large-scale, prospective cohort studies: the Nurses’ Health Studies I and II, and the Health Professionals Follow-up Study. These databases include nearly 300,000 individuals with follow-up dating back as far as 1976. The investigators identified 900 cases of primary, untreated CRC with adequate tissue for analysis, then, for each case, performed whole exome sequencing on both tumor tissue and normal colorectal tissue.

This revealed an alkylating mutational signature previously undescribed in CRC that was significantly associated with consumption of red meat prior to diagnosis, but not other dietary or lifestyle factors. The signature occurred most frequently in tumors and normal crypts in the distal colon and rectum.

According to the investigators, the presence of the alkylating signature in normal colorectal crypts “suggests that mutational changes due to such damage may start to occur early in the path of colorectal carcinogenesis.”

Further analysis showed that tumors harboring common KRAS and PIK3CA driver mutations had the highest levels of alkylating damage, with higher levels predicting worse survival.

“These results ... further implicate the role of red meat in CRC initiation and progression,” the investigators concluded.
 

Early findings, important implications

Cosenior author Kana Wu, MD, PhD, principal research scientist in the department of nutrition at Harvard School of Public Health, Boston, noted that these are early findings, although they may pave the way toward new dietary recommendations and methods of food production.

“While more detailed analysis needs to be conducted, and our results need to be confirmed in other studies, this study is a promising first step to better understand the biological mechanisms underlying the role of red and processed meats in colorectal cancers,” Dr. Wu said in an interview. “It is important to gain more insight into the biological mechanisms so we can improve dietary guidelines for cancer prevention and guide food reformulation efforts to lower cancer risk.”

For now, Dr. Wu predicted that standing dietary recommendations will remain unchanged.

“This study will not alter current diet recommendations to limit intake of red and processed meats,” Dr. Wu said, referring to similar recommendations across several organizations, including the American Heart Association, the World Cancer Research Fund/American Institute for Cancer Research, and the American Cancer Society.

“For example,” Dr. Wu said, “the WCRF/AICR recommends limiting consumption of red and processed meat to ‘no more than moderate amounts [12-18 ounces per week] of red meat, such as beef, pork, and lamb, and [to] eat little, if any, processed meat.’”
 

Possible biomarker?

According to Patricia Thompson-Carino, PhD, deputy director of the Stony Brook (N.Y.) Cancer Center, the study provides convincing evidence linking red meat consumption with development of CRC.

“Higher frequency of the signature in the distal colon is compelling for its consistency with epidemiologic evidence,” Dr. Thompson-Carino said in an interview. “Combined with the observed worse survival in patients harboring the signature and association with oncogenic KRAS and PIK3CA driver mutations, this study significantly elevates the biological plausibility that red meat is a modifiable source of NOC mutagenicity and carcinogenesis in humans.”

The signature could be used as a biomarker to detect exposure to NOCs, and susceptibility to CRC, she added.

Still, Dr. Thompson-Carino suggested that more work is needed to fully elucidate underlying mechanisms of action, which are needed to accurately shape dietary guidance.

“Key to advancing red meat dietary recommendations will be understanding the relationships between the new mutation signature and the NOCs derived from red meat and their source, whether endogenous [for example, intestinal N-nitrosation] or exogenous [for example, chemical preservation or charring],” she said. The study was supported by the National Institutes of Health, the Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (coadministered by the American Association for Cancer Research), the Project P Fund, and others. The investigators, Dr. Wu, and Dr. Thompson-Carino reported no conflicts of interest related to this study.

Help your patients understand colorectal cancer prevention and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

A mechanistic link between red meat consumption and colorectal cancer (CRC) has been identified in the form of an alkylating mutational signature, according to investigators.

This is the first time a colorectal mutational signature has been associated with a component of diet, which demonstrates the value of large-scale molecular epidemiologic studies and suggests potential for early, precision dietary intervention, reported lead author Carino Gurjao, MSc, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, and colleagues.

“Red meat consumption has been consistently linked to the incidence of colorectal cancer,” the investigators wrote in Cancer Discovery. “The suggested mechanism is mutagenesis through alkylating damage induced by N-nitroso-compounds (NOCs), which are metabolic products of blood heme iron or meat nitrites/nitrates. Nevertheless, this mutational damage is yet to be observed directly in patients’ tumors.”

To this end, the investigators turned to three long-term, large-scale, prospective cohort studies: the Nurses’ Health Studies I and II, and the Health Professionals Follow-up Study. These databases include nearly 300,000 individuals with follow-up dating back as far as 1976. The investigators identified 900 cases of primary, untreated CRC with adequate tissue for analysis, then, for each case, performed whole exome sequencing on both tumor tissue and normal colorectal tissue.

This revealed an alkylating mutational signature previously undescribed in CRC that was significantly associated with consumption of red meat prior to diagnosis, but not other dietary or lifestyle factors. The signature occurred most frequently in tumors and normal crypts in the distal colon and rectum.

According to the investigators, the presence of the alkylating signature in normal colorectal crypts “suggests that mutational changes due to such damage may start to occur early in the path of colorectal carcinogenesis.”

Further analysis showed that tumors harboring common KRAS and PIK3CA driver mutations had the highest levels of alkylating damage, with higher levels predicting worse survival.

“These results ... further implicate the role of red meat in CRC initiation and progression,” the investigators concluded.
 

Early findings, important implications

Cosenior author Kana Wu, MD, PhD, principal research scientist in the department of nutrition at Harvard School of Public Health, Boston, noted that these are early findings, although they may pave the way toward new dietary recommendations and methods of food production.

“While more detailed analysis needs to be conducted, and our results need to be confirmed in other studies, this study is a promising first step to better understand the biological mechanisms underlying the role of red and processed meats in colorectal cancers,” Dr. Wu said in an interview. “It is important to gain more insight into the biological mechanisms so we can improve dietary guidelines for cancer prevention and guide food reformulation efforts to lower cancer risk.”

For now, Dr. Wu predicted that standing dietary recommendations will remain unchanged.

“This study will not alter current diet recommendations to limit intake of red and processed meats,” Dr. Wu said, referring to similar recommendations across several organizations, including the American Heart Association, the World Cancer Research Fund/American Institute for Cancer Research, and the American Cancer Society.

“For example,” Dr. Wu said, “the WCRF/AICR recommends limiting consumption of red and processed meat to ‘no more than moderate amounts [12-18 ounces per week] of red meat, such as beef, pork, and lamb, and [to] eat little, if any, processed meat.’”
 

Possible biomarker?

According to Patricia Thompson-Carino, PhD, deputy director of the Stony Brook (N.Y.) Cancer Center, the study provides convincing evidence linking red meat consumption with development of CRC.

“Higher frequency of the signature in the distal colon is compelling for its consistency with epidemiologic evidence,” Dr. Thompson-Carino said in an interview. “Combined with the observed worse survival in patients harboring the signature and association with oncogenic KRAS and PIK3CA driver mutations, this study significantly elevates the biological plausibility that red meat is a modifiable source of NOC mutagenicity and carcinogenesis in humans.”

The signature could be used as a biomarker to detect exposure to NOCs, and susceptibility to CRC, she added.

Still, Dr. Thompson-Carino suggested that more work is needed to fully elucidate underlying mechanisms of action, which are needed to accurately shape dietary guidance.

“Key to advancing red meat dietary recommendations will be understanding the relationships between the new mutation signature and the NOCs derived from red meat and their source, whether endogenous [for example, intestinal N-nitrosation] or exogenous [for example, chemical preservation or charring],” she said. The study was supported by the National Institutes of Health, the Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (coadministered by the American Association for Cancer Research), the Project P Fund, and others. The investigators, Dr. Wu, and Dr. Thompson-Carino reported no conflicts of interest related to this study.

Help your patients understand colorectal cancer prevention and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

A mechanistic link between red meat consumption and colorectal cancer (CRC) has been identified in the form of an alkylating mutational signature, according to investigators.

This is the first time a colorectal mutational signature has been associated with a component of diet, which demonstrates the value of large-scale molecular epidemiologic studies and suggests potential for early, precision dietary intervention, reported lead author Carino Gurjao, MSc, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, and colleagues.

“Red meat consumption has been consistently linked to the incidence of colorectal cancer,” the investigators wrote in Cancer Discovery. “The suggested mechanism is mutagenesis through alkylating damage induced by N-nitroso-compounds (NOCs), which are metabolic products of blood heme iron or meat nitrites/nitrates. Nevertheless, this mutational damage is yet to be observed directly in patients’ tumors.”

To this end, the investigators turned to three long-term, large-scale, prospective cohort studies: the Nurses’ Health Studies I and II, and the Health Professionals Follow-up Study. These databases include nearly 300,000 individuals with follow-up dating back as far as 1976. The investigators identified 900 cases of primary, untreated CRC with adequate tissue for analysis, then, for each case, performed whole exome sequencing on both tumor tissue and normal colorectal tissue.

This revealed an alkylating mutational signature previously undescribed in CRC that was significantly associated with consumption of red meat prior to diagnosis, but not other dietary or lifestyle factors. The signature occurred most frequently in tumors and normal crypts in the distal colon and rectum.

According to the investigators, the presence of the alkylating signature in normal colorectal crypts “suggests that mutational changes due to such damage may start to occur early in the path of colorectal carcinogenesis.”

Further analysis showed that tumors harboring common KRAS and PIK3CA driver mutations had the highest levels of alkylating damage, with higher levels predicting worse survival.

“These results ... further implicate the role of red meat in CRC initiation and progression,” the investigators concluded.
 

Early findings, important implications

Cosenior author Kana Wu, MD, PhD, principal research scientist in the department of nutrition at Harvard School of Public Health, Boston, noted that these are early findings, although they may pave the way toward new dietary recommendations and methods of food production.

“While more detailed analysis needs to be conducted, and our results need to be confirmed in other studies, this study is a promising first step to better understand the biological mechanisms underlying the role of red and processed meats in colorectal cancers,” Dr. Wu said in an interview. “It is important to gain more insight into the biological mechanisms so we can improve dietary guidelines for cancer prevention and guide food reformulation efforts to lower cancer risk.”

For now, Dr. Wu predicted that standing dietary recommendations will remain unchanged.

“This study will not alter current diet recommendations to limit intake of red and processed meats,” Dr. Wu said, referring to similar recommendations across several organizations, including the American Heart Association, the World Cancer Research Fund/American Institute for Cancer Research, and the American Cancer Society.

“For example,” Dr. Wu said, “the WCRF/AICR recommends limiting consumption of red and processed meat to ‘no more than moderate amounts [12-18 ounces per week] of red meat, such as beef, pork, and lamb, and [to] eat little, if any, processed meat.’”
 

Possible biomarker?

According to Patricia Thompson-Carino, PhD, deputy director of the Stony Brook (N.Y.) Cancer Center, the study provides convincing evidence linking red meat consumption with development of CRC.

“Higher frequency of the signature in the distal colon is compelling for its consistency with epidemiologic evidence,” Dr. Thompson-Carino said in an interview. “Combined with the observed worse survival in patients harboring the signature and association with oncogenic KRAS and PIK3CA driver mutations, this study significantly elevates the biological plausibility that red meat is a modifiable source of NOC mutagenicity and carcinogenesis in humans.”

The signature could be used as a biomarker to detect exposure to NOCs, and susceptibility to CRC, she added.

Still, Dr. Thompson-Carino suggested that more work is needed to fully elucidate underlying mechanisms of action, which are needed to accurately shape dietary guidance.

“Key to advancing red meat dietary recommendations will be understanding the relationships between the new mutation signature and the NOCs derived from red meat and their source, whether endogenous [for example, intestinal N-nitrosation] or exogenous [for example, chemical preservation or charring],” she said. The study was supported by the National Institutes of Health, the Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (coadministered by the American Association for Cancer Research), the Project P Fund, and others. The investigators, Dr. Wu, and Dr. Thompson-Carino reported no conflicts of interest related to this study.

Help your patients understand colorectal cancer prevention and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

The U.S. Food and Drug Administration approved finerenone (Kerendia), the first agent from a new class of nonsteroidal mineralocorticoid receptor antagonists (MRAs), on July 9 for treating patients with chronic kidney disease (CKD) associated with type 2 diabetes.

Janani Rangaswami, MD, a nephrologist not involved with finerenone’s development, hailed the action as a “welcome addition to therapies in the cardiorenal space.”

She also highlighted that until more evidence accumulates, finerenone will take a back seat to two more established renal-protective drug classes for patients with type 2 diabetes, the renin-angiotensin system inhibitors (RASIs), and the sodium-glucose cotransporter 2 (SGLT2) inhibitors.

RASIs, which include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, remain first-line treatments for slowing the progression of CKD in patients with type 2 diabetes. The efficacy and safety of these agents are well-established. The trial that led to the FDA’s decision to approve finerenone, FIDELIO-DKD, compared it against placebo in more than 5,700 patients with type 2 diabetes who were all already taking a maximum-tolerated dose of an RASI.
 

Scant data on combining finerenone with an SGLT2 inhibitor

Two agents in the SGLT2 inhibitor class, approved initially for type 2 diabetes, received additional FDA approvals for slowing kidney disease: Canagliflozin (Invokana), which was approved in September 2019 on the basis of the CREDENCE trial, and dapagliflozin (Forxiga/Farxiga), which was approved in April 2021 on the basis of DAPA-CKD. Nephrologists now speak of this drug class as “practice changing.”

When FIDELIO-DKD enrolled patients from September 2015 to June 2018, it was still early days for use of SGLT2 inhibitors for patients with type 2 diabetes; hence, fewer than 5% of enrolled patients received an SGLT2 inhibitor, making it impossible to say how well finerenone works when taken along with one of these drugs.

“The big question that persists is the incremental benefit [from finerenone] on top of an SGLT2 inhibitor,” commented Dr. Rangaswami, director of the cardiorenal program at George Washington University, Washington, and chair-elect of the Council on the Kidney in Cardiovascular Disease of the American Heart Association.

“It is hard to extrapolate incremental benefit from existing finerenone trial data given the low background use of SGLT2 inhibitors [in FIDELIO-DKD],” she said in an interview.

George Bakris, MD, lead investigator for FIDELIO-DKD, agrees.
 

SGLT2 inhibitors are a ‘must’ for CKD

An SGLT2 inhibitor “must be used, period,” for patients with type 2 diabetes and CKD. “The evidence is very strong,” said Dr. Bakris, speaking in June 2021 during a session of the virtual annual Congress of the European Renal Association and European Dialysis and Transplant Association.

Because of inadequate evidence on how finerenone works when administered in addition to an SGLT2 inhibitor, for the time being, the combination must be considered investigational, he added.

Study results “need to show that combination therapy [with an SGLT2 inhibitor and finerenone] is better” than an SGLT2 inhibitor alone, said Dr. Bakris, professor of medicine and director of the Comprehensive Hypertension Center of the University of Chicago.

During his June talk, Dr. Bakris predicted that by 2023, enough data will exist from patients treated with both an SGLT2 inhibitor and finerenone to allow an evidence-based approach to combination treatment.

Finerenone’s approval makes it an immediate choice for patients with type 2 diabetes and CKD secondary to polycystic kidney disease, a group who are not candidates for an SGLT2 inhibitor, said Dr. Rangaswami.

But “if a patient is eligible for an SGLT2 inhibitor, I would not stop that in favor of starting finerenone” on the basis of current knowledge, she noted.
 

‘Not your mother’s spironolactone’

Although finerenone is classified an MRA, the class that also includes the steroidal agents spironolactone and eplerenone, the nonsteroidal structure of finerenone means “it has nothing to do with spironolactone. It’s a different molecule with different chemistry,” Dr. Bakris said in his June talk.

Although the risk for hyperkalemia has been a limiting factor and a deterrent to routine use of steroidal MRAs for preventing progression of CKD, hyperkalemia is much less of a problem with finerenone.

Main results from FIDELIO-DKD, published in late 2020, showed that the percentage of patients receiving finerenone who permanently stopped taking the drug because of hyperkalemia was 2.3%, higher than the 0.9% rate among patients in the trial who received placebo but about a third of the rate of patients treated with spironolactone in a historical cohort.

“You need to pay attention” to the potential development of hyperkalemia in patients taking finerenone, “but it is not a major issue,” Dr. Bakris said. “Finerenone is not your mother’s spironolactone,” he declared.

FIDELIO-DKD’s primary outcome, a combination of several adverse renal events, showed that treatment with finerenone cut this endpoint by a significant 18% compared with placebo. The study’s main secondary endpoint showed that finerenone cut the incidence of combined cardiovascular disease events by a significant 14% compared with placebo. Adverse events were similar in the finerenone and placebo arms.
 

Finerenone also shows promise for reducing CVD events

Bayer, the company that developed and will market finerenone, announced in May 2021 topline results from a companion trial, FIGARO-DKD. That trial also enrolled patients with type 2 diabetes and CKD, but a primary endpoint of that trial combined the rates of cardiovascular death and nonfatal cardiovascular disease events. The results from this trial showed a significant difference in favor of finerenone compared with placebo.

“Given the common pathways that progression of CKD and cardiovascular disease share with respect to [moderating] inflammation and [slowing development of] fibrosis, it is not surprising that a signal for benefit was seen at the different ends of the cardiorenal spectrum,” Dr. Rangaswami said.

FIDELIO-DKD and FIGARO-DKD were sponsored by Bayer, the company that markets finerenone (Kerendia). Dr. Bakris has been a consultant to and has received research funding from Bayer and from numerous other companies. Dr. Rangaswami has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration approved finerenone (Kerendia), the first agent from a new class of nonsteroidal mineralocorticoid receptor antagonists (MRAs), on July 9 for treating patients with chronic kidney disease (CKD) associated with type 2 diabetes.

Janani Rangaswami, MD, a nephrologist not involved with finerenone’s development, hailed the action as a “welcome addition to therapies in the cardiorenal space.”

She also highlighted that until more evidence accumulates, finerenone will take a back seat to two more established renal-protective drug classes for patients with type 2 diabetes, the renin-angiotensin system inhibitors (RASIs), and the sodium-glucose cotransporter 2 (SGLT2) inhibitors.

RASIs, which include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, remain first-line treatments for slowing the progression of CKD in patients with type 2 diabetes. The efficacy and safety of these agents are well-established. The trial that led to the FDA’s decision to approve finerenone, FIDELIO-DKD, compared it against placebo in more than 5,700 patients with type 2 diabetes who were all already taking a maximum-tolerated dose of an RASI.
 

Scant data on combining finerenone with an SGLT2 inhibitor

Two agents in the SGLT2 inhibitor class, approved initially for type 2 diabetes, received additional FDA approvals for slowing kidney disease: Canagliflozin (Invokana), which was approved in September 2019 on the basis of the CREDENCE trial, and dapagliflozin (Forxiga/Farxiga), which was approved in April 2021 on the basis of DAPA-CKD. Nephrologists now speak of this drug class as “practice changing.”

When FIDELIO-DKD enrolled patients from September 2015 to June 2018, it was still early days for use of SGLT2 inhibitors for patients with type 2 diabetes; hence, fewer than 5% of enrolled patients received an SGLT2 inhibitor, making it impossible to say how well finerenone works when taken along with one of these drugs.

“The big question that persists is the incremental benefit [from finerenone] on top of an SGLT2 inhibitor,” commented Dr. Rangaswami, director of the cardiorenal program at George Washington University, Washington, and chair-elect of the Council on the Kidney in Cardiovascular Disease of the American Heart Association.

“It is hard to extrapolate incremental benefit from existing finerenone trial data given the low background use of SGLT2 inhibitors [in FIDELIO-DKD],” she said in an interview.

George Bakris, MD, lead investigator for FIDELIO-DKD, agrees.
 

SGLT2 inhibitors are a ‘must’ for CKD

An SGLT2 inhibitor “must be used, period,” for patients with type 2 diabetes and CKD. “The evidence is very strong,” said Dr. Bakris, speaking in June 2021 during a session of the virtual annual Congress of the European Renal Association and European Dialysis and Transplant Association.

Because of inadequate evidence on how finerenone works when administered in addition to an SGLT2 inhibitor, for the time being, the combination must be considered investigational, he added.

Study results “need to show that combination therapy [with an SGLT2 inhibitor and finerenone] is better” than an SGLT2 inhibitor alone, said Dr. Bakris, professor of medicine and director of the Comprehensive Hypertension Center of the University of Chicago.

During his June talk, Dr. Bakris predicted that by 2023, enough data will exist from patients treated with both an SGLT2 inhibitor and finerenone to allow an evidence-based approach to combination treatment.

Finerenone’s approval makes it an immediate choice for patients with type 2 diabetes and CKD secondary to polycystic kidney disease, a group who are not candidates for an SGLT2 inhibitor, said Dr. Rangaswami.

But “if a patient is eligible for an SGLT2 inhibitor, I would not stop that in favor of starting finerenone” on the basis of current knowledge, she noted.
 

‘Not your mother’s spironolactone’

Although finerenone is classified an MRA, the class that also includes the steroidal agents spironolactone and eplerenone, the nonsteroidal structure of finerenone means “it has nothing to do with spironolactone. It’s a different molecule with different chemistry,” Dr. Bakris said in his June talk.

Although the risk for hyperkalemia has been a limiting factor and a deterrent to routine use of steroidal MRAs for preventing progression of CKD, hyperkalemia is much less of a problem with finerenone.

Main results from FIDELIO-DKD, published in late 2020, showed that the percentage of patients receiving finerenone who permanently stopped taking the drug because of hyperkalemia was 2.3%, higher than the 0.9% rate among patients in the trial who received placebo but about a third of the rate of patients treated with spironolactone in a historical cohort.

“You need to pay attention” to the potential development of hyperkalemia in patients taking finerenone, “but it is not a major issue,” Dr. Bakris said. “Finerenone is not your mother’s spironolactone,” he declared.

FIDELIO-DKD’s primary outcome, a combination of several adverse renal events, showed that treatment with finerenone cut this endpoint by a significant 18% compared with placebo. The study’s main secondary endpoint showed that finerenone cut the incidence of combined cardiovascular disease events by a significant 14% compared with placebo. Adverse events were similar in the finerenone and placebo arms.
 

Finerenone also shows promise for reducing CVD events

Bayer, the company that developed and will market finerenone, announced in May 2021 topline results from a companion trial, FIGARO-DKD. That trial also enrolled patients with type 2 diabetes and CKD, but a primary endpoint of that trial combined the rates of cardiovascular death and nonfatal cardiovascular disease events. The results from this trial showed a significant difference in favor of finerenone compared with placebo.

“Given the common pathways that progression of CKD and cardiovascular disease share with respect to [moderating] inflammation and [slowing development of] fibrosis, it is not surprising that a signal for benefit was seen at the different ends of the cardiorenal spectrum,” Dr. Rangaswami said.

FIDELIO-DKD and FIGARO-DKD were sponsored by Bayer, the company that markets finerenone (Kerendia). Dr. Bakris has been a consultant to and has received research funding from Bayer and from numerous other companies. Dr. Rangaswami has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration approved finerenone (Kerendia), the first agent from a new class of nonsteroidal mineralocorticoid receptor antagonists (MRAs), on July 9 for treating patients with chronic kidney disease (CKD) associated with type 2 diabetes.

Janani Rangaswami, MD, a nephrologist not involved with finerenone’s development, hailed the action as a “welcome addition to therapies in the cardiorenal space.”

She also highlighted that until more evidence accumulates, finerenone will take a back seat to two more established renal-protective drug classes for patients with type 2 diabetes, the renin-angiotensin system inhibitors (RASIs), and the sodium-glucose cotransporter 2 (SGLT2) inhibitors.

RASIs, which include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, remain first-line treatments for slowing the progression of CKD in patients with type 2 diabetes. The efficacy and safety of these agents are well-established. The trial that led to the FDA’s decision to approve finerenone, FIDELIO-DKD, compared it against placebo in more than 5,700 patients with type 2 diabetes who were all already taking a maximum-tolerated dose of an RASI.
 

Scant data on combining finerenone with an SGLT2 inhibitor

Two agents in the SGLT2 inhibitor class, approved initially for type 2 diabetes, received additional FDA approvals for slowing kidney disease: Canagliflozin (Invokana), which was approved in September 2019 on the basis of the CREDENCE trial, and dapagliflozin (Forxiga/Farxiga), which was approved in April 2021 on the basis of DAPA-CKD. Nephrologists now speak of this drug class as “practice changing.”

When FIDELIO-DKD enrolled patients from September 2015 to June 2018, it was still early days for use of SGLT2 inhibitors for patients with type 2 diabetes; hence, fewer than 5% of enrolled patients received an SGLT2 inhibitor, making it impossible to say how well finerenone works when taken along with one of these drugs.

“The big question that persists is the incremental benefit [from finerenone] on top of an SGLT2 inhibitor,” commented Dr. Rangaswami, director of the cardiorenal program at George Washington University, Washington, and chair-elect of the Council on the Kidney in Cardiovascular Disease of the American Heart Association.

“It is hard to extrapolate incremental benefit from existing finerenone trial data given the low background use of SGLT2 inhibitors [in FIDELIO-DKD],” she said in an interview.

George Bakris, MD, lead investigator for FIDELIO-DKD, agrees.
 

SGLT2 inhibitors are a ‘must’ for CKD

An SGLT2 inhibitor “must be used, period,” for patients with type 2 diabetes and CKD. “The evidence is very strong,” said Dr. Bakris, speaking in June 2021 during a session of the virtual annual Congress of the European Renal Association and European Dialysis and Transplant Association.

Because of inadequate evidence on how finerenone works when administered in addition to an SGLT2 inhibitor, for the time being, the combination must be considered investigational, he added.

Study results “need to show that combination therapy [with an SGLT2 inhibitor and finerenone] is better” than an SGLT2 inhibitor alone, said Dr. Bakris, professor of medicine and director of the Comprehensive Hypertension Center of the University of Chicago.

During his June talk, Dr. Bakris predicted that by 2023, enough data will exist from patients treated with both an SGLT2 inhibitor and finerenone to allow an evidence-based approach to combination treatment.

Finerenone’s approval makes it an immediate choice for patients with type 2 diabetes and CKD secondary to polycystic kidney disease, a group who are not candidates for an SGLT2 inhibitor, said Dr. Rangaswami.

But “if a patient is eligible for an SGLT2 inhibitor, I would not stop that in favor of starting finerenone” on the basis of current knowledge, she noted.
 

‘Not your mother’s spironolactone’

Although finerenone is classified an MRA, the class that also includes the steroidal agents spironolactone and eplerenone, the nonsteroidal structure of finerenone means “it has nothing to do with spironolactone. It’s a different molecule with different chemistry,” Dr. Bakris said in his June talk.

Although the risk for hyperkalemia has been a limiting factor and a deterrent to routine use of steroidal MRAs for preventing progression of CKD, hyperkalemia is much less of a problem with finerenone.

Main results from FIDELIO-DKD, published in late 2020, showed that the percentage of patients receiving finerenone who permanently stopped taking the drug because of hyperkalemia was 2.3%, higher than the 0.9% rate among patients in the trial who received placebo but about a third of the rate of patients treated with spironolactone in a historical cohort.

“You need to pay attention” to the potential development of hyperkalemia in patients taking finerenone, “but it is not a major issue,” Dr. Bakris said. “Finerenone is not your mother’s spironolactone,” he declared.

FIDELIO-DKD’s primary outcome, a combination of several adverse renal events, showed that treatment with finerenone cut this endpoint by a significant 18% compared with placebo. The study’s main secondary endpoint showed that finerenone cut the incidence of combined cardiovascular disease events by a significant 14% compared with placebo. Adverse events were similar in the finerenone and placebo arms.
 

Finerenone also shows promise for reducing CVD events

Bayer, the company that developed and will market finerenone, announced in May 2021 topline results from a companion trial, FIGARO-DKD. That trial also enrolled patients with type 2 diabetes and CKD, but a primary endpoint of that trial combined the rates of cardiovascular death and nonfatal cardiovascular disease events. The results from this trial showed a significant difference in favor of finerenone compared with placebo.

“Given the common pathways that progression of CKD and cardiovascular disease share with respect to [moderating] inflammation and [slowing development of] fibrosis, it is not surprising that a signal for benefit was seen at the different ends of the cardiorenal spectrum,” Dr. Rangaswami said.

FIDELIO-DKD and FIGARO-DKD were sponsored by Bayer, the company that markets finerenone (Kerendia). Dr. Bakris has been a consultant to and has received research funding from Bayer and from numerous other companies. Dr. Rangaswami has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Compared with oral propranolol for the treatment of infantile hemangiomas, oral nadolol resulted in faster and greater size involution and color resolution with a similar safety profile out to 52 weeks, results from a prospective analysis of 71 patients showed.

“In clinical practice, we notice that nadolol works very well in terms of controlling the size and the appearance of the hemangioma,” lead study author Elena Pope, MD, MSc, said during the annual meeting of the Society for Pediatric Dermatology. Hence, she and her colleagues were interested in comparing their clinical experience with the standard treatment with propranolol, and designed a prospective, randomized, controlled, double-blinded study, with the aim of proving that “nadolol is noninferior to propranolol, with a margin of noninferiority of 10%.”

Between 2016 and 2020, Dr. Pope and colleagues at two academic Canadian pediatric dermatology centers enrolled 71 infants aged 1-6 months with significant hemangioma that had either the potential for functional impairment or cosmetic deformity, defined as a lesion greater than 1.5 cm on the face or greater than 3 cm on another body part. Treatment consisted of oral propranolol or nadolol in escalating doses up to 2 mg/kg per day. “The blinding portion of the study was for 24 weeks with a follow-up up to 52 weeks,” said Dr. Pope, professor of pediatrics at the University of Toronto and section head of pediatric dermatology at The Hospital for Sick Children, also in Toronto. “After the unblinding at 24 weeks, patients were allowed to switch their intervention if they were not happy with the results.”

Of the 71 patients, 35 received nadolol and 36 received propranolol. The two groups were similar in terms of clinical and demographic characteristics. Their mean age at enrollment was 3.15 months, 80% were female, 61% were White, 20% were Asian, and the rest were from other ethnic backgrounds.

At 24 weeks, the researchers found that the mean size involution was 97.94% in the nadolol group and 89.14% in the propranolol group (P = .005), while the mean color fading on the visual analogue scale (VAS) was 94.47% in the nadolol group and 80.54% in the propranolol group (P < .001). At 52 weeks, the mean size involution was 99.63% in the nadolol group and 93.63% in the propranolol group (P = .001), while the mean VAS color fading was 97.34% in the nadolol group and 87.23% in the propranolol group (P = .001).

According to Dr. Pope, Kaplan-Meir analysis showed that patients in the propranolol group responded slower to treatment (P = .019), while safety data was similar between the two groups. For example, between weeks 25 and 52, 84.2% of patients in the nadolol group experienced an adverse event, compared with 74.2% of patients in the propranolol group (P = .466). The most common respiratory adverse event was upper respiratory tract infection, which affected 87.5% of patients in the nadolol group, compared with 100% of patients in the propranolol group (P = 0.341).

The most common gastrointestinal adverse event was diarrhea, which affected 66.7% of patients in both groups. One patient in the propranolol group was admitted to the hospital with pneumonia and fully recovered. The incident was not suspected to be related to the medication.

“We believe that this data backs up our clinical experience and it may offer an alternative treatment in other centers where patients experience propranolol unresponsiveness, side effects, or intolerance, or where a fast response is needed,” Dr. Pope said. As for the potential cost implications, “nadolol is cheaper than the Hemangiol but comparable with the compounded formulation of propranolol.”

Concern over the safety of nadolol was raised in a case report published in Pediatrics in 2020. Authors from Alberta reported the case of a 10-week-old girl who was started on nadolol for infantile hemangioma, died 7 weeks later, and was found to have an elevated postmortem cardiac blood nadolol level of 0.94 mg/L. “The infant had no bowel movements for 10 days before her death, which we hypothesize contributed to nadolol toxicity,” the authors wrote.

In a reply to the authors in the same issue of Pediatrics, Dr. Pope, Cathryn Sibbald, MD, and Erin Chung, PhD, pointed out that postmortem redistribution of medications “is complex and measured postmortem cardiac blood concentrations may be significantly higher than the true blood nadolol concentration at the time of death due to significant diffusion from the peripheral tissues.”

They added that the report did not address “other potential errors such as in compounding, dispensing, and administration of the solution,” they wrote, adding: “Finally, we are aware of a Canadian case of death in an infant receiving propranolol, although the cause of death in that case was unable to be determined (ISMP Canada 2016 Safety Bulletin).We agree with the authors that careful consideration of the risks and benefits of beta-blocker therapy should be employed, parents need to be informed when to discontinue therapy and that further research into the pharmacokinetics and pharmacogenetics of beta-blockers are warranted.”

Following publication of the case report in Pediatrics, Dr. Pope said that the only change she made in her practice was to ask families to temporarily discontinue nadolol if their child had constipation for more than 5 days.

The study was supported by a grant from Physician Services, Inc. Dr. Pope reported having no financial disclosures.

[email protected]

Compared with oral propranolol for the treatment of infantile hemangiomas, oral nadolol resulted in faster and greater size involution and color resolution with a similar safety profile out to 52 weeks, results from a prospective analysis of 71 patients showed.

“In clinical practice, we notice that nadolol works very well in terms of controlling the size and the appearance of the hemangioma,” lead study author Elena Pope, MD, MSc, said during the annual meeting of the Society for Pediatric Dermatology. Hence, she and her colleagues were interested in comparing their clinical experience with the standard treatment with propranolol, and designed a prospective, randomized, controlled, double-blinded study, with the aim of proving that “nadolol is noninferior to propranolol, with a margin of noninferiority of 10%.”

Between 2016 and 2020, Dr. Pope and colleagues at two academic Canadian pediatric dermatology centers enrolled 71 infants aged 1-6 months with significant hemangioma that had either the potential for functional impairment or cosmetic deformity, defined as a lesion greater than 1.5 cm on the face or greater than 3 cm on another body part. Treatment consisted of oral propranolol or nadolol in escalating doses up to 2 mg/kg per day. “The blinding portion of the study was for 24 weeks with a follow-up up to 52 weeks,” said Dr. Pope, professor of pediatrics at the University of Toronto and section head of pediatric dermatology at The Hospital for Sick Children, also in Toronto. “After the unblinding at 24 weeks, patients were allowed to switch their intervention if they were not happy with the results.”

Of the 71 patients, 35 received nadolol and 36 received propranolol. The two groups were similar in terms of clinical and demographic characteristics. Their mean age at enrollment was 3.15 months, 80% were female, 61% were White, 20% were Asian, and the rest were from other ethnic backgrounds.

At 24 weeks, the researchers found that the mean size involution was 97.94% in the nadolol group and 89.14% in the propranolol group (P = .005), while the mean color fading on the visual analogue scale (VAS) was 94.47% in the nadolol group and 80.54% in the propranolol group (P < .001). At 52 weeks, the mean size involution was 99.63% in the nadolol group and 93.63% in the propranolol group (P = .001), while the mean VAS color fading was 97.34% in the nadolol group and 87.23% in the propranolol group (P = .001).

According to Dr. Pope, Kaplan-Meir analysis showed that patients in the propranolol group responded slower to treatment (P = .019), while safety data was similar between the two groups. For example, between weeks 25 and 52, 84.2% of patients in the nadolol group experienced an adverse event, compared with 74.2% of patients in the propranolol group (P = .466). The most common respiratory adverse event was upper respiratory tract infection, which affected 87.5% of patients in the nadolol group, compared with 100% of patients in the propranolol group (P = 0.341).

The most common gastrointestinal adverse event was diarrhea, which affected 66.7% of patients in both groups. One patient in the propranolol group was admitted to the hospital with pneumonia and fully recovered. The incident was not suspected to be related to the medication.

“We believe that this data backs up our clinical experience and it may offer an alternative treatment in other centers where patients experience propranolol unresponsiveness, side effects, or intolerance, or where a fast response is needed,” Dr. Pope said. As for the potential cost implications, “nadolol is cheaper than the Hemangiol but comparable with the compounded formulation of propranolol.”

Concern over the safety of nadolol was raised in a case report published in Pediatrics in 2020. Authors from Alberta reported the case of a 10-week-old girl who was started on nadolol for infantile hemangioma, died 7 weeks later, and was found to have an elevated postmortem cardiac blood nadolol level of 0.94 mg/L. “The infant had no bowel movements for 10 days before her death, which we hypothesize contributed to nadolol toxicity,” the authors wrote.

In a reply to the authors in the same issue of Pediatrics, Dr. Pope, Cathryn Sibbald, MD, and Erin Chung, PhD, pointed out that postmortem redistribution of medications “is complex and measured postmortem cardiac blood concentrations may be significantly higher than the true blood nadolol concentration at the time of death due to significant diffusion from the peripheral tissues.”

They added that the report did not address “other potential errors such as in compounding, dispensing, and administration of the solution,” they wrote, adding: “Finally, we are aware of a Canadian case of death in an infant receiving propranolol, although the cause of death in that case was unable to be determined (ISMP Canada 2016 Safety Bulletin).We agree with the authors that careful consideration of the risks and benefits of beta-blocker therapy should be employed, parents need to be informed when to discontinue therapy and that further research into the pharmacokinetics and pharmacogenetics of beta-blockers are warranted.”

Following publication of the case report in Pediatrics, Dr. Pope said that the only change she made in her practice was to ask families to temporarily discontinue nadolol if their child had constipation for more than 5 days.

The study was supported by a grant from Physician Services, Inc. Dr. Pope reported having no financial disclosures.

[email protected]

Compared with oral propranolol for the treatment of infantile hemangiomas, oral nadolol resulted in faster and greater size involution and color resolution with a similar safety profile out to 52 weeks, results from a prospective analysis of 71 patients showed.

“In clinical practice, we notice that nadolol works very well in terms of controlling the size and the appearance of the hemangioma,” lead study author Elena Pope, MD, MSc, said during the annual meeting of the Society for Pediatric Dermatology. Hence, she and her colleagues were interested in comparing their clinical experience with the standard treatment with propranolol, and designed a prospective, randomized, controlled, double-blinded study, with the aim of proving that “nadolol is noninferior to propranolol, with a margin of noninferiority of 10%.”

Between 2016 and 2020, Dr. Pope and colleagues at two academic Canadian pediatric dermatology centers enrolled 71 infants aged 1-6 months with significant hemangioma that had either the potential for functional impairment or cosmetic deformity, defined as a lesion greater than 1.5 cm on the face or greater than 3 cm on another body part. Treatment consisted of oral propranolol or nadolol in escalating doses up to 2 mg/kg per day. “The blinding portion of the study was for 24 weeks with a follow-up up to 52 weeks,” said Dr. Pope, professor of pediatrics at the University of Toronto and section head of pediatric dermatology at The Hospital for Sick Children, also in Toronto. “After the unblinding at 24 weeks, patients were allowed to switch their intervention if they were not happy with the results.”

Of the 71 patients, 35 received nadolol and 36 received propranolol. The two groups were similar in terms of clinical and demographic characteristics. Their mean age at enrollment was 3.15 months, 80% were female, 61% were White, 20% were Asian, and the rest were from other ethnic backgrounds.

At 24 weeks, the researchers found that the mean size involution was 97.94% in the nadolol group and 89.14% in the propranolol group (P = .005), while the mean color fading on the visual analogue scale (VAS) was 94.47% in the nadolol group and 80.54% in the propranolol group (P < .001). At 52 weeks, the mean size involution was 99.63% in the nadolol group and 93.63% in the propranolol group (P = .001), while the mean VAS color fading was 97.34% in the nadolol group and 87.23% in the propranolol group (P = .001).

According to Dr. Pope, Kaplan-Meir analysis showed that patients in the propranolol group responded slower to treatment (P = .019), while safety data was similar between the two groups. For example, between weeks 25 and 52, 84.2% of patients in the nadolol group experienced an adverse event, compared with 74.2% of patients in the propranolol group (P = .466). The most common respiratory adverse event was upper respiratory tract infection, which affected 87.5% of patients in the nadolol group, compared with 100% of patients in the propranolol group (P = 0.341).

The most common gastrointestinal adverse event was diarrhea, which affected 66.7% of patients in both groups. One patient in the propranolol group was admitted to the hospital with pneumonia and fully recovered. The incident was not suspected to be related to the medication.

“We believe that this data backs up our clinical experience and it may offer an alternative treatment in other centers where patients experience propranolol unresponsiveness, side effects, or intolerance, or where a fast response is needed,” Dr. Pope said. As for the potential cost implications, “nadolol is cheaper than the Hemangiol but comparable with the compounded formulation of propranolol.”

Concern over the safety of nadolol was raised in a case report published in Pediatrics in 2020. Authors from Alberta reported the case of a 10-week-old girl who was started on nadolol for infantile hemangioma, died 7 weeks later, and was found to have an elevated postmortem cardiac blood nadolol level of 0.94 mg/L. “The infant had no bowel movements for 10 days before her death, which we hypothesize contributed to nadolol toxicity,” the authors wrote.

In a reply to the authors in the same issue of Pediatrics, Dr. Pope, Cathryn Sibbald, MD, and Erin Chung, PhD, pointed out that postmortem redistribution of medications “is complex and measured postmortem cardiac blood concentrations may be significantly higher than the true blood nadolol concentration at the time of death due to significant diffusion from the peripheral tissues.”

They added that the report did not address “other potential errors such as in compounding, dispensing, and administration of the solution,” they wrote, adding: “Finally, we are aware of a Canadian case of death in an infant receiving propranolol, although the cause of death in that case was unable to be determined (ISMP Canada 2016 Safety Bulletin).We agree with the authors that careful consideration of the risks and benefits of beta-blocker therapy should be employed, parents need to be informed when to discontinue therapy and that further research into the pharmacokinetics and pharmacogenetics of beta-blockers are warranted.”

Following publication of the case report in Pediatrics, Dr. Pope said that the only change she made in her practice was to ask families to temporarily discontinue nadolol if their child had constipation for more than 5 days.

The study was supported by a grant from Physician Services, Inc. Dr. Pope reported having no financial disclosures.

[email protected]

The reported prevalence and severity of obstructive sleep apnea in women is lower, compared with men, but the consequences of the disease are “at least the same, if not worse,” with women appearing to have greater susceptibility to adverse OSA-related cardiovascular consequences – particularly as it pertains to endothelial dysfunction, Reena Mehra, MD, MS, said at the virtual annual meeting of the Associated Professional Sleep Societies.

Women more so than men have endothelial dysfunction associated with OSA, “suggesting there is an enhanced sensitivity of the female vascular endothelium to intermittent hypoxia,” said Dr. Mehra, director of sleep disorders research at the Cleveland Clinic and professor of medicine at Case Western Reserve University, also in Cleveland.

Sex-specific differences in the anatomic and physiological characteristics of the upper airway, in fat distribution and in respiratory stability as they relate to OSA have been documented for some time – and today, these and other differences relating to the diagnosis, treatment, and consequences of sleep apnea continue to be studied and elucidated, said Dr. Mehra, Anita Rajagopal, MD, and Chitra Lal, MD, in a session on OSA in women. Each spoke about the breath and implications of these differences, and of increasing recognition of the significance of OSA in women.
 

Likely underdiagnosis

Epidemiologic studies have suggested a three- to fivefold higher prevalence of OSA in men than in women in the general population. But it has also been estimated that 17%-25% of women have sleep apnea, and the prevalence reported in various studies has generally increased with time, said Dr. Rajagopal, department medical director for sleep medicine at Community Physician Network in Indianapolis, and medical director of the Community Health Network Sleep/Wake Disorders Center, also in Indianapolis.

One population-based study in Sweden, reported in 2013, found OSA (defined as an apnea-hypopnea index [AHI] ≥5) in 50% of women aged 20-70, she noted.

It’s quite possible women are being misdiagnosed or underdiagnosed because of their reporting of different symptoms, Dr. Rajagopal said. The Epworth Sleepiness Scale, commonly used to screen for OSA, has not been validated for use in women and has not been strongly associated with daytime sleepiness in women in population-based studies, she said, noting that women who report similar levels of daytime sleepiness to men are less likely to have an ESS score greater than 10.

“We shouldn’t rule out obstructive sleep apnea in women with a low ESS,” Dr. Rajagopal said in an interview after the meeting. Attentiveness to the symptoms more often reported by women – generalized daytime fatigue/lack of energy, insomnia, morning headaches, mood disturbances, and nightmares – is important, as is performance of overnight polysomnography when a home sleep study is negative and there is clinical suspicion of OSA.Respiratory disturbances in women are frequently associated with arousals – which induce less ventilatory instability in women than in men – rather than oxygen desaturations, leading to underestimation of OSA on home sleep testing. Insomnia associated with OSA in women may also increase the likelihood of a false negative result, Dr. Rajagopal said at the meeting.

“It’s really important [in sleep testing] to consider your AHI values in women,” she said. “The AHI value may not provide a true indication of the degree of sleep fragmentation being experienced by patients.” That OSA symptoms manifest in women with lower AHIs has been elucidated in research showing, for instance, that those with an AHI of 2-5 per hour have a similar level of symptoms to men with an AHI of at least 15 per hour, she said.

Women tend to have a clustering of apnea during REM sleep, and it’s possible that “the long-term effects of REM disruption contribute to greater symptomatology at lower AHI values in women compared to men,” Dr. Rajagopal said.

Also at play are when it comes to testing and diagnosis are several other key sex differences, she said. For one, the upper airways in women are less collapsible and more stable during sleep (most evident during non-REM sleep), and respiratory events during sleep are less frequently associated with complete upper airway collapse.

Women also have shorter apneic episodes, but “the longest apneas are associated with a more severe oxygen desaturation,” she said. Moreover, they have more episodes of upper airway resistance during sleep, which in and of itself “has been shown to produce clinical symptoms such as daytime fatigue and clinical depression.”

In her presentation, Dr. Mehra similarly commented on a likely underdiagnosis of OSA in women. In addition to differing symptoms, including palpitations, “women are less likely to have arousals, and have a lesser degree of nocturnal hypoxia compared to men ... perhaps leading to even more of an underdiagnosis.”
 

Unique consequences

Differences in upper airway physiology and other sex-specific differences impacting OSA susceptibility are at least partly attributable to sex hormones, said Dr. Mehra and Dr. Lal, associate professor of medicine at the Medical University of South Carolina, Charleston.

A significant increase in prevalence is seen after menopause, and research has shown that each additional year in menopause is associated with a greater AHI – a “dose-response effect,” Dr. Lal said. An inverse association between hormone replacement therapy and OSA severity has been seen in epidemiological studies including the Sleep Heart Health Study, Dr. Mehra said. But in prospective studies, Dr. Lal noted, hormone replacement therapy has not been shown to decrease AHI.

Experimental and clinical studies suggest that the vascular endothelium is influenced by sex hormones, Dr. Mehra said. Estrogen is known to improve endothelial function by inducing increased nitric oxide bioavailability – important in the setting of hypoxemia, which leads to reduced bioavailability of nitric oxide. “Alterations of sex-specific hormones in OSA may represent a key factor in increasing vulnerability to vascular dysfunction,” Dr. Mehra added.

The Sleep Heart Health Study also documented sex-specific differences, showing a graded increase of troponin with increasing OSA severity category as well as an increase in left ventricular mass thickness, and a 30% increased risk of heart failure or death in women with moderate/severe OSA, compared with women without OSA or with mild OSA, Dr. Mehra said. These findings were not observed in men.

The dominance of REM-related OSA in women raises risk because sleep disturbances during REM sleep are associated with adverse cardiometabolic outcomes including prevalent and incident hypertension, Dr. Mehra noted. “REM-related OSA may also adversely impact glucose metabolism,” she said, “even in the absence of non-REM obstructive sleep apnea.”

Regarding OSA treatment and responsivity, Dr. Mehra said that preliminary, post hoc data from a randomized, controlled trial of the impact of continuous positive airway pressure (CPAP) therapy on cardiovascular biomarkers showed a sex-specific effect. “There were differences in men versus women in terms of responsiveness with regards to biomarkers of inflammation and oxidative stress ... with reductions from CPAP observed in women but not in men,” said Dr. Mehra, a co-investigator of the study.

The data suggests, she said that “these biomarkers may be more responsive to treatment and a reversal of sleep apnea pathophysiology in women.”

Women also appear to respond better than men to upper airway nerve stimulation (UAS), she said, referring to an international registry study showing a 3.6-fold higher odds of responsiveness to the therapy relative to men. Women in the study were 60% less likely to be approved by insurance for UAS, however, making it “a public policy issue, said Dr. Mehra, a coinvestigator.

Dr. Rajagopal, Dr. Mehra, and Dr. Lal all reported that they had no potential conflicts of interest.

The reported prevalence and severity of obstructive sleep apnea in women is lower, compared with men, but the consequences of the disease are “at least the same, if not worse,” with women appearing to have greater susceptibility to adverse OSA-related cardiovascular consequences – particularly as it pertains to endothelial dysfunction, Reena Mehra, MD, MS, said at the virtual annual meeting of the Associated Professional Sleep Societies.

Women more so than men have endothelial dysfunction associated with OSA, “suggesting there is an enhanced sensitivity of the female vascular endothelium to intermittent hypoxia,” said Dr. Mehra, director of sleep disorders research at the Cleveland Clinic and professor of medicine at Case Western Reserve University, also in Cleveland.

Sex-specific differences in the anatomic and physiological characteristics of the upper airway, in fat distribution and in respiratory stability as they relate to OSA have been documented for some time – and today, these and other differences relating to the diagnosis, treatment, and consequences of sleep apnea continue to be studied and elucidated, said Dr. Mehra, Anita Rajagopal, MD, and Chitra Lal, MD, in a session on OSA in women. Each spoke about the breath and implications of these differences, and of increasing recognition of the significance of OSA in women.
 

Likely underdiagnosis

Epidemiologic studies have suggested a three- to fivefold higher prevalence of OSA in men than in women in the general population. But it has also been estimated that 17%-25% of women have sleep apnea, and the prevalence reported in various studies has generally increased with time, said Dr. Rajagopal, department medical director for sleep medicine at Community Physician Network in Indianapolis, and medical director of the Community Health Network Sleep/Wake Disorders Center, also in Indianapolis.

One population-based study in Sweden, reported in 2013, found OSA (defined as an apnea-hypopnea index [AHI] ≥5) in 50% of women aged 20-70, she noted.

It’s quite possible women are being misdiagnosed or underdiagnosed because of their reporting of different symptoms, Dr. Rajagopal said. The Epworth Sleepiness Scale, commonly used to screen for OSA, has not been validated for use in women and has not been strongly associated with daytime sleepiness in women in population-based studies, she said, noting that women who report similar levels of daytime sleepiness to men are less likely to have an ESS score greater than 10.

“We shouldn’t rule out obstructive sleep apnea in women with a low ESS,” Dr. Rajagopal said in an interview after the meeting. Attentiveness to the symptoms more often reported by women – generalized daytime fatigue/lack of energy, insomnia, morning headaches, mood disturbances, and nightmares – is important, as is performance of overnight polysomnography when a home sleep study is negative and there is clinical suspicion of OSA.Respiratory disturbances in women are frequently associated with arousals – which induce less ventilatory instability in women than in men – rather than oxygen desaturations, leading to underestimation of OSA on home sleep testing. Insomnia associated with OSA in women may also increase the likelihood of a false negative result, Dr. Rajagopal said at the meeting.

“It’s really important [in sleep testing] to consider your AHI values in women,” she said. “The AHI value may not provide a true indication of the degree of sleep fragmentation being experienced by patients.” That OSA symptoms manifest in women with lower AHIs has been elucidated in research showing, for instance, that those with an AHI of 2-5 per hour have a similar level of symptoms to men with an AHI of at least 15 per hour, she said.

Women tend to have a clustering of apnea during REM sleep, and it’s possible that “the long-term effects of REM disruption contribute to greater symptomatology at lower AHI values in women compared to men,” Dr. Rajagopal said.

Also at play are when it comes to testing and diagnosis are several other key sex differences, she said. For one, the upper airways in women are less collapsible and more stable during sleep (most evident during non-REM sleep), and respiratory events during sleep are less frequently associated with complete upper airway collapse.

Women also have shorter apneic episodes, but “the longest apneas are associated with a more severe oxygen desaturation,” she said. Moreover, they have more episodes of upper airway resistance during sleep, which in and of itself “has been shown to produce clinical symptoms such as daytime fatigue and clinical depression.”

In her presentation, Dr. Mehra similarly commented on a likely underdiagnosis of OSA in women. In addition to differing symptoms, including palpitations, “women are less likely to have arousals, and have a lesser degree of nocturnal hypoxia compared to men ... perhaps leading to even more of an underdiagnosis.”
 

Unique consequences

Differences in upper airway physiology and other sex-specific differences impacting OSA susceptibility are at least partly attributable to sex hormones, said Dr. Mehra and Dr. Lal, associate professor of medicine at the Medical University of South Carolina, Charleston.

A significant increase in prevalence is seen after menopause, and research has shown that each additional year in menopause is associated with a greater AHI – a “dose-response effect,” Dr. Lal said. An inverse association between hormone replacement therapy and OSA severity has been seen in epidemiological studies including the Sleep Heart Health Study, Dr. Mehra said. But in prospective studies, Dr. Lal noted, hormone replacement therapy has not been shown to decrease AHI.

Experimental and clinical studies suggest that the vascular endothelium is influenced by sex hormones, Dr. Mehra said. Estrogen is known to improve endothelial function by inducing increased nitric oxide bioavailability – important in the setting of hypoxemia, which leads to reduced bioavailability of nitric oxide. “Alterations of sex-specific hormones in OSA may represent a key factor in increasing vulnerability to vascular dysfunction,” Dr. Mehra added.

The Sleep Heart Health Study also documented sex-specific differences, showing a graded increase of troponin with increasing OSA severity category as well as an increase in left ventricular mass thickness, and a 30% increased risk of heart failure or death in women with moderate/severe OSA, compared with women without OSA or with mild OSA, Dr. Mehra said. These findings were not observed in men.

The dominance of REM-related OSA in women raises risk because sleep disturbances during REM sleep are associated with adverse cardiometabolic outcomes including prevalent and incident hypertension, Dr. Mehra noted. “REM-related OSA may also adversely impact glucose metabolism,” she said, “even in the absence of non-REM obstructive sleep apnea.”

Regarding OSA treatment and responsivity, Dr. Mehra said that preliminary, post hoc data from a randomized, controlled trial of the impact of continuous positive airway pressure (CPAP) therapy on cardiovascular biomarkers showed a sex-specific effect. “There were differences in men versus women in terms of responsiveness with regards to biomarkers of inflammation and oxidative stress ... with reductions from CPAP observed in women but not in men,” said Dr. Mehra, a co-investigator of the study.

The data suggests, she said that “these biomarkers may be more responsive to treatment and a reversal of sleep apnea pathophysiology in women.”

Women also appear to respond better than men to upper airway nerve stimulation (UAS), she said, referring to an international registry study showing a 3.6-fold higher odds of responsiveness to the therapy relative to men. Women in the study were 60% less likely to be approved by insurance for UAS, however, making it “a public policy issue, said Dr. Mehra, a coinvestigator.

Dr. Rajagopal, Dr. Mehra, and Dr. Lal all reported that they had no potential conflicts of interest.

The reported prevalence and severity of obstructive sleep apnea in women is lower, compared with men, but the consequences of the disease are “at least the same, if not worse,” with women appearing to have greater susceptibility to adverse OSA-related cardiovascular consequences – particularly as it pertains to endothelial dysfunction, Reena Mehra, MD, MS, said at the virtual annual meeting of the Associated Professional Sleep Societies.

Women more so than men have endothelial dysfunction associated with OSA, “suggesting there is an enhanced sensitivity of the female vascular endothelium to intermittent hypoxia,” said Dr. Mehra, director of sleep disorders research at the Cleveland Clinic and professor of medicine at Case Western Reserve University, also in Cleveland.

Sex-specific differences in the anatomic and physiological characteristics of the upper airway, in fat distribution and in respiratory stability as they relate to OSA have been documented for some time – and today, these and other differences relating to the diagnosis, treatment, and consequences of sleep apnea continue to be studied and elucidated, said Dr. Mehra, Anita Rajagopal, MD, and Chitra Lal, MD, in a session on OSA in women. Each spoke about the breath and implications of these differences, and of increasing recognition of the significance of OSA in women.
 

Likely underdiagnosis

Epidemiologic studies have suggested a three- to fivefold higher prevalence of OSA in men than in women in the general population. But it has also been estimated that 17%-25% of women have sleep apnea, and the prevalence reported in various studies has generally increased with time, said Dr. Rajagopal, department medical director for sleep medicine at Community Physician Network in Indianapolis, and medical director of the Community Health Network Sleep/Wake Disorders Center, also in Indianapolis.

One population-based study in Sweden, reported in 2013, found OSA (defined as an apnea-hypopnea index [AHI] ≥5) in 50% of women aged 20-70, she noted.

It’s quite possible women are being misdiagnosed or underdiagnosed because of their reporting of different symptoms, Dr. Rajagopal said. The Epworth Sleepiness Scale, commonly used to screen for OSA, has not been validated for use in women and has not been strongly associated with daytime sleepiness in women in population-based studies, she said, noting that women who report similar levels of daytime sleepiness to men are less likely to have an ESS score greater than 10.

“We shouldn’t rule out obstructive sleep apnea in women with a low ESS,” Dr. Rajagopal said in an interview after the meeting. Attentiveness to the symptoms more often reported by women – generalized daytime fatigue/lack of energy, insomnia, morning headaches, mood disturbances, and nightmares – is important, as is performance of overnight polysomnography when a home sleep study is negative and there is clinical suspicion of OSA.Respiratory disturbances in women are frequently associated with arousals – which induce less ventilatory instability in women than in men – rather than oxygen desaturations, leading to underestimation of OSA on home sleep testing. Insomnia associated with OSA in women may also increase the likelihood of a false negative result, Dr. Rajagopal said at the meeting.

“It’s really important [in sleep testing] to consider your AHI values in women,” she said. “The AHI value may not provide a true indication of the degree of sleep fragmentation being experienced by patients.” That OSA symptoms manifest in women with lower AHIs has been elucidated in research showing, for instance, that those with an AHI of 2-5 per hour have a similar level of symptoms to men with an AHI of at least 15 per hour, she said.

Women tend to have a clustering of apnea during REM sleep, and it’s possible that “the long-term effects of REM disruption contribute to greater symptomatology at lower AHI values in women compared to men,” Dr. Rajagopal said.

Also at play are when it comes to testing and diagnosis are several other key sex differences, she said. For one, the upper airways in women are less collapsible and more stable during sleep (most evident during non-REM sleep), and respiratory events during sleep are less frequently associated with complete upper airway collapse.

Women also have shorter apneic episodes, but “the longest apneas are associated with a more severe oxygen desaturation,” she said. Moreover, they have more episodes of upper airway resistance during sleep, which in and of itself “has been shown to produce clinical symptoms such as daytime fatigue and clinical depression.”

In her presentation, Dr. Mehra similarly commented on a likely underdiagnosis of OSA in women. In addition to differing symptoms, including palpitations, “women are less likely to have arousals, and have a lesser degree of nocturnal hypoxia compared to men ... perhaps leading to even more of an underdiagnosis.”
 

Unique consequences

Differences in upper airway physiology and other sex-specific differences impacting OSA susceptibility are at least partly attributable to sex hormones, said Dr. Mehra and Dr. Lal, associate professor of medicine at the Medical University of South Carolina, Charleston.

A significant increase in prevalence is seen after menopause, and research has shown that each additional year in menopause is associated with a greater AHI – a “dose-response effect,” Dr. Lal said. An inverse association between hormone replacement therapy and OSA severity has been seen in epidemiological studies including the Sleep Heart Health Study, Dr. Mehra said. But in prospective studies, Dr. Lal noted, hormone replacement therapy has not been shown to decrease AHI.

Experimental and clinical studies suggest that the vascular endothelium is influenced by sex hormones, Dr. Mehra said. Estrogen is known to improve endothelial function by inducing increased nitric oxide bioavailability – important in the setting of hypoxemia, which leads to reduced bioavailability of nitric oxide. “Alterations of sex-specific hormones in OSA may represent a key factor in increasing vulnerability to vascular dysfunction,” Dr. Mehra added.

The Sleep Heart Health Study also documented sex-specific differences, showing a graded increase of troponin with increasing OSA severity category as well as an increase in left ventricular mass thickness, and a 30% increased risk of heart failure or death in women with moderate/severe OSA, compared with women without OSA or with mild OSA, Dr. Mehra said. These findings were not observed in men.

The dominance of REM-related OSA in women raises risk because sleep disturbances during REM sleep are associated with adverse cardiometabolic outcomes including prevalent and incident hypertension, Dr. Mehra noted. “REM-related OSA may also adversely impact glucose metabolism,” she said, “even in the absence of non-REM obstructive sleep apnea.”

Regarding OSA treatment and responsivity, Dr. Mehra said that preliminary, post hoc data from a randomized, controlled trial of the impact of continuous positive airway pressure (CPAP) therapy on cardiovascular biomarkers showed a sex-specific effect. “There were differences in men versus women in terms of responsiveness with regards to biomarkers of inflammation and oxidative stress ... with reductions from CPAP observed in women but not in men,” said Dr. Mehra, a co-investigator of the study.

The data suggests, she said that “these biomarkers may be more responsive to treatment and a reversal of sleep apnea pathophysiology in women.”

Women also appear to respond better than men to upper airway nerve stimulation (UAS), she said, referring to an international registry study showing a 3.6-fold higher odds of responsiveness to the therapy relative to men. Women in the study were 60% less likely to be approved by insurance for UAS, however, making it “a public policy issue, said Dr. Mehra, a coinvestigator.

Dr. Rajagopal, Dr. Mehra, and Dr. Lal all reported that they had no potential conflicts of interest.