Endocrinology

Osteopenia was present in more than a quarter of both men and women in early middle age, according to findings from a cross-sectional study.

The high prevalence of osteopenia – once viewed as restricted largely to older women – in the study’s younger, cross-sex population should spur physicians to ask all patients about calcium intake and exercise as well as to screen for osteoporosis in all patients, Martha A. Bass, PhD,`wrote in the Journal of the American Osteopathic Association.

“It is important that early detection of the precursors for osteoporosis become part of the annual physical for people in this age range, as well as in older patients,” noted Dr Bass of the University of Mississippi School of Applied Sciences in Oxford, and coauthors. “Primary care physicians should begin educating patients as early as adolescence or young adulthood so the consequences of osteoporosis can be prevented. The result would be the prevention of future bone fractures and the morbidity and mortality associated with bone fractures, thus leading to improved quality of life.”

The researchers set out to examine the likelihood of low bone mineral density (BMD) and related risk factors in 173 adults aged 35-50 years. All of the participants completed a questionnaire assessing calcium intake, weekly exercise, smoking, and body mass index, and all underwent screening for BMD. The study’s primary outcome was BMD at the femoral neck, trochanter, intertrochanteric crest, total femur, and lumbar spine.

Among the 81 men in the sample, 25 (30%) had a normal body mass index, and the remainder were either overweight (47.5%) or obese (22.5%). One of the women was underweight, 48.9% were normal weight, 28.3% were overweight, and 21.7% were obese.

Most of the sample, regardless of gender, reported consuming fewer than three dairy items per day. Exercise frequency was better, with 68% of men and 56.4% of women saying they exercised at least 20 times per month.

There were no total femur osteoporosis findings in either sex. However, osteopenia at the femoral neck was present in 28.4% of the men and 26.1% of the women. Osteopenia at the lumbar spine occurred in 21% of men and 15.2% of women, with 6.2% of men and 2.2% of women showing osteoporosis at this site.

An adjusted analysis determined that exercise correlated significantly and negatively with femoral neck BMD in men. But in women, there was a significant and positive correlation with BMD at the lumbar spine and at all femoral measurements.

Body mass index also played into the risk picture. Among men, almost all BMD measurements (trochanter, intertrochanteric crest, total femur, and lumbar spine) were positively associated with higher BMI. For women, higher BMI was associated with better BMD at the all the femoral sites, but not at the lumbar spine.

The negative correlation between femoral neck BMD and exercise in men seemed to contradict findings from previous studies. The authors said that could be a result of reporting bias, with men overestimating their amount of exercise, and could suggest that higher BMI confers some protection against bone loss in men.

The study found no significant correlations between dairy intake and BMD at any site in either sex. The finding suggests that both sexes need to improve both vitamin D and calcium intake.

None of the authors reported any financial disclosures.

[email protected]

SOURCE: Bass MA et al. J Am Osteopath Assoc. 2019;119(6):357-63.

Osteopenia was present in more than a quarter of both men and women in early middle age, according to findings from a cross-sectional study.

The high prevalence of osteopenia – once viewed as restricted largely to older women – in the study’s younger, cross-sex population should spur physicians to ask all patients about calcium intake and exercise as well as to screen for osteoporosis in all patients, Martha A. Bass, PhD,`wrote in the Journal of the American Osteopathic Association.

“It is important that early detection of the precursors for osteoporosis become part of the annual physical for people in this age range, as well as in older patients,” noted Dr Bass of the University of Mississippi School of Applied Sciences in Oxford, and coauthors. “Primary care physicians should begin educating patients as early as adolescence or young adulthood so the consequences of osteoporosis can be prevented. The result would be the prevention of future bone fractures and the morbidity and mortality associated with bone fractures, thus leading to improved quality of life.”

The researchers set out to examine the likelihood of low bone mineral density (BMD) and related risk factors in 173 adults aged 35-50 years. All of the participants completed a questionnaire assessing calcium intake, weekly exercise, smoking, and body mass index, and all underwent screening for BMD. The study’s primary outcome was BMD at the femoral neck, trochanter, intertrochanteric crest, total femur, and lumbar spine.

Among the 81 men in the sample, 25 (30%) had a normal body mass index, and the remainder were either overweight (47.5%) or obese (22.5%). One of the women was underweight, 48.9% were normal weight, 28.3% were overweight, and 21.7% were obese.

Most of the sample, regardless of gender, reported consuming fewer than three dairy items per day. Exercise frequency was better, with 68% of men and 56.4% of women saying they exercised at least 20 times per month.

There were no total femur osteoporosis findings in either sex. However, osteopenia at the femoral neck was present in 28.4% of the men and 26.1% of the women. Osteopenia at the lumbar spine occurred in 21% of men and 15.2% of women, with 6.2% of men and 2.2% of women showing osteoporosis at this site.

An adjusted analysis determined that exercise correlated significantly and negatively with femoral neck BMD in men. But in women, there was a significant and positive correlation with BMD at the lumbar spine and at all femoral measurements.

Body mass index also played into the risk picture. Among men, almost all BMD measurements (trochanter, intertrochanteric crest, total femur, and lumbar spine) were positively associated with higher BMI. For women, higher BMI was associated with better BMD at the all the femoral sites, but not at the lumbar spine.

The negative correlation between femoral neck BMD and exercise in men seemed to contradict findings from previous studies. The authors said that could be a result of reporting bias, with men overestimating their amount of exercise, and could suggest that higher BMI confers some protection against bone loss in men.

The study found no significant correlations between dairy intake and BMD at any site in either sex. The finding suggests that both sexes need to improve both vitamin D and calcium intake.

None of the authors reported any financial disclosures.

[email protected]

SOURCE: Bass MA et al. J Am Osteopath Assoc. 2019;119(6):357-63.

Osteopenia was present in more than a quarter of both men and women in early middle age, according to findings from a cross-sectional study.

The high prevalence of osteopenia – once viewed as restricted largely to older women – in the study’s younger, cross-sex population should spur physicians to ask all patients about calcium intake and exercise as well as to screen for osteoporosis in all patients, Martha A. Bass, PhD,`wrote in the Journal of the American Osteopathic Association.

“It is important that early detection of the precursors for osteoporosis become part of the annual physical for people in this age range, as well as in older patients,” noted Dr Bass of the University of Mississippi School of Applied Sciences in Oxford, and coauthors. “Primary care physicians should begin educating patients as early as adolescence or young adulthood so the consequences of osteoporosis can be prevented. The result would be the prevention of future bone fractures and the morbidity and mortality associated with bone fractures, thus leading to improved quality of life.”

The researchers set out to examine the likelihood of low bone mineral density (BMD) and related risk factors in 173 adults aged 35-50 years. All of the participants completed a questionnaire assessing calcium intake, weekly exercise, smoking, and body mass index, and all underwent screening for BMD. The study’s primary outcome was BMD at the femoral neck, trochanter, intertrochanteric crest, total femur, and lumbar spine.

Among the 81 men in the sample, 25 (30%) had a normal body mass index, and the remainder were either overweight (47.5%) or obese (22.5%). One of the women was underweight, 48.9% were normal weight, 28.3% were overweight, and 21.7% were obese.

Most of the sample, regardless of gender, reported consuming fewer than three dairy items per day. Exercise frequency was better, with 68% of men and 56.4% of women saying they exercised at least 20 times per month.

There were no total femur osteoporosis findings in either sex. However, osteopenia at the femoral neck was present in 28.4% of the men and 26.1% of the women. Osteopenia at the lumbar spine occurred in 21% of men and 15.2% of women, with 6.2% of men and 2.2% of women showing osteoporosis at this site.

An adjusted analysis determined that exercise correlated significantly and negatively with femoral neck BMD in men. But in women, there was a significant and positive correlation with BMD at the lumbar spine and at all femoral measurements.

Body mass index also played into the risk picture. Among men, almost all BMD measurements (trochanter, intertrochanteric crest, total femur, and lumbar spine) were positively associated with higher BMI. For women, higher BMI was associated with better BMD at the all the femoral sites, but not at the lumbar spine.

The negative correlation between femoral neck BMD and exercise in men seemed to contradict findings from previous studies. The authors said that could be a result of reporting bias, with men overestimating their amount of exercise, and could suggest that higher BMI confers some protection against bone loss in men.

The study found no significant correlations between dairy intake and BMD at any site in either sex. The finding suggests that both sexes need to improve both vitamin D and calcium intake.

None of the authors reported any financial disclosures.

[email protected]

SOURCE: Bass MA et al. J Am Osteopath Assoc. 2019;119(6):357-63.

Keeping up with current evidence-based healthcare practices is key to providing good clinical care to patients. This review presents 5 vignettes that highlight key issues in women’s health: osteoporosis screening, hormonal contraceptive interactions with antibiotics, hormone replacement therapy in carriers of the BRCA1 gene mutation, risks associated with hormonal contraception, and breast cancer diagnosis using digital tomosynthesis in addition to digital mammography. Supporting articles, all published in 2017 and 2018, were selected from high-impact medical and women’s health journals.

OSTEOPOROSIS SCREENING FOR FRACTURE PREVENTION

A 60-year-old woman reports that her last menstrual period was 7 years ago. She has no history of falls or fractures, and she takes no medications. She smokes 10 cigarettes per day and drinks 3 to 4 alcoholic beverages on most days of the week. She is 5 feet 6 inches (170 cm) tall and weighs 107 lb. Should she be screened for osteoporosis?

Osteoporosis is underdiagnosed

It is estimated that, in the United States, 12.3 million individuals older than 50 will develop osteoporosis by 2020. Missed opportunities to screen high-risk individuals can lead to fractures, including fractures of the hip.¹

Updated screening recommendations

In 2018, the US Preventive Services Task Force (USPSTF) developed and published evidence-based recommendations for osteoporosis screening to help providers identify and treat osteoporosis early to prevent fractures.² Available evidence on screening and treatment in women and men were reviewed with the intention of updating the 2011 USPSTF recommendations. The review also evaluated risk assessment tools, screening intervals, and efficacy of screening and treatment in various subpopulations.

Since the 2011 recommendations, more data have become available on fracture risk assessment with or without bone mineral density measurements. In its 2018 report, the USPSTF recommends that postmenopausal women younger than 65 should undergo screening with a bone density test if their 10-year risk of major osteoporotic fracture is more than 8.4%. This is equivalent to the fracture risk of a 65-year-old white woman with no major risk factors for fracture (grade B recommendation—high certainty that the benefit is moderate, or moderate certainty that the benefit is moderate to substantial).²

Assessment of fracture risk

For postmenopausal women who are under age 65 and who have at least 1 risk factor for fracture, it is reasonable to use a clinical risk assessment tool to determine who should undergo screening with bone mineral density measurement. Risk factors associated with an increased risk of osteoporotic fractures include a parental history of hip fracture, smoking, intake of 3 or more alcoholic drinks per day, low body weight, malabsorption, rheumatoid arthritis, diabetes, and postmenopausal status (not using estrogen replacement). Medications should be carefully reviewed for those that can increase the risk of fractures, including steroids and antiestrogen treatments.

The 10-year risk of a major osteoporotic or hip fracture can be assessed using the Fractional Risk Assessment Tool (FRAX), available at www.sheffield.ac.uk/FRAX/. Other acceptable tools that perform similarly to FRAX include the Osteoporosis Risk Assessment Instrument (ORAI) (10 studies; N = 16,780), Osteoporosis Index of Risk (OSIRIS) (5 studies; N = 5,649), Osteoporosis Self-Assessment Tool (OST) (13 studies; N = 44,323), and Simple Calculated Osteoporosis Risk Estimation (SCORE) (8 studies; N = 15,362).

Should this patient be screened for osteoporosis?

Based on the FRAX, this patient’s 10-year risk of major osteoporosis fracture is 9.2%. She would benefit from osteoporosis screening with a bone density test.

DO ANTIBIOTICS REDUCE EFFECTIVENESS OF HORMONAL CONTRACEPTION?

A 27-year-old woman presents with a dog bite on her right hand and is started on oral antibiotics. She takes an oral contraceptive that contains 35 µg of ethinyl estradiol and 0.25 mg of norgestimate. She asks if she should use condoms while taking antibiotics.

The antibiotics rifampin and rifabutin are known inducers of the hepatic enzymes required for contraceptive steroid metabolism, whereas other antibiotics are not. Despite the lack of compelling evidence that broad-spectrum antibiotics interfere with the efficacy of hormonal contraception, most pharmacists recommend backup contraception for women who use concomitant antibiotics.³ This practice could lead to poor compliance with the contraceptive regimen, the antibiotic regimen, or both.³

Simmons et al³ conducted a systematic review of randomized and nonrandomized studies that assessed pregnancy rates, breakthrough bleeding, ovulation suppression, and hormone pharmacokinetics in women taking oral or vaginal hormonal contraceptives in combination with nonrifamycin antibiotics, including oral, intramuscular, and intravenous forms. Oral contraceptives used in the studies included a range of doses and progestins, but lowest-dose pills, such as those containing less than 30 µg ethinyl estradiol or less than 150 µg levonorgestrel, were not included.

The contraceptive formulations in this systematic review³ included oral contraceptive pills, emergency contraception pills, and the contraceptive vaginal ring. The effect of antibiotics on other nonoral contraceptives, such as the transdermal patch, injectables, and progestin implants was not studied.

Four observational studies³ evaluated pregnancy rates or hormonal contraception failure with any antibiotic use. In 2 of these 4 studies, there was no difference in pregnancy rates in women who used oral contraceptives with and without nonrifamycin antibiotics. However, ethinyl estradiol was shown to have increased clearance when administered with dirithromycin (a macrolide).³ Twenty-five of the studies reported measures of contraceptive effectiveness (ovulation) and pharmacokinetic outcomes.

There were no observed differences in ovulation suppression or breakthrough bleeding in any study that combined hormonal contraceptives with an antibiotic. Furthermore, there was no significant decrease in progestin pharmacokinetic parameters during coadministration with an antibiotic.³ Study limitations included small sample sizes and the observational nature of the data.

How would you counsel this patient?

Available evidence suggests that nonrifamycin antibiotics do not diminish the effectiveness of the vaginal contraceptive ring or an oral hormonal contraceptive that contains at least 30 µg of ethinyl estradiol or 150 µg of levonorgestrel. Current guidelines do not recommend the use of additional backup contraception, regardless of hormonal contraception dose or formulation.⁴ Likewise, the most recent guidance for dental practitioners (ie, from 2012) no longer advises women to use additional contraceptive protection when taking nonrifamycin antibiotics.⁵

In our practice, we discuss the option of additional protection when prescribing formulations with lower estrogen doses (< 30 µg), not only because of the limitations of the available data, but also because of the high rates of unintended pregnancy with typical use of combined hormonal contraceptives (9% per year, unrelated to use of antibiotics).⁴ However, if our patient would rather not use additional barrier methods, she can be reassured that concomitant nonrifamycin antibiotic use is unlikely to affect contraceptive effectiveness.

A 41-year-old healthy mother of 3 was recently found to be a carrier of the BRCA1 mutation. She is planning to undergo prophylactic bilateral salpingo-oophorectomy for ovarian cancer prevention. However, she is apprehensive about undergoing surgical menopause. Should she be started on hormone replacement therapy after oophorectomy? How would hormone replacement therapy affect her risk of breast cancer?

In females who carry the BRCA1 mutation, the cumulative risk of both ovarian and breast cancer approaches 44% (95% confidence interval [CI] 36%–53%) and 72% (95% CI 65%–79%) by age 80.⁶ Prophylactic salpingo-oophorectomy reduces the risk of breast cancer by 50% and the risk of ovarian cancer by 90%. Unfortunately, premature withdrawal of ovarian hormones has been associated with long-term adverse effects including significant vasomotor symptoms, decreased quality of life, sexual dysfunction, early mortality, bone loss, decline in mood and cognition, and poor cardiovascular outcomes.⁷ Many of these effects can be avoided or lessened with hormone replacement therapy.

Kotsopoulos et al⁸ conducted a longitudinal, prospective analysis of BRCA1 mutation carriers in a multicenter study between 1995 and 2017. The mean follow-up period was 7.6 years (range 0.4–22.1). The study assessed associations between the use of hormone replacement therapy and breast cancer risk in carriers of the BRCA1 mutation who underwent prophylactic salpingo-oophorectomy. Study participants did not have a personal history of cancer. Those with a history of prophylactic mastectomy were excluded.

Participants completed a series of questionnaires every 2 years, disclosing updates in personal medical, cancer, and reproductive history. The questionnaires also inquired about the use of hormone replacement therapy, including the type used (estrogen only, progestin only, estrogen plus progestin, other), brand name, duration of use, and dose and route of administration (pill, patch, suppository).

Of the 13,087 BRCA1 mutation carriers identified, 872 met the study criteria. Of those, 377 (43%) reported using some form of hormone replacement therapy after salpingo-oophorectomy, and 495 (57%) did not. The average duration of use was 3.9 years (range 0.5–19), with most (69%) using estrogen alone; 18% used other regimens, including estrogen plus progestin and progestin only. A small percentage of participants did not indicate which formulation they used. On average, women using hormone replacement therapy underwent prophylactic oophorectomy earlier than nonusers (age 43.0 vs 48.4; absolute difference 5.5 years, P < .001).

During follow-up, there was no significant difference noted in the proportion of women diagnosed with breast cancer between hormone replacement therapy users and nonusers (10.3 vs 10.7%; absolute difference 0.4%; P = .86). In fact, for each year of estrogen-containing hormone replacement therapy, there was an 18% reduction in breast cancer risk when oophorectomy was performed before age 45 (95% CI 0.69–0.97). The authors also noted a nonsignificant 14% trend toward an increase in breast cancer risk for each year of progestin use after oophorectomy when surgery was performed before age 45 (95% CI 0.9–1.46).

Although prophylactic hysterectomy was not recommended, the authors noted that hysterectomy would eliminate the need for progestin-containing hormone replacement therapy. For those who underwent oophorectomy after age 45, hormone replacement therapy did not increase or decrease the risk of breast cancer.⁷

A meta-analysis by Marchetti et al⁹ also supports the safety of hormone replacement therapy after risk-reducing salpingo-oophorectomy. Three studies that included 1,100 patients were analyzed (including the Kotsopoulos study⁸ noted above). There was a nonsignificant decrease in breast cancer risk in women on estrogen-only hormone replacement therapy compared with women on estrogen-plus-progestin therapy (odds ratio 0.53, 95% CI 0.25–1.15). Overall, the authors regarded hormone replacement therapy as a safe therapeutic option after prophylactic salpingo-oophorectomy in carriers of the BRCA1 and BRCA2 mutations.⁹

In a case-control study published in 2016,¹⁰ hormone replacement therapy was assessed in 432 postmenopausal BRCA1 mutation carriers with invasive breast cancer (cases) and in 432 BRCA1 mutation carriers without a history of breast cancer (controls). Results showed no difference in breast cancer risk between hormone replacement therapy users and nonusers.¹⁰

Rebbeck et al¹¹ evaluated short-term hormone replacement therapy in BRCA1 and BRCA2 gene-mutation carriers after they underwent prophylactic salpingo-oophorectomy. The results showed that hormone replacement did not affect the breast cancer risk-reduction conferred with prophylactic bilateral salpingo-oophorectomy.

Johansen et al¹² evaluated hormone replacement therapy in premenopausal women after prophylactic salpingo-oophorectomy. They studied 324 carriers of BRCA gene mutations after they underwent prophylactic salpingo-oophorectomy and a subset of 950 controls who had bilateral salpingo-oophorectomy for reasons unrelated to cancer. In both groups, hormone replacement therapy was underutilized. The authors recommended using it when clinically indicated.

Should your patient start hormone replacement therapy?

This patient is healthy, and in the absence of contraindications, systemic hormone replacement therapy after prophylactic oophorectomy could mitigate the potential adverse effects of surgically induced menopause. The patient can be reassured that estrogen-containing short-term hormone replacement therapy is unlikely to increase her breast cancer risk.

A 44-year-old woman presents to your office for an annual visit. She is sexually active but does not wish to become pregnant. She has a family history of breast cancer: her mother was diagnosed at age 53. She is interested in an oral contraceptive to prevent pregnancy and acne. However, she is nervous about being on any contraceptive that may increase her risk of breast cancer.

To date, studies assessing the effect of hormonal contraception on the risk of breast cancer have produced inconsistent results. Although most studies have shown no associated risk, a few have shown a temporary 20% to 30% increased risk of breast cancer during use.^13,14 Case-controlled studies that reported an association between hormonal contraception and breast cancer included populations taking higher-dose combination pills, which are no longer prescribed. Most studies do not evaluate specific formulations of hormonal contraception, and little is known about effects associated with intrauterine devices or progestin-only contraception.

A prospective study performed by Mørch et al¹³ followed more than 1 million reproductive-aged women for a mean of 10.9 years. The Danish Cancer Registry was used to identify cases of invasive breast cancer. Women who used hormonal contraceptives had a relative risk of breast cancer of 1.20 compared with women not on hormonal contraception (95% CI 1.14–1.26). The study suggested that those who had been on contraceptive agents for more than 5 years had an increased risk and that this risk remained for 5 years after the agents were discontinued. Conversely, no increased risk of cancer was noted in those who used hormonal contraception for less than 5 years. No notable differences were seen among various formulations.

For women using the levonorgestrel-containing intrauterine device, the relative risk of breast cancer was 1.21 (95% CI 1.11–1.33). A few cancers were noted in those who used the progestin-only implant or those using depot medroxyprogesterone acetate. While the study showed an increased relative risk of breast cancer, the absolute risk was low—13 cases per 100,000, or approximately 1 additional case of breast cancer per 7,690 per year.¹³

This study had several important limitations. The authors did not adjust for common breast cancer risk factors including age at menarche, alcohol use, or breastfeeding. Additionally, the study did not account for the use of hormonal contraception before the study period and conversely, did not account for women who may have stopped taking their contraceptive despite their prescribed duration. The frequency of mammography was not explicitly noted, which could have shifted results for women who had more aggressive screening.

It is also noteworthy that the use of high-dose systemic progestins was not associated with an increased risk, whereas the levonorgestrel intrauterine device, which contains only 1/20th the dose of a low-dose oral contraceptive pill, was associated with an increased risk. This discrepancy in risk warrants further investigation, and clinicians should be aware that this inconsistency needs validation before changing clinical practice.

In an observational cohort study,¹⁵ more than 100,000 women ages 50 to 71 were followed prospectively for 15 years to evaluate the association between hormonal contraceptive use and the risk of gynecologic and breast cancers. In this study, the duration of hormonal contraceptive use, smoking status, alcohol use, body mass index, physical activity, and family history of cancer were recorded. Long-term hormonal contraceptive use reduced ovarian and endometrial cancer risks by 40% and 34%, respectively, with no increase in breast cancer risk regardless of family history.

How would you counsel the patient?

The patient should be educated on the benefits of hormonal contraception that extend beyond pregnancy prevention, including regulation of menses, improved acne, decreased risk of endometrial and ovarian cancer, and likely reductions in colorectal cancer and overall mortality risk.^13–16 Further, after their own systematic review of the data assessing risk of breast cancer with hormonal contraception, the US Centers for Disease Control and Prevention state in their guidelines that all contraceptives may be used without limitation in those who have a family history of breast cancer.⁴ Any potential increased risk of breast cancer in women using hormonal contraception is small and would not outweigh the benefits associated with use.

One must consider the impact of an unintended pregnancy in such women, including effects on the health of the fetus and mother. Recent reports on the increasing rates of maternal death in the US (23.8 of 100,000 live births) serve as a reminder of the complications that can arise with pregnancy, especially if a mother’s health is not optimized before conception.¹⁷

The same 44-year-old patient now inquires about screening for breast cancer. She is curious about 3-dimensional mammography and whether it would be a better screening test for her.

Digital breast tomosynthesis (DBT) is a newer imaging modality that provides a 3-dimensional reconstruction of the breast using low-dose x-ray imaging. Some studies have shown that combining DBT with digital mammography may be superior to digital mammography alone in detecting cancers.¹⁸ However, digital mammography is currently the gold standard for breast cancer screening and is the only test proven to reduce mortality.^18,19

In a retrospective US study of 13 medical centers,²⁰ breast cancer detection rates increased by 41% the year after DBT was introduced, from 2.9 to 4.1 per 1,000 cases. DBT was associated with 16 fewer patients recalled for repeat imaging out of 1,000 women screened (as opposed to mammography alone). Two European studies similarly suggested an increase in cancer detection with lower recall rates.^21,22

Is 3-D mammography a better option?

In a 2-arm study by Pattacini et al,¹⁸ nearly 20,000 women ages 45 to 70 were randomized to undergo either digital mammography or digital mammography plus DBT for primary breast cancer screening. Women were enrolled over a 2-year period and were followed for 4.5 years, and the development of a primary invasive cancer was the primary end point. Recall rates, reading times, and radiation doses were also compared between the 2 groups.

Overall, the cancer detection rate was higher in the digital mammography plus DBT arm compared with digital mammography alone (8.6 vs 4.5 per 1,000). The detection rates were higher in the combined screening group among all age subgroups, with relative risks ranging from 1.83 to 2.04 (P = .93). The recall rate was 3.5% in the 2 arms, with relative risks ranging from 0.93 to 1.11 (P = .52). There was a reduction in the number of false positives seen in women undergoing digital mammography plus DBT when compared with digital mammography alone, from 30 per 1,000 to 27 per 1,000.

Detection of ductal carcinoma in situ increased in the experimental arm (relative detection 2.80, 95% CI 1.01–7.65) compared with invasive cancers. Comparing radiation, the dose was 2.3 times higher in those who underwent digital mammography plus DBT. The average reading times for digital mammography alone were 20 to 85 seconds; adding DBT added 35 to 81 seconds.¹⁹

Should you advise 3-D mammography?

The patient should be educated on the benefits of both digital mammography alone and digital mammography plus DBT. The use of digital mammography plus DBT has been supported in various studies and has been shown to increase cancer detection rates, although data are still conflicting regarding recall rates.^19,20 More studies are needed to determine its effect on breast cancer morality.

Routine use of DBT in women with or without dense breast tissue has not been recommended by organizations such as the USPSTF and the American College of Obstetricians and Gynecologists.^23,24 While there is an increased dose of radiation, it still falls below the US Food and Drug Administration limits and should not be the sole barrier to use.

Keeping up with current evidence-based healthcare practices is key to providing good clinical care to patients. This review presents 5 vignettes that highlight key issues in women’s health: osteoporosis screening, hormonal contraceptive interactions with antibiotics, hormone replacement therapy in carriers of the BRCA1 gene mutation, risks associated with hormonal contraception, and breast cancer diagnosis using digital tomosynthesis in addition to digital mammography. Supporting articles, all published in 2017 and 2018, were selected from high-impact medical and women’s health journals.

OSTEOPOROSIS SCREENING FOR FRACTURE PREVENTION

A 60-year-old woman reports that her last menstrual period was 7 years ago. She has no history of falls or fractures, and she takes no medications. She smokes 10 cigarettes per day and drinks 3 to 4 alcoholic beverages on most days of the week. She is 5 feet 6 inches (170 cm) tall and weighs 107 lb. Should she be screened for osteoporosis?

Osteoporosis is underdiagnosed

It is estimated that, in the United States, 12.3 million individuals older than 50 will develop osteoporosis by 2020. Missed opportunities to screen high-risk individuals can lead to fractures, including fractures of the hip.¹

Updated screening recommendations

In 2018, the US Preventive Services Task Force (USPSTF) developed and published evidence-based recommendations for osteoporosis screening to help providers identify and treat osteoporosis early to prevent fractures.² Available evidence on screening and treatment in women and men were reviewed with the intention of updating the 2011 USPSTF recommendations. The review also evaluated risk assessment tools, screening intervals, and efficacy of screening and treatment in various subpopulations.

Since the 2011 recommendations, more data have become available on fracture risk assessment with or without bone mineral density measurements. In its 2018 report, the USPSTF recommends that postmenopausal women younger than 65 should undergo screening with a bone density test if their 10-year risk of major osteoporotic fracture is more than 8.4%. This is equivalent to the fracture risk of a 65-year-old white woman with no major risk factors for fracture (grade B recommendation—high certainty that the benefit is moderate, or moderate certainty that the benefit is moderate to substantial).²

Assessment of fracture risk

For postmenopausal women who are under age 65 and who have at least 1 risk factor for fracture, it is reasonable to use a clinical risk assessment tool to determine who should undergo screening with bone mineral density measurement. Risk factors associated with an increased risk of osteoporotic fractures include a parental history of hip fracture, smoking, intake of 3 or more alcoholic drinks per day, low body weight, malabsorption, rheumatoid arthritis, diabetes, and postmenopausal status (not using estrogen replacement). Medications should be carefully reviewed for those that can increase the risk of fractures, including steroids and antiestrogen treatments.

The 10-year risk of a major osteoporotic or hip fracture can be assessed using the Fractional Risk Assessment Tool (FRAX), available at www.sheffield.ac.uk/FRAX/. Other acceptable tools that perform similarly to FRAX include the Osteoporosis Risk Assessment Instrument (ORAI) (10 studies; N = 16,780), Osteoporosis Index of Risk (OSIRIS) (5 studies; N = 5,649), Osteoporosis Self-Assessment Tool (OST) (13 studies; N = 44,323), and Simple Calculated Osteoporosis Risk Estimation (SCORE) (8 studies; N = 15,362).

Should this patient be screened for osteoporosis?

Based on the FRAX, this patient’s 10-year risk of major osteoporosis fracture is 9.2%. She would benefit from osteoporosis screening with a bone density test.

DO ANTIBIOTICS REDUCE EFFECTIVENESS OF HORMONAL CONTRACEPTION?

A 27-year-old woman presents with a dog bite on her right hand and is started on oral antibiotics. She takes an oral contraceptive that contains 35 µg of ethinyl estradiol and 0.25 mg of norgestimate. She asks if she should use condoms while taking antibiotics.

The antibiotics rifampin and rifabutin are known inducers of the hepatic enzymes required for contraceptive steroid metabolism, whereas other antibiotics are not. Despite the lack of compelling evidence that broad-spectrum antibiotics interfere with the efficacy of hormonal contraception, most pharmacists recommend backup contraception for women who use concomitant antibiotics.³ This practice could lead to poor compliance with the contraceptive regimen, the antibiotic regimen, or both.³

Simmons et al³ conducted a systematic review of randomized and nonrandomized studies that assessed pregnancy rates, breakthrough bleeding, ovulation suppression, and hormone pharmacokinetics in women taking oral or vaginal hormonal contraceptives in combination with nonrifamycin antibiotics, including oral, intramuscular, and intravenous forms. Oral contraceptives used in the studies included a range of doses and progestins, but lowest-dose pills, such as those containing less than 30 µg ethinyl estradiol or less than 150 µg levonorgestrel, were not included.

The contraceptive formulations in this systematic review³ included oral contraceptive pills, emergency contraception pills, and the contraceptive vaginal ring. The effect of antibiotics on other nonoral contraceptives, such as the transdermal patch, injectables, and progestin implants was not studied.

Four observational studies³ evaluated pregnancy rates or hormonal contraception failure with any antibiotic use. In 2 of these 4 studies, there was no difference in pregnancy rates in women who used oral contraceptives with and without nonrifamycin antibiotics. However, ethinyl estradiol was shown to have increased clearance when administered with dirithromycin (a macrolide).³ Twenty-five of the studies reported measures of contraceptive effectiveness (ovulation) and pharmacokinetic outcomes.

There were no observed differences in ovulation suppression or breakthrough bleeding in any study that combined hormonal contraceptives with an antibiotic. Furthermore, there was no significant decrease in progestin pharmacokinetic parameters during coadministration with an antibiotic.³ Study limitations included small sample sizes and the observational nature of the data.

How would you counsel this patient?

Available evidence suggests that nonrifamycin antibiotics do not diminish the effectiveness of the vaginal contraceptive ring or an oral hormonal contraceptive that contains at least 30 µg of ethinyl estradiol or 150 µg of levonorgestrel. Current guidelines do not recommend the use of additional backup contraception, regardless of hormonal contraception dose or formulation.⁴ Likewise, the most recent guidance for dental practitioners (ie, from 2012) no longer advises women to use additional contraceptive protection when taking nonrifamycin antibiotics.⁵

In our practice, we discuss the option of additional protection when prescribing formulations with lower estrogen doses (< 30 µg), not only because of the limitations of the available data, but also because of the high rates of unintended pregnancy with typical use of combined hormonal contraceptives (9% per year, unrelated to use of antibiotics).⁴ However, if our patient would rather not use additional barrier methods, she can be reassured that concomitant nonrifamycin antibiotic use is unlikely to affect contraceptive effectiveness.

A 41-year-old healthy mother of 3 was recently found to be a carrier of the BRCA1 mutation. She is planning to undergo prophylactic bilateral salpingo-oophorectomy for ovarian cancer prevention. However, she is apprehensive about undergoing surgical menopause. Should she be started on hormone replacement therapy after oophorectomy? How would hormone replacement therapy affect her risk of breast cancer?

In females who carry the BRCA1 mutation, the cumulative risk of both ovarian and breast cancer approaches 44% (95% confidence interval [CI] 36%–53%) and 72% (95% CI 65%–79%) by age 80.⁶ Prophylactic salpingo-oophorectomy reduces the risk of breast cancer by 50% and the risk of ovarian cancer by 90%. Unfortunately, premature withdrawal of ovarian hormones has been associated with long-term adverse effects including significant vasomotor symptoms, decreased quality of life, sexual dysfunction, early mortality, bone loss, decline in mood and cognition, and poor cardiovascular outcomes.⁷ Many of these effects can be avoided or lessened with hormone replacement therapy.

Kotsopoulos et al⁸ conducted a longitudinal, prospective analysis of BRCA1 mutation carriers in a multicenter study between 1995 and 2017. The mean follow-up period was 7.6 years (range 0.4–22.1). The study assessed associations between the use of hormone replacement therapy and breast cancer risk in carriers of the BRCA1 mutation who underwent prophylactic salpingo-oophorectomy. Study participants did not have a personal history of cancer. Those with a history of prophylactic mastectomy were excluded.

Participants completed a series of questionnaires every 2 years, disclosing updates in personal medical, cancer, and reproductive history. The questionnaires also inquired about the use of hormone replacement therapy, including the type used (estrogen only, progestin only, estrogen plus progestin, other), brand name, duration of use, and dose and route of administration (pill, patch, suppository).

Of the 13,087 BRCA1 mutation carriers identified, 872 met the study criteria. Of those, 377 (43%) reported using some form of hormone replacement therapy after salpingo-oophorectomy, and 495 (57%) did not. The average duration of use was 3.9 years (range 0.5–19), with most (69%) using estrogen alone; 18% used other regimens, including estrogen plus progestin and progestin only. A small percentage of participants did not indicate which formulation they used. On average, women using hormone replacement therapy underwent prophylactic oophorectomy earlier than nonusers (age 43.0 vs 48.4; absolute difference 5.5 years, P < .001).

During follow-up, there was no significant difference noted in the proportion of women diagnosed with breast cancer between hormone replacement therapy users and nonusers (10.3 vs 10.7%; absolute difference 0.4%; P = .86). In fact, for each year of estrogen-containing hormone replacement therapy, there was an 18% reduction in breast cancer risk when oophorectomy was performed before age 45 (95% CI 0.69–0.97). The authors also noted a nonsignificant 14% trend toward an increase in breast cancer risk for each year of progestin use after oophorectomy when surgery was performed before age 45 (95% CI 0.9–1.46).

Although prophylactic hysterectomy was not recommended, the authors noted that hysterectomy would eliminate the need for progestin-containing hormone replacement therapy. For those who underwent oophorectomy after age 45, hormone replacement therapy did not increase or decrease the risk of breast cancer.⁷

A meta-analysis by Marchetti et al⁹ also supports the safety of hormone replacement therapy after risk-reducing salpingo-oophorectomy. Three studies that included 1,100 patients were analyzed (including the Kotsopoulos study⁸ noted above). There was a nonsignificant decrease in breast cancer risk in women on estrogen-only hormone replacement therapy compared with women on estrogen-plus-progestin therapy (odds ratio 0.53, 95% CI 0.25–1.15). Overall, the authors regarded hormone replacement therapy as a safe therapeutic option after prophylactic salpingo-oophorectomy in carriers of the BRCA1 and BRCA2 mutations.⁹

In a case-control study published in 2016,¹⁰ hormone replacement therapy was assessed in 432 postmenopausal BRCA1 mutation carriers with invasive breast cancer (cases) and in 432 BRCA1 mutation carriers without a history of breast cancer (controls). Results showed no difference in breast cancer risk between hormone replacement therapy users and nonusers.¹⁰

Rebbeck et al¹¹ evaluated short-term hormone replacement therapy in BRCA1 and BRCA2 gene-mutation carriers after they underwent prophylactic salpingo-oophorectomy. The results showed that hormone replacement did not affect the breast cancer risk-reduction conferred with prophylactic bilateral salpingo-oophorectomy.

Johansen et al¹² evaluated hormone replacement therapy in premenopausal women after prophylactic salpingo-oophorectomy. They studied 324 carriers of BRCA gene mutations after they underwent prophylactic salpingo-oophorectomy and a subset of 950 controls who had bilateral salpingo-oophorectomy for reasons unrelated to cancer. In both groups, hormone replacement therapy was underutilized. The authors recommended using it when clinically indicated.

Should your patient start hormone replacement therapy?

This patient is healthy, and in the absence of contraindications, systemic hormone replacement therapy after prophylactic oophorectomy could mitigate the potential adverse effects of surgically induced menopause. The patient can be reassured that estrogen-containing short-term hormone replacement therapy is unlikely to increase her breast cancer risk.

A 44-year-old woman presents to your office for an annual visit. She is sexually active but does not wish to become pregnant. She has a family history of breast cancer: her mother was diagnosed at age 53. She is interested in an oral contraceptive to prevent pregnancy and acne. However, she is nervous about being on any contraceptive that may increase her risk of breast cancer.

To date, studies assessing the effect of hormonal contraception on the risk of breast cancer have produced inconsistent results. Although most studies have shown no associated risk, a few have shown a temporary 20% to 30% increased risk of breast cancer during use.^13,14 Case-controlled studies that reported an association between hormonal contraception and breast cancer included populations taking higher-dose combination pills, which are no longer prescribed. Most studies do not evaluate specific formulations of hormonal contraception, and little is known about effects associated with intrauterine devices or progestin-only contraception.

A prospective study performed by Mørch et al¹³ followed more than 1 million reproductive-aged women for a mean of 10.9 years. The Danish Cancer Registry was used to identify cases of invasive breast cancer. Women who used hormonal contraceptives had a relative risk of breast cancer of 1.20 compared with women not on hormonal contraception (95% CI 1.14–1.26). The study suggested that those who had been on contraceptive agents for more than 5 years had an increased risk and that this risk remained for 5 years after the agents were discontinued. Conversely, no increased risk of cancer was noted in those who used hormonal contraception for less than 5 years. No notable differences were seen among various formulations.

For women using the levonorgestrel-containing intrauterine device, the relative risk of breast cancer was 1.21 (95% CI 1.11–1.33). A few cancers were noted in those who used the progestin-only implant or those using depot medroxyprogesterone acetate. While the study showed an increased relative risk of breast cancer, the absolute risk was low—13 cases per 100,000, or approximately 1 additional case of breast cancer per 7,690 per year.¹³

This study had several important limitations. The authors did not adjust for common breast cancer risk factors including age at menarche, alcohol use, or breastfeeding. Additionally, the study did not account for the use of hormonal contraception before the study period and conversely, did not account for women who may have stopped taking their contraceptive despite their prescribed duration. The frequency of mammography was not explicitly noted, which could have shifted results for women who had more aggressive screening.

It is also noteworthy that the use of high-dose systemic progestins was not associated with an increased risk, whereas the levonorgestrel intrauterine device, which contains only 1/20th the dose of a low-dose oral contraceptive pill, was associated with an increased risk. This discrepancy in risk warrants further investigation, and clinicians should be aware that this inconsistency needs validation before changing clinical practice.

In an observational cohort study,¹⁵ more than 100,000 women ages 50 to 71 were followed prospectively for 15 years to evaluate the association between hormonal contraceptive use and the risk of gynecologic and breast cancers. In this study, the duration of hormonal contraceptive use, smoking status, alcohol use, body mass index, physical activity, and family history of cancer were recorded. Long-term hormonal contraceptive use reduced ovarian and endometrial cancer risks by 40% and 34%, respectively, with no increase in breast cancer risk regardless of family history.

How would you counsel the patient?

The patient should be educated on the benefits of hormonal contraception that extend beyond pregnancy prevention, including regulation of menses, improved acne, decreased risk of endometrial and ovarian cancer, and likely reductions in colorectal cancer and overall mortality risk.^13–16 Further, after their own systematic review of the data assessing risk of breast cancer with hormonal contraception, the US Centers for Disease Control and Prevention state in their guidelines that all contraceptives may be used without limitation in those who have a family history of breast cancer.⁴ Any potential increased risk of breast cancer in women using hormonal contraception is small and would not outweigh the benefits associated with use.

One must consider the impact of an unintended pregnancy in such women, including effects on the health of the fetus and mother. Recent reports on the increasing rates of maternal death in the US (23.8 of 100,000 live births) serve as a reminder of the complications that can arise with pregnancy, especially if a mother’s health is not optimized before conception.¹⁷

The same 44-year-old patient now inquires about screening for breast cancer. She is curious about 3-dimensional mammography and whether it would be a better screening test for her.

Digital breast tomosynthesis (DBT) is a newer imaging modality that provides a 3-dimensional reconstruction of the breast using low-dose x-ray imaging. Some studies have shown that combining DBT with digital mammography may be superior to digital mammography alone in detecting cancers.¹⁸ However, digital mammography is currently the gold standard for breast cancer screening and is the only test proven to reduce mortality.^18,19

In a retrospective US study of 13 medical centers,²⁰ breast cancer detection rates increased by 41% the year after DBT was introduced, from 2.9 to 4.1 per 1,000 cases. DBT was associated with 16 fewer patients recalled for repeat imaging out of 1,000 women screened (as opposed to mammography alone). Two European studies similarly suggested an increase in cancer detection with lower recall rates.^21,22

Is 3-D mammography a better option?

In a 2-arm study by Pattacini et al,¹⁸ nearly 20,000 women ages 45 to 70 were randomized to undergo either digital mammography or digital mammography plus DBT for primary breast cancer screening. Women were enrolled over a 2-year period and were followed for 4.5 years, and the development of a primary invasive cancer was the primary end point. Recall rates, reading times, and radiation doses were also compared between the 2 groups.

Overall, the cancer detection rate was higher in the digital mammography plus DBT arm compared with digital mammography alone (8.6 vs 4.5 per 1,000). The detection rates were higher in the combined screening group among all age subgroups, with relative risks ranging from 1.83 to 2.04 (P = .93). The recall rate was 3.5% in the 2 arms, with relative risks ranging from 0.93 to 1.11 (P = .52). There was a reduction in the number of false positives seen in women undergoing digital mammography plus DBT when compared with digital mammography alone, from 30 per 1,000 to 27 per 1,000.

Detection of ductal carcinoma in situ increased in the experimental arm (relative detection 2.80, 95% CI 1.01–7.65) compared with invasive cancers. Comparing radiation, the dose was 2.3 times higher in those who underwent digital mammography plus DBT. The average reading times for digital mammography alone were 20 to 85 seconds; adding DBT added 35 to 81 seconds.¹⁹

Should you advise 3-D mammography?

The patient should be educated on the benefits of both digital mammography alone and digital mammography plus DBT. The use of digital mammography plus DBT has been supported in various studies and has been shown to increase cancer detection rates, although data are still conflicting regarding recall rates.^19,20 More studies are needed to determine its effect on breast cancer morality.

Routine use of DBT in women with or without dense breast tissue has not been recommended by organizations such as the USPSTF and the American College of Obstetricians and Gynecologists.^23,24 While there is an increased dose of radiation, it still falls below the US Food and Drug Administration limits and should not be the sole barrier to use.

Keeping up with current evidence-based healthcare practices is key to providing good clinical care to patients. This review presents 5 vignettes that highlight key issues in women’s health: osteoporosis screening, hormonal contraceptive interactions with antibiotics, hormone replacement therapy in carriers of the BRCA1 gene mutation, risks associated with hormonal contraception, and breast cancer diagnosis using digital tomosynthesis in addition to digital mammography. Supporting articles, all published in 2017 and 2018, were selected from high-impact medical and women’s health journals.

OSTEOPOROSIS SCREENING FOR FRACTURE PREVENTION

A 60-year-old woman reports that her last menstrual period was 7 years ago. She has no history of falls or fractures, and she takes no medications. She smokes 10 cigarettes per day and drinks 3 to 4 alcoholic beverages on most days of the week. She is 5 feet 6 inches (170 cm) tall and weighs 107 lb. Should she be screened for osteoporosis?

Osteoporosis is underdiagnosed

It is estimated that, in the United States, 12.3 million individuals older than 50 will develop osteoporosis by 2020. Missed opportunities to screen high-risk individuals can lead to fractures, including fractures of the hip.¹

Updated screening recommendations

In 2018, the US Preventive Services Task Force (USPSTF) developed and published evidence-based recommendations for osteoporosis screening to help providers identify and treat osteoporosis early to prevent fractures.² Available evidence on screening and treatment in women and men were reviewed with the intention of updating the 2011 USPSTF recommendations. The review also evaluated risk assessment tools, screening intervals, and efficacy of screening and treatment in various subpopulations.

Since the 2011 recommendations, more data have become available on fracture risk assessment with or without bone mineral density measurements. In its 2018 report, the USPSTF recommends that postmenopausal women younger than 65 should undergo screening with a bone density test if their 10-year risk of major osteoporotic fracture is more than 8.4%. This is equivalent to the fracture risk of a 65-year-old white woman with no major risk factors for fracture (grade B recommendation—high certainty that the benefit is moderate, or moderate certainty that the benefit is moderate to substantial).²

Assessment of fracture risk

For postmenopausal women who are under age 65 and who have at least 1 risk factor for fracture, it is reasonable to use a clinical risk assessment tool to determine who should undergo screening with bone mineral density measurement. Risk factors associated with an increased risk of osteoporotic fractures include a parental history of hip fracture, smoking, intake of 3 or more alcoholic drinks per day, low body weight, malabsorption, rheumatoid arthritis, diabetes, and postmenopausal status (not using estrogen replacement). Medications should be carefully reviewed for those that can increase the risk of fractures, including steroids and antiestrogen treatments.

The 10-year risk of a major osteoporotic or hip fracture can be assessed using the Fractional Risk Assessment Tool (FRAX), available at www.sheffield.ac.uk/FRAX/. Other acceptable tools that perform similarly to FRAX include the Osteoporosis Risk Assessment Instrument (ORAI) (10 studies; N = 16,780), Osteoporosis Index of Risk (OSIRIS) (5 studies; N = 5,649), Osteoporosis Self-Assessment Tool (OST) (13 studies; N = 44,323), and Simple Calculated Osteoporosis Risk Estimation (SCORE) (8 studies; N = 15,362).

Should this patient be screened for osteoporosis?

Based on the FRAX, this patient’s 10-year risk of major osteoporosis fracture is 9.2%. She would benefit from osteoporosis screening with a bone density test.

DO ANTIBIOTICS REDUCE EFFECTIVENESS OF HORMONAL CONTRACEPTION?

A 27-year-old woman presents with a dog bite on her right hand and is started on oral antibiotics. She takes an oral contraceptive that contains 35 µg of ethinyl estradiol and 0.25 mg of norgestimate. She asks if she should use condoms while taking antibiotics.

The antibiotics rifampin and rifabutin are known inducers of the hepatic enzymes required for contraceptive steroid metabolism, whereas other antibiotics are not. Despite the lack of compelling evidence that broad-spectrum antibiotics interfere with the efficacy of hormonal contraception, most pharmacists recommend backup contraception for women who use concomitant antibiotics.³ This practice could lead to poor compliance with the contraceptive regimen, the antibiotic regimen, or both.³

Simmons et al³ conducted a systematic review of randomized and nonrandomized studies that assessed pregnancy rates, breakthrough bleeding, ovulation suppression, and hormone pharmacokinetics in women taking oral or vaginal hormonal contraceptives in combination with nonrifamycin antibiotics, including oral, intramuscular, and intravenous forms. Oral contraceptives used in the studies included a range of doses and progestins, but lowest-dose pills, such as those containing less than 30 µg ethinyl estradiol or less than 150 µg levonorgestrel, were not included.

The contraceptive formulations in this systematic review³ included oral contraceptive pills, emergency contraception pills, and the contraceptive vaginal ring. The effect of antibiotics on other nonoral contraceptives, such as the transdermal patch, injectables, and progestin implants was not studied.

Four observational studies³ evaluated pregnancy rates or hormonal contraception failure with any antibiotic use. In 2 of these 4 studies, there was no difference in pregnancy rates in women who used oral contraceptives with and without nonrifamycin antibiotics. However, ethinyl estradiol was shown to have increased clearance when administered with dirithromycin (a macrolide).³ Twenty-five of the studies reported measures of contraceptive effectiveness (ovulation) and pharmacokinetic outcomes.

There were no observed differences in ovulation suppression or breakthrough bleeding in any study that combined hormonal contraceptives with an antibiotic. Furthermore, there was no significant decrease in progestin pharmacokinetic parameters during coadministration with an antibiotic.³ Study limitations included small sample sizes and the observational nature of the data.

How would you counsel this patient?

Available evidence suggests that nonrifamycin antibiotics do not diminish the effectiveness of the vaginal contraceptive ring or an oral hormonal contraceptive that contains at least 30 µg of ethinyl estradiol or 150 µg of levonorgestrel. Current guidelines do not recommend the use of additional backup contraception, regardless of hormonal contraception dose or formulation.⁴ Likewise, the most recent guidance for dental practitioners (ie, from 2012) no longer advises women to use additional contraceptive protection when taking nonrifamycin antibiotics.⁵

In our practice, we discuss the option of additional protection when prescribing formulations with lower estrogen doses (< 30 µg), not only because of the limitations of the available data, but also because of the high rates of unintended pregnancy with typical use of combined hormonal contraceptives (9% per year, unrelated to use of antibiotics).⁴ However, if our patient would rather not use additional barrier methods, she can be reassured that concomitant nonrifamycin antibiotic use is unlikely to affect contraceptive effectiveness.

A 41-year-old healthy mother of 3 was recently found to be a carrier of the BRCA1 mutation. She is planning to undergo prophylactic bilateral salpingo-oophorectomy for ovarian cancer prevention. However, she is apprehensive about undergoing surgical menopause. Should she be started on hormone replacement therapy after oophorectomy? How would hormone replacement therapy affect her risk of breast cancer?

In females who carry the BRCA1 mutation, the cumulative risk of both ovarian and breast cancer approaches 44% (95% confidence interval [CI] 36%–53%) and 72% (95% CI 65%–79%) by age 80.⁶ Prophylactic salpingo-oophorectomy reduces the risk of breast cancer by 50% and the risk of ovarian cancer by 90%. Unfortunately, premature withdrawal of ovarian hormones has been associated with long-term adverse effects including significant vasomotor symptoms, decreased quality of life, sexual dysfunction, early mortality, bone loss, decline in mood and cognition, and poor cardiovascular outcomes.⁷ Many of these effects can be avoided or lessened with hormone replacement therapy.

Kotsopoulos et al⁸ conducted a longitudinal, prospective analysis of BRCA1 mutation carriers in a multicenter study between 1995 and 2017. The mean follow-up period was 7.6 years (range 0.4–22.1). The study assessed associations between the use of hormone replacement therapy and breast cancer risk in carriers of the BRCA1 mutation who underwent prophylactic salpingo-oophorectomy. Study participants did not have a personal history of cancer. Those with a history of prophylactic mastectomy were excluded.

Participants completed a series of questionnaires every 2 years, disclosing updates in personal medical, cancer, and reproductive history. The questionnaires also inquired about the use of hormone replacement therapy, including the type used (estrogen only, progestin only, estrogen plus progestin, other), brand name, duration of use, and dose and route of administration (pill, patch, suppository).

Of the 13,087 BRCA1 mutation carriers identified, 872 met the study criteria. Of those, 377 (43%) reported using some form of hormone replacement therapy after salpingo-oophorectomy, and 495 (57%) did not. The average duration of use was 3.9 years (range 0.5–19), with most (69%) using estrogen alone; 18% used other regimens, including estrogen plus progestin and progestin only. A small percentage of participants did not indicate which formulation they used. On average, women using hormone replacement therapy underwent prophylactic oophorectomy earlier than nonusers (age 43.0 vs 48.4; absolute difference 5.5 years, P < .001).

During follow-up, there was no significant difference noted in the proportion of women diagnosed with breast cancer between hormone replacement therapy users and nonusers (10.3 vs 10.7%; absolute difference 0.4%; P = .86). In fact, for each year of estrogen-containing hormone replacement therapy, there was an 18% reduction in breast cancer risk when oophorectomy was performed before age 45 (95% CI 0.69–0.97). The authors also noted a nonsignificant 14% trend toward an increase in breast cancer risk for each year of progestin use after oophorectomy when surgery was performed before age 45 (95% CI 0.9–1.46).

Although prophylactic hysterectomy was not recommended, the authors noted that hysterectomy would eliminate the need for progestin-containing hormone replacement therapy. For those who underwent oophorectomy after age 45, hormone replacement therapy did not increase or decrease the risk of breast cancer.⁷

A meta-analysis by Marchetti et al⁹ also supports the safety of hormone replacement therapy after risk-reducing salpingo-oophorectomy. Three studies that included 1,100 patients were analyzed (including the Kotsopoulos study⁸ noted above). There was a nonsignificant decrease in breast cancer risk in women on estrogen-only hormone replacement therapy compared with women on estrogen-plus-progestin therapy (odds ratio 0.53, 95% CI 0.25–1.15). Overall, the authors regarded hormone replacement therapy as a safe therapeutic option after prophylactic salpingo-oophorectomy in carriers of the BRCA1 and BRCA2 mutations.⁹

In a case-control study published in 2016,¹⁰ hormone replacement therapy was assessed in 432 postmenopausal BRCA1 mutation carriers with invasive breast cancer (cases) and in 432 BRCA1 mutation carriers without a history of breast cancer (controls). Results showed no difference in breast cancer risk between hormone replacement therapy users and nonusers.¹⁰

Rebbeck et al¹¹ evaluated short-term hormone replacement therapy in BRCA1 and BRCA2 gene-mutation carriers after they underwent prophylactic salpingo-oophorectomy. The results showed that hormone replacement did not affect the breast cancer risk-reduction conferred with prophylactic bilateral salpingo-oophorectomy.

Johansen et al¹² evaluated hormone replacement therapy in premenopausal women after prophylactic salpingo-oophorectomy. They studied 324 carriers of BRCA gene mutations after they underwent prophylactic salpingo-oophorectomy and a subset of 950 controls who had bilateral salpingo-oophorectomy for reasons unrelated to cancer. In both groups, hormone replacement therapy was underutilized. The authors recommended using it when clinically indicated.

Should your patient start hormone replacement therapy?

This patient is healthy, and in the absence of contraindications, systemic hormone replacement therapy after prophylactic oophorectomy could mitigate the potential adverse effects of surgically induced menopause. The patient can be reassured that estrogen-containing short-term hormone replacement therapy is unlikely to increase her breast cancer risk.

A 44-year-old woman presents to your office for an annual visit. She is sexually active but does not wish to become pregnant. She has a family history of breast cancer: her mother was diagnosed at age 53. She is interested in an oral contraceptive to prevent pregnancy and acne. However, she is nervous about being on any contraceptive that may increase her risk of breast cancer.

To date, studies assessing the effect of hormonal contraception on the risk of breast cancer have produced inconsistent results. Although most studies have shown no associated risk, a few have shown a temporary 20% to 30% increased risk of breast cancer during use.^13,14 Case-controlled studies that reported an association between hormonal contraception and breast cancer included populations taking higher-dose combination pills, which are no longer prescribed. Most studies do not evaluate specific formulations of hormonal contraception, and little is known about effects associated with intrauterine devices or progestin-only contraception.

A prospective study performed by Mørch et al¹³ followed more than 1 million reproductive-aged women for a mean of 10.9 years. The Danish Cancer Registry was used to identify cases of invasive breast cancer. Women who used hormonal contraceptives had a relative risk of breast cancer of 1.20 compared with women not on hormonal contraception (95% CI 1.14–1.26). The study suggested that those who had been on contraceptive agents for more than 5 years had an increased risk and that this risk remained for 5 years after the agents were discontinued. Conversely, no increased risk of cancer was noted in those who used hormonal contraception for less than 5 years. No notable differences were seen among various formulations.

For women using the levonorgestrel-containing intrauterine device, the relative risk of breast cancer was 1.21 (95% CI 1.11–1.33). A few cancers were noted in those who used the progestin-only implant or those using depot medroxyprogesterone acetate. While the study showed an increased relative risk of breast cancer, the absolute risk was low—13 cases per 100,000, or approximately 1 additional case of breast cancer per 7,690 per year.¹³

This study had several important limitations. The authors did not adjust for common breast cancer risk factors including age at menarche, alcohol use, or breastfeeding. Additionally, the study did not account for the use of hormonal contraception before the study period and conversely, did not account for women who may have stopped taking their contraceptive despite their prescribed duration. The frequency of mammography was not explicitly noted, which could have shifted results for women who had more aggressive screening.

It is also noteworthy that the use of high-dose systemic progestins was not associated with an increased risk, whereas the levonorgestrel intrauterine device, which contains only 1/20th the dose of a low-dose oral contraceptive pill, was associated with an increased risk. This discrepancy in risk warrants further investigation, and clinicians should be aware that this inconsistency needs validation before changing clinical practice.

In an observational cohort study,¹⁵ more than 100,000 women ages 50 to 71 were followed prospectively for 15 years to evaluate the association between hormonal contraceptive use and the risk of gynecologic and breast cancers. In this study, the duration of hormonal contraceptive use, smoking status, alcohol use, body mass index, physical activity, and family history of cancer were recorded. Long-term hormonal contraceptive use reduced ovarian and endometrial cancer risks by 40% and 34%, respectively, with no increase in breast cancer risk regardless of family history.

How would you counsel the patient?

The patient should be educated on the benefits of hormonal contraception that extend beyond pregnancy prevention, including regulation of menses, improved acne, decreased risk of endometrial and ovarian cancer, and likely reductions in colorectal cancer and overall mortality risk.^13–16 Further, after their own systematic review of the data assessing risk of breast cancer with hormonal contraception, the US Centers for Disease Control and Prevention state in their guidelines that all contraceptives may be used without limitation in those who have a family history of breast cancer.⁴ Any potential increased risk of breast cancer in women using hormonal contraception is small and would not outweigh the benefits associated with use.

One must consider the impact of an unintended pregnancy in such women, including effects on the health of the fetus and mother. Recent reports on the increasing rates of maternal death in the US (23.8 of 100,000 live births) serve as a reminder of the complications that can arise with pregnancy, especially if a mother’s health is not optimized before conception.¹⁷

The same 44-year-old patient now inquires about screening for breast cancer. She is curious about 3-dimensional mammography and whether it would be a better screening test for her.

Digital breast tomosynthesis (DBT) is a newer imaging modality that provides a 3-dimensional reconstruction of the breast using low-dose x-ray imaging. Some studies have shown that combining DBT with digital mammography may be superior to digital mammography alone in detecting cancers.¹⁸ However, digital mammography is currently the gold standard for breast cancer screening and is the only test proven to reduce mortality.^18,19

In a retrospective US study of 13 medical centers,²⁰ breast cancer detection rates increased by 41% the year after DBT was introduced, from 2.9 to 4.1 per 1,000 cases. DBT was associated with 16 fewer patients recalled for repeat imaging out of 1,000 women screened (as opposed to mammography alone). Two European studies similarly suggested an increase in cancer detection with lower recall rates.^21,22

Is 3-D mammography a better option?

In a 2-arm study by Pattacini et al,¹⁸ nearly 20,000 women ages 45 to 70 were randomized to undergo either digital mammography or digital mammography plus DBT for primary breast cancer screening. Women were enrolled over a 2-year period and were followed for 4.5 years, and the development of a primary invasive cancer was the primary end point. Recall rates, reading times, and radiation doses were also compared between the 2 groups.

Overall, the cancer detection rate was higher in the digital mammography plus DBT arm compared with digital mammography alone (8.6 vs 4.5 per 1,000). The detection rates were higher in the combined screening group among all age subgroups, with relative risks ranging from 1.83 to 2.04 (P = .93). The recall rate was 3.5% in the 2 arms, with relative risks ranging from 0.93 to 1.11 (P = .52). There was a reduction in the number of false positives seen in women undergoing digital mammography plus DBT when compared with digital mammography alone, from 30 per 1,000 to 27 per 1,000.

Detection of ductal carcinoma in situ increased in the experimental arm (relative detection 2.80, 95% CI 1.01–7.65) compared with invasive cancers. Comparing radiation, the dose was 2.3 times higher in those who underwent digital mammography plus DBT. The average reading times for digital mammography alone were 20 to 85 seconds; adding DBT added 35 to 81 seconds.¹⁹

Should you advise 3-D mammography?

The patient should be educated on the benefits of both digital mammography alone and digital mammography plus DBT. The use of digital mammography plus DBT has been supported in various studies and has been shown to increase cancer detection rates, although data are still conflicting regarding recall rates.^19,20 More studies are needed to determine its effect on breast cancer morality.

Routine use of DBT in women with or without dense breast tissue has not been recommended by organizations such as the USPSTF and the American College of Obstetricians and Gynecologists.^23,24 While there is an increased dose of radiation, it still falls below the US Food and Drug Administration limits and should not be the sole barrier to use.

In Azim S, Nasr C, “Subclinical hypothyroidism: When to treat,” Cleve Clin J Med 2019; 86(2):101–110, on page 103, in the section “Subclinical hypothyroidism can resolve or progress,” the sentence “The rate of progression to overt hypothyroidism is estimated to be 33% to 35% over 10 to 20 years of follow-up” contained an error. The correct rate of progression is 33% to 55%. This error has been corrected online.

In Azim S, Nasr C, “Subclinical hypothyroidism: When to treat,” Cleve Clin J Med 2019; 86(2):101–110, on page 103, in the section “Subclinical hypothyroidism can resolve or progress,” the sentence “The rate of progression to overt hypothyroidism is estimated to be 33% to 35% over 10 to 20 years of follow-up” contained an error. The correct rate of progression is 33% to 55%. This error has been corrected online.

In Azim S, Nasr C, “Subclinical hypothyroidism: When to treat,” Cleve Clin J Med 2019; 86(2):101–110, on page 103, in the section “Subclinical hypothyroidism can resolve or progress,” the sentence “The rate of progression to overt hypothyroidism is estimated to be 33% to 35% over 10 to 20 years of follow-up” contained an error. The correct rate of progression is 33% to 55%. This error has been corrected online.

Background: Multiple large, randomized, controlled trials and meta-analyses that used aspirin as primary prevention for vascular events showed decreased vascular events, but a significant counterbalanced risk of bleeding. Since diabetes carries a higher risk of vascular events, this study examines aspirin for primary prevention of vascular events in diabetic patients.

Overall, aspirin provided no difference in mortality but showed an absolute 1.3% decrease in first vascular events or revascularization procedures with an absolute 1.1% increase in first occurrence of major bleeding event. Approximately 60% of the bleeding events were gastrointestinal or “other” urinary/nose bleeding, and there was no statistically significant increase in intracranial hemorrhage, hemorrhagic stroke, or vision-threatening eye bleeding. Vascular events were defined as transient ischemic attack (TIA), nonfatal MI, nonfatal ischemic stroke, or vascular death excluding intracranial hemorrhage. The major limitation of this study is that it had a composite of endpoints of different clinical significance. Furthermore, TIA as a major vascular event was added after the study began to increase statistical power, and when it is excluded, the difference for vascular events is not statistically significant.

Bottom line: Aspirin when used in primary prevention of vascular events in diabetes provides no improvement in mortality, and the benefit of prevention of vascular events must be weighed against the risks of bleeding.

Citation: The ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in diabetes. N Eng J Med. 2018 Oct 18;379(16):1529-39.

Dr. Scott is an assistant professor in the division of hospital medicine, University of New Mexico.

Background: Multiple large, randomized, controlled trials and meta-analyses that used aspirin as primary prevention for vascular events showed decreased vascular events, but a significant counterbalanced risk of bleeding. Since diabetes carries a higher risk of vascular events, this study examines aspirin for primary prevention of vascular events in diabetic patients.

Overall, aspirin provided no difference in mortality but showed an absolute 1.3% decrease in first vascular events or revascularization procedures with an absolute 1.1% increase in first occurrence of major bleeding event. Approximately 60% of the bleeding events were gastrointestinal or “other” urinary/nose bleeding, and there was no statistically significant increase in intracranial hemorrhage, hemorrhagic stroke, or vision-threatening eye bleeding. Vascular events were defined as transient ischemic attack (TIA), nonfatal MI, nonfatal ischemic stroke, or vascular death excluding intracranial hemorrhage. The major limitation of this study is that it had a composite of endpoints of different clinical significance. Furthermore, TIA as a major vascular event was added after the study began to increase statistical power, and when it is excluded, the difference for vascular events is not statistically significant.

Bottom line: Aspirin when used in primary prevention of vascular events in diabetes provides no improvement in mortality, and the benefit of prevention of vascular events must be weighed against the risks of bleeding.

Citation: The ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in diabetes. N Eng J Med. 2018 Oct 18;379(16):1529-39.

Dr. Scott is an assistant professor in the division of hospital medicine, University of New Mexico.

Background: Multiple large, randomized, controlled trials and meta-analyses that used aspirin as primary prevention for vascular events showed decreased vascular events, but a significant counterbalanced risk of bleeding. Since diabetes carries a higher risk of vascular events, this study examines aspirin for primary prevention of vascular events in diabetic patients.

Overall, aspirin provided no difference in mortality but showed an absolute 1.3% decrease in first vascular events or revascularization procedures with an absolute 1.1% increase in first occurrence of major bleeding event. Approximately 60% of the bleeding events were gastrointestinal or “other” urinary/nose bleeding, and there was no statistically significant increase in intracranial hemorrhage, hemorrhagic stroke, or vision-threatening eye bleeding. Vascular events were defined as transient ischemic attack (TIA), nonfatal MI, nonfatal ischemic stroke, or vascular death excluding intracranial hemorrhage. The major limitation of this study is that it had a composite of endpoints of different clinical significance. Furthermore, TIA as a major vascular event was added after the study began to increase statistical power, and when it is excluded, the difference for vascular events is not statistically significant.

Bottom line: Aspirin when used in primary prevention of vascular events in diabetes provides no improvement in mortality, and the benefit of prevention of vascular events must be weighed against the risks of bleeding.

Citation: The ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in diabetes. N Eng J Med. 2018 Oct 18;379(16):1529-39.

Dr. Scott is an assistant professor in the division of hospital medicine, University of New Mexico.

LOS ANGELES – In the opinion of Felicia Cosman, MD, the current state of osteoporosis treatment is fraught with clinical challenges.

First, most patients at highest risk for future fractures are not being treated. “In fact, fewer than 25% of patients with new clinical fractures are treated for their underlying disease,” Dr. Cosman, professor of medicine at Columbia University, New York, said at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists (AACE).

“One of the reasons doctors are not treating these patients is that many of them do not have a T-score in the osteoporosis range. There’s a misunderstanding here. A fracture that occurs in people with low bone mass in the setting of minimal trauma – such as a fall from standing height – meets the criteria for the clinical diagnosis of osteoporosis and qualifies a person for being at high risk of more fractures. This is likely because bone weakness or fragility is related not just to quantitative aspects, but also to structural and qualitative aspects that cannot be measured as easily.”

Another problem is that some of the highest-risk patients are those with a vertebral fracture. “However, vertebral fractures are particularly difficult to find and treat because they’re often asymptomatic and we’re not [identifying] these patients,” she said. “Targeted screening [with] spine imaging to find vertebral fractures is probably as important as BMD [bone mineral density] testing.”

To complicate matters, Dr. Cosman said that clinicians and patients “misunderstand the balance between benefits and risks of osteoporosis medications and they don’t consider the risk of not treating the underlying disease. Lastly, there’s little evidence to help guide long-term strategies. Guidelines across medical specialties are incredibly inconsistent. With the exception of guidelines from AACE, the one thing that they’re very consistent about is underrecognizing the value of anabolic therapy for people with severe osteoporosis.”

It is well known that previous bone fracture is the most important risk factor for a future fracture, but the recency of the fracture is also important. In a recent study, researchers followed 377,561 female Medicare beneficiaries with a first fracture for up to 5 years (Osteoporos Int. 2019;30[1]:79-92). They found that at 1 year, the risk of another fracture was 10%. The fracture risk rose to 18% at 2 years, and to 31% at 5 years. “I like to think of this as the osteoporosis emergency,” said Dr. Cosman, co–editor-in-chief of Osteoporosis International. “We need to treat these people right away to prevent more fractures and related disability, morbidity, and mortality.”

According to data from pivotal trials, the anabolic agents teriparatide, abaloparatide, and romosozumab appear to produce more rapid and larger effects against all fractures, compared with even the best antiresorptive agents. “However, comparing across studies can be problematic, because the different populations have varying baseline characteristics and different underlying risk,” Dr. Cosman said. “The protocols and the outcome definitions might be different. It’s better to compare anabolic agents with antiresorptive agents in head-to-head trials, and we now have a few of these.”

Two trials are older studies in which fracture outcomes were not the primary endpoints. One study evaluated a population of patients with glucocorticoid-induced osteoporosis and found that over 18 months, teriparatide reduced vertebral fractures by 90%, compared with alendronate (N Engl J Med. 2007;357[20]:2028-39). The other trial focused on a population of patients with acute, painful vertebral fractures. It found that over 1 year, teriparatide reduced vertebral fractures by 50%, compared with risedronate (Osteoporos Int. 2012;23[8]:2141-50). Two more recent studies compared anabolic and antiresorptive therapies on fracture outcomes as primary endpoints in patients with prevalent fractures. The VERO trial compared teriparatide with risedronate (Lancet. 2018;391[10117]:230-40), and ARCH compared romosozumab with alendronate (N Engl J Med. 2017;377[15]:1417-27).

In VERO, 1,360 patients with a prevalent vertebral fracture were randomized to receive teriparatide or risedronate for 2 years. At 12 months, the proportion of patients with a new vertebral fracture was 3.1% and 6% in the teriparatide and risedronate groups, respectively, a pattern that held true at 24 months (6.4% vs. 12%). The study also showed that the number of nonvertebral fractures was significantly lower in teriparatide-treated patients, compared with those on risedronate. In ARCH, 4,093 postmenopausal women at high risk of fracture were randomized to receive romosozumab or alendronate for 1 year and then followed for a median period of 33 months. At 12 months, the proportion of patients with a new vertebral fracture was 4% and 6.3% in the romosozumab and alendronate groups, respectively, a pattern that held true at 24 months (6.2% vs. 11.9%).

“These trials showed that the antifracture effects are faster and larger with anabolic agents, compared with antiresorptive agents,” Dr. Cosman said. “They also showed that antifracture effects are sustained after transition to antiresorptive therapy.” In ARCH, both nonvertebral and hip fracture incidences were lower in the romosozumab group, compared with the alendronate group.

The trials demonstrated that improving total hip BMD is associated with improved bone strength and resistance to fracture, yet treatment sequence matters. “The greatest BMD gains of the hip are seen when anabolic agents are used first-line, followed by a potent antiresorptive agent,” she said.

Dr. Cosman offered a strategy for patients on potent antiresorptive agents who need anabolic medication. In patients on bisphosphonates, especially with an incident hip fracture or very low hip BMD, consider combination therapy with initiation of teriparatide or abaloparatide, along with an antiresorptive agent. “There are very little data addressing patients on denosumab, but I would suggest perhaps adding teriparatide or abaloparatide in this population, and continuing denosumab,” she said. “That could lead to BMD gain. Switching to romosozumab might also be an option. But, if possible, use an anabolic agent first. The role of anabolic medication for osteoporosis is evolving as evidence continues to suggest superior benefit of anabolic-first regimens for high-risk patients.”

Dr. Cosman disclosed that she has received advising, consulting, and speaking fees from Amgen and Radius. She has received consulting fees from Tarsa and research grants and medication from Amgen.

[email protected]

LOS ANGELES – In the opinion of Felicia Cosman, MD, the current state of osteoporosis treatment is fraught with clinical challenges.

First, most patients at highest risk for future fractures are not being treated. “In fact, fewer than 25% of patients with new clinical fractures are treated for their underlying disease,” Dr. Cosman, professor of medicine at Columbia University, New York, said at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists (AACE).

“One of the reasons doctors are not treating these patients is that many of them do not have a T-score in the osteoporosis range. There’s a misunderstanding here. A fracture that occurs in people with low bone mass in the setting of minimal trauma – such as a fall from standing height – meets the criteria for the clinical diagnosis of osteoporosis and qualifies a person for being at high risk of more fractures. This is likely because bone weakness or fragility is related not just to quantitative aspects, but also to structural and qualitative aspects that cannot be measured as easily.”

Another problem is that some of the highest-risk patients are those with a vertebral fracture. “However, vertebral fractures are particularly difficult to find and treat because they’re often asymptomatic and we’re not [identifying] these patients,” she said. “Targeted screening [with] spine imaging to find vertebral fractures is probably as important as BMD [bone mineral density] testing.”

To complicate matters, Dr. Cosman said that clinicians and patients “misunderstand the balance between benefits and risks of osteoporosis medications and they don’t consider the risk of not treating the underlying disease. Lastly, there’s little evidence to help guide long-term strategies. Guidelines across medical specialties are incredibly inconsistent. With the exception of guidelines from AACE, the one thing that they’re very consistent about is underrecognizing the value of anabolic therapy for people with severe osteoporosis.”

It is well known that previous bone fracture is the most important risk factor for a future fracture, but the recency of the fracture is also important. In a recent study, researchers followed 377,561 female Medicare beneficiaries with a first fracture for up to 5 years (Osteoporos Int. 2019;30[1]:79-92). They found that at 1 year, the risk of another fracture was 10%. The fracture risk rose to 18% at 2 years, and to 31% at 5 years. “I like to think of this as the osteoporosis emergency,” said Dr. Cosman, co–editor-in-chief of Osteoporosis International. “We need to treat these people right away to prevent more fractures and related disability, morbidity, and mortality.”

According to data from pivotal trials, the anabolic agents teriparatide, abaloparatide, and romosozumab appear to produce more rapid and larger effects against all fractures, compared with even the best antiresorptive agents. “However, comparing across studies can be problematic, because the different populations have varying baseline characteristics and different underlying risk,” Dr. Cosman said. “The protocols and the outcome definitions might be different. It’s better to compare anabolic agents with antiresorptive agents in head-to-head trials, and we now have a few of these.”

Two trials are older studies in which fracture outcomes were not the primary endpoints. One study evaluated a population of patients with glucocorticoid-induced osteoporosis and found that over 18 months, teriparatide reduced vertebral fractures by 90%, compared with alendronate (N Engl J Med. 2007;357[20]:2028-39). The other trial focused on a population of patients with acute, painful vertebral fractures. It found that over 1 year, teriparatide reduced vertebral fractures by 50%, compared with risedronate (Osteoporos Int. 2012;23[8]:2141-50). Two more recent studies compared anabolic and antiresorptive therapies on fracture outcomes as primary endpoints in patients with prevalent fractures. The VERO trial compared teriparatide with risedronate (Lancet. 2018;391[10117]:230-40), and ARCH compared romosozumab with alendronate (N Engl J Med. 2017;377[15]:1417-27).

In VERO, 1,360 patients with a prevalent vertebral fracture were randomized to receive teriparatide or risedronate for 2 years. At 12 months, the proportion of patients with a new vertebral fracture was 3.1% and 6% in the teriparatide and risedronate groups, respectively, a pattern that held true at 24 months (6.4% vs. 12%). The study also showed that the number of nonvertebral fractures was significantly lower in teriparatide-treated patients, compared with those on risedronate. In ARCH, 4,093 postmenopausal women at high risk of fracture were randomized to receive romosozumab or alendronate for 1 year and then followed for a median period of 33 months. At 12 months, the proportion of patients with a new vertebral fracture was 4% and 6.3% in the romosozumab and alendronate groups, respectively, a pattern that held true at 24 months (6.2% vs. 11.9%).

“These trials showed that the antifracture effects are faster and larger with anabolic agents, compared with antiresorptive agents,” Dr. Cosman said. “They also showed that antifracture effects are sustained after transition to antiresorptive therapy.” In ARCH, both nonvertebral and hip fracture incidences were lower in the romosozumab group, compared with the alendronate group.

The trials demonstrated that improving total hip BMD is associated with improved bone strength and resistance to fracture, yet treatment sequence matters. “The greatest BMD gains of the hip are seen when anabolic agents are used first-line, followed by a potent antiresorptive agent,” she said.

Dr. Cosman offered a strategy for patients on potent antiresorptive agents who need anabolic medication. In patients on bisphosphonates, especially with an incident hip fracture or very low hip BMD, consider combination therapy with initiation of teriparatide or abaloparatide, along with an antiresorptive agent. “There are very little data addressing patients on denosumab, but I would suggest perhaps adding teriparatide or abaloparatide in this population, and continuing denosumab,” she said. “That could lead to BMD gain. Switching to romosozumab might also be an option. But, if possible, use an anabolic agent first. The role of anabolic medication for osteoporosis is evolving as evidence continues to suggest superior benefit of anabolic-first regimens for high-risk patients.”

Dr. Cosman disclosed that she has received advising, consulting, and speaking fees from Amgen and Radius. She has received consulting fees from Tarsa and research grants and medication from Amgen.

[email protected]

LOS ANGELES – In the opinion of Felicia Cosman, MD, the current state of osteoporosis treatment is fraught with clinical challenges.

First, most patients at highest risk for future fractures are not being treated. “In fact, fewer than 25% of patients with new clinical fractures are treated for their underlying disease,” Dr. Cosman, professor of medicine at Columbia University, New York, said at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists (AACE).

“One of the reasons doctors are not treating these patients is that many of them do not have a T-score in the osteoporosis range. There’s a misunderstanding here. A fracture that occurs in people with low bone mass in the setting of minimal trauma – such as a fall from standing height – meets the criteria for the clinical diagnosis of osteoporosis and qualifies a person for being at high risk of more fractures. This is likely because bone weakness or fragility is related not just to quantitative aspects, but also to structural and qualitative aspects that cannot be measured as easily.”

Another problem is that some of the highest-risk patients are those with a vertebral fracture. “However, vertebral fractures are particularly difficult to find and treat because they’re often asymptomatic and we’re not [identifying] these patients,” she said. “Targeted screening [with] spine imaging to find vertebral fractures is probably as important as BMD [bone mineral density] testing.”

To complicate matters, Dr. Cosman said that clinicians and patients “misunderstand the balance between benefits and risks of osteoporosis medications and they don’t consider the risk of not treating the underlying disease. Lastly, there’s little evidence to help guide long-term strategies. Guidelines across medical specialties are incredibly inconsistent. With the exception of guidelines from AACE, the one thing that they’re very consistent about is underrecognizing the value of anabolic therapy for people with severe osteoporosis.”

It is well known that previous bone fracture is the most important risk factor for a future fracture, but the recency of the fracture is also important. In a recent study, researchers followed 377,561 female Medicare beneficiaries with a first fracture for up to 5 years (Osteoporos Int. 2019;30[1]:79-92). They found that at 1 year, the risk of another fracture was 10%. The fracture risk rose to 18% at 2 years, and to 31% at 5 years. “I like to think of this as the osteoporosis emergency,” said Dr. Cosman, co–editor-in-chief of Osteoporosis International. “We need to treat these people right away to prevent more fractures and related disability, morbidity, and mortality.”

According to data from pivotal trials, the anabolic agents teriparatide, abaloparatide, and romosozumab appear to produce more rapid and larger effects against all fractures, compared with even the best antiresorptive agents. “However, comparing across studies can be problematic, because the different populations have varying baseline characteristics and different underlying risk,” Dr. Cosman said. “The protocols and the outcome definitions might be different. It’s better to compare anabolic agents with antiresorptive agents in head-to-head trials, and we now have a few of these.”

Two trials are older studies in which fracture outcomes were not the primary endpoints. One study evaluated a population of patients with glucocorticoid-induced osteoporosis and found that over 18 months, teriparatide reduced vertebral fractures by 90%, compared with alendronate (N Engl J Med. 2007;357[20]:2028-39). The other trial focused on a population of patients with acute, painful vertebral fractures. It found that over 1 year, teriparatide reduced vertebral fractures by 50%, compared with risedronate (Osteoporos Int. 2012;23[8]:2141-50). Two more recent studies compared anabolic and antiresorptive therapies on fracture outcomes as primary endpoints in patients with prevalent fractures. The VERO trial compared teriparatide with risedronate (Lancet. 2018;391[10117]:230-40), and ARCH compared romosozumab with alendronate (N Engl J Med. 2017;377[15]:1417-27).

In VERO, 1,360 patients with a prevalent vertebral fracture were randomized to receive teriparatide or risedronate for 2 years. At 12 months, the proportion of patients with a new vertebral fracture was 3.1% and 6% in the teriparatide and risedronate groups, respectively, a pattern that held true at 24 months (6.4% vs. 12%). The study also showed that the number of nonvertebral fractures was significantly lower in teriparatide-treated patients, compared with those on risedronate. In ARCH, 4,093 postmenopausal women at high risk of fracture were randomized to receive romosozumab or alendronate for 1 year and then followed for a median period of 33 months. At 12 months, the proportion of patients with a new vertebral fracture was 4% and 6.3% in the romosozumab and alendronate groups, respectively, a pattern that held true at 24 months (6.2% vs. 11.9%).

“These trials showed that the antifracture effects are faster and larger with anabolic agents, compared with antiresorptive agents,” Dr. Cosman said. “They also showed that antifracture effects are sustained after transition to antiresorptive therapy.” In ARCH, both nonvertebral and hip fracture incidences were lower in the romosozumab group, compared with the alendronate group.

The trials demonstrated that improving total hip BMD is associated with improved bone strength and resistance to fracture, yet treatment sequence matters. “The greatest BMD gains of the hip are seen when anabolic agents are used first-line, followed by a potent antiresorptive agent,” she said.

Dr. Cosman offered a strategy for patients on potent antiresorptive agents who need anabolic medication. In patients on bisphosphonates, especially with an incident hip fracture or very low hip BMD, consider combination therapy with initiation of teriparatide or abaloparatide, along with an antiresorptive agent. “There are very little data addressing patients on denosumab, but I would suggest perhaps adding teriparatide or abaloparatide in this population, and continuing denosumab,” she said. “That could lead to BMD gain. Switching to romosozumab might also be an option. But, if possible, use an anabolic agent first. The role of anabolic medication for osteoporosis is evolving as evidence continues to suggest superior benefit of anabolic-first regimens for high-risk patients.”

Dr. Cosman disclosed that she has received advising, consulting, and speaking fees from Amgen and Radius. She has received consulting fees from Tarsa and research grants and medication from Amgen.

[email protected]

LOS ANGELES – Recent research, a new test, and upcoming guidelines are providing insight into the diagnosis of adult growth hormone deficiency and the importance of treatment, Kevin C.J. Yuen, MD, FRCP(UK), FACE, told colleagues at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists (AACE).

“The data show that growth hormone replacement is safe and may improve survival,” said Dr Yuen, professor of medicine and medical director at Barrow Neurological Institute Pituitary Center in Phoenix.

Dr. Yuen is chair of the AACE’s growth hormone task force and coauthored both the 2009 and soon-to-be-published 2019 AACE guidelines for the treatment of adult growth hormone deficiency (AGHD).

Updated AGHD guidelines were needed for a variety of reasons, including a greater awareness of the benefits of hormone replacement in these patients and new developments in areas such as testing, he said. The guidelines also are also necessary because of the skepticism about the cost and benefits of AGHD therapy, concerns about the safety of long-term therapy, and the misuse of treatment in certain patients, he added.

On the treatment front, Dr. Yuen said it has become more clear over recent years that patients with AGHD benefit from hormone replacement. Findings from two studies have linked treatment to improvements in exercise capacity (Clin Endocrinol [Oxf]. 2016;85[4]:660-8) and patient quality of life (Eur J Endocrinol. 2017;176:99-109). “Even just after 6 months there’s an improvement in aerobic power,” he said.

And, he continued, other findings have suggested that treatment could lower mortality in men and reduce the number of deaths from malignant neoplasms in all patients (Eur J Endocrinol. 2017;176[1]:67-75).

However, Dr. Yuen cautioned that the confirmation of a survival benefit from hormone replacement will be speculative as long as there are no prospective data available.

He offered five tips about diagnosing and treating AGHD:

First, be aware that a number of conditions other than AGHD can cause low levels of insulin-like growth factor 1, including malnutrition, diabetes, untreated hypothyroidism, liver disease, and kidney failure.

Second, follow recommended algorithms for testing adult patients and transition those pediatric patients who seem to be at risk of having the condition. (Those moving from pediatric to adult care are known as transition patients.) The algorithms suggest that three diagnostic tests can be helpful, depending on the situation: the macimorelin test, the insulin tolerance test, and the glucagon stimulation test.

In 2017, the Food and Drug Administration approved the macimorelin (Macrilen) test, which requires the administration of an oral medication before a blood test. Dr. Yuen cited a phase 3 study that demonstrated that the test was “highly reproducible” and has a “good safety profile” (J Clin Endocrinol Metab. 2018;103[8]:3083-93). Dr. Yuen believes the test will become the preferred alternative to the insulin tolerance test.

Third, transition patients require special care as they move from pediatric care. “The handover is still very challenging,” Dr. Yuen said. “There’s still much to be done to improve the quality of treatment for these patients.” Challenges during the transition can include the patient’s reluctance to continue taking hormones in adulthood, he said. “Encourage pediatricians to start educating patients from early on that they’ll need to remain on hormones,” he advised, and help patients take accountability for their health in areas such as self-injection.

Patients may suffer from “injection fatigue,” they may be concerned about the side effects of the therapy, and/or they may be overwhelmed by the cost of care, he said. They may not understand how to manage their care and lack insight into the consequences of treatment cessation.

He advised endocrinologists to monitor transition patients who aren’t growth-hormone deficient because their status may change in the future.

Fourth, start treatment in adults with recommended doses of growth hormone. For those younger than 30 years, use 0.4-0.5 mg/day (higher for transition patients); for those aged between 30 and 60 years, use 0.2-0.3 mg/day; and for those who are older than 60 years, use 0.1-0.2 mg/day. Doses should be adjusted to 0.1-0.2 mg/day in patients with diabetes, obesity, and/or previous gestational diabetes.

Fifth, treat patients with growth hormone indefinitely if benefits are seen, but consider stopping treatment after a year if there doesn’t seem to be a benefit, Dr. Yuen advised. Follow up at 6 months, he recommended.

Dr. Yuen disclosed receiving research grants from and consulting for Pfizer, Novo Nordisk, and Aeterna Zentaris. He has also consulted for Strongbridge.

LOS ANGELES – Recent research, a new test, and upcoming guidelines are providing insight into the diagnosis of adult growth hormone deficiency and the importance of treatment, Kevin C.J. Yuen, MD, FRCP(UK), FACE, told colleagues at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists (AACE).

“The data show that growth hormone replacement is safe and may improve survival,” said Dr Yuen, professor of medicine and medical director at Barrow Neurological Institute Pituitary Center in Phoenix.

Dr. Yuen is chair of the AACE’s growth hormone task force and coauthored both the 2009 and soon-to-be-published 2019 AACE guidelines for the treatment of adult growth hormone deficiency (AGHD).

Updated AGHD guidelines were needed for a variety of reasons, including a greater awareness of the benefits of hormone replacement in these patients and new developments in areas such as testing, he said. The guidelines also are also necessary because of the skepticism about the cost and benefits of AGHD therapy, concerns about the safety of long-term therapy, and the misuse of treatment in certain patients, he added.

On the treatment front, Dr. Yuen said it has become more clear over recent years that patients with AGHD benefit from hormone replacement. Findings from two studies have linked treatment to improvements in exercise capacity (Clin Endocrinol [Oxf]. 2016;85[4]:660-8) and patient quality of life (Eur J Endocrinol. 2017;176:99-109). “Even just after 6 months there’s an improvement in aerobic power,” he said.

And, he continued, other findings have suggested that treatment could lower mortality in men and reduce the number of deaths from malignant neoplasms in all patients (Eur J Endocrinol. 2017;176[1]:67-75).

However, Dr. Yuen cautioned that the confirmation of a survival benefit from hormone replacement will be speculative as long as there are no prospective data available.

He offered five tips about diagnosing and treating AGHD:

First, be aware that a number of conditions other than AGHD can cause low levels of insulin-like growth factor 1, including malnutrition, diabetes, untreated hypothyroidism, liver disease, and kidney failure.

Second, follow recommended algorithms for testing adult patients and transition those pediatric patients who seem to be at risk of having the condition. (Those moving from pediatric to adult care are known as transition patients.) The algorithms suggest that three diagnostic tests can be helpful, depending on the situation: the macimorelin test, the insulin tolerance test, and the glucagon stimulation test.

In 2017, the Food and Drug Administration approved the macimorelin (Macrilen) test, which requires the administration of an oral medication before a blood test. Dr. Yuen cited a phase 3 study that demonstrated that the test was “highly reproducible” and has a “good safety profile” (J Clin Endocrinol Metab. 2018;103[8]:3083-93). Dr. Yuen believes the test will become the preferred alternative to the insulin tolerance test.

Third, transition patients require special care as they move from pediatric care. “The handover is still very challenging,” Dr. Yuen said. “There’s still much to be done to improve the quality of treatment for these patients.” Challenges during the transition can include the patient’s reluctance to continue taking hormones in adulthood, he said. “Encourage pediatricians to start educating patients from early on that they’ll need to remain on hormones,” he advised, and help patients take accountability for their health in areas such as self-injection.

Patients may suffer from “injection fatigue,” they may be concerned about the side effects of the therapy, and/or they may be overwhelmed by the cost of care, he said. They may not understand how to manage their care and lack insight into the consequences of treatment cessation.

He advised endocrinologists to monitor transition patients who aren’t growth-hormone deficient because their status may change in the future.

Fourth, start treatment in adults with recommended doses of growth hormone. For those younger than 30 years, use 0.4-0.5 mg/day (higher for transition patients); for those aged between 30 and 60 years, use 0.2-0.3 mg/day; and for those who are older than 60 years, use 0.1-0.2 mg/day. Doses should be adjusted to 0.1-0.2 mg/day in patients with diabetes, obesity, and/or previous gestational diabetes.

Fifth, treat patients with growth hormone indefinitely if benefits are seen, but consider stopping treatment after a year if there doesn’t seem to be a benefit, Dr. Yuen advised. Follow up at 6 months, he recommended.

Dr. Yuen disclosed receiving research grants from and consulting for Pfizer, Novo Nordisk, and Aeterna Zentaris. He has also consulted for Strongbridge.

LOS ANGELES – Recent research, a new test, and upcoming guidelines are providing insight into the diagnosis of adult growth hormone deficiency and the importance of treatment, Kevin C.J. Yuen, MD, FRCP(UK), FACE, told colleagues at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists (AACE).

“The data show that growth hormone replacement is safe and may improve survival,” said Dr Yuen, professor of medicine and medical director at Barrow Neurological Institute Pituitary Center in Phoenix.

Dr. Yuen is chair of the AACE’s growth hormone task force and coauthored both the 2009 and soon-to-be-published 2019 AACE guidelines for the treatment of adult growth hormone deficiency (AGHD).

Updated AGHD guidelines were needed for a variety of reasons, including a greater awareness of the benefits of hormone replacement in these patients and new developments in areas such as testing, he said. The guidelines also are also necessary because of the skepticism about the cost and benefits of AGHD therapy, concerns about the safety of long-term therapy, and the misuse of treatment in certain patients, he added.

On the treatment front, Dr. Yuen said it has become more clear over recent years that patients with AGHD benefit from hormone replacement. Findings from two studies have linked treatment to improvements in exercise capacity (Clin Endocrinol [Oxf]. 2016;85[4]:660-8) and patient quality of life (Eur J Endocrinol. 2017;176:99-109). “Even just after 6 months there’s an improvement in aerobic power,” he said.

And, he continued, other findings have suggested that treatment could lower mortality in men and reduce the number of deaths from malignant neoplasms in all patients (Eur J Endocrinol. 2017;176[1]:67-75).

However, Dr. Yuen cautioned that the confirmation of a survival benefit from hormone replacement will be speculative as long as there are no prospective data available.

He offered five tips about diagnosing and treating AGHD:

First, be aware that a number of conditions other than AGHD can cause low levels of insulin-like growth factor 1, including malnutrition, diabetes, untreated hypothyroidism, liver disease, and kidney failure.

Second, follow recommended algorithms for testing adult patients and transition those pediatric patients who seem to be at risk of having the condition. (Those moving from pediatric to adult care are known as transition patients.) The algorithms suggest that three diagnostic tests can be helpful, depending on the situation: the macimorelin test, the insulin tolerance test, and the glucagon stimulation test.

In 2017, the Food and Drug Administration approved the macimorelin (Macrilen) test, which requires the administration of an oral medication before a blood test. Dr. Yuen cited a phase 3 study that demonstrated that the test was “highly reproducible” and has a “good safety profile” (J Clin Endocrinol Metab. 2018;103[8]:3083-93). Dr. Yuen believes the test will become the preferred alternative to the insulin tolerance test.

Third, transition patients require special care as they move from pediatric care. “The handover is still very challenging,” Dr. Yuen said. “There’s still much to be done to improve the quality of treatment for these patients.” Challenges during the transition can include the patient’s reluctance to continue taking hormones in adulthood, he said. “Encourage pediatricians to start educating patients from early on that they’ll need to remain on hormones,” he advised, and help patients take accountability for their health in areas such as self-injection.

Patients may suffer from “injection fatigue,” they may be concerned about the side effects of the therapy, and/or they may be overwhelmed by the cost of care, he said. They may not understand how to manage their care and lack insight into the consequences of treatment cessation.

He advised endocrinologists to monitor transition patients who aren’t growth-hormone deficient because their status may change in the future.

Fourth, start treatment in adults with recommended doses of growth hormone. For those younger than 30 years, use 0.4-0.5 mg/day (higher for transition patients); for those aged between 30 and 60 years, use 0.2-0.3 mg/day; and for those who are older than 60 years, use 0.1-0.2 mg/day. Doses should be adjusted to 0.1-0.2 mg/day in patients with diabetes, obesity, and/or previous gestational diabetes.

Fifth, treat patients with growth hormone indefinitely if benefits are seen, but consider stopping treatment after a year if there doesn’t seem to be a benefit, Dr. Yuen advised. Follow up at 6 months, he recommended.

Dr. Yuen disclosed receiving research grants from and consulting for Pfizer, Novo Nordisk, and Aeterna Zentaris. He has also consulted for Strongbridge.

LOS ANGELES – A phase 3 clinical trial shows promising results for an experimental drug called teprotumumab, which treats thyroid eye disease, researchers reported at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists.

“For the first time, there appears to be a medicine that can be given during the active phase of the disease and can actually reverse not just the eyelid swelling and the clinical activity score, but also reduce the eye bulging and double vision and [improve] the [patient’s] quality of life. It could be a watershed moment in the treatment of the disease,” said ophthalmologist Raymond Douglas, MD, PhD, professor of surgery at Cedar-Sinai Medical Center Los Angeles and the study’s coprincipal investigator, in an interview at the meeting.

According to Dr. Douglas, thyroid eye disease, which is also known as Graves’ eye disease, is a severely disabling condition that causes swelling, pain, discomfort, and blindness. “The burden really is quite significant,” he said, with an impact that’s been compared with that of breast cancer in quality-of-life studies.

“Current treatments for thyroid eye disease are rather limited,” he said. “They really encompass just reducing the swelling and the short-term manifestations of the disease. Treatments such as IV steroids and radiation have been shown to not have any effect on long-term manifestations such as eye bulging and double vision.”

Teprotumumab is a fully human monoclonal antibody that targets the insulinlike growth factor I receptor (IGF-IR). It seems to downregulate thyroid eye disease, Dr. Douglas said.

Researchers studied the drug in a randomized, placebo-controlled study: 41 patients were designated to receive eight intravenous infusions of the drug over 21 weeks (10 mg/kg for the first infusion, then 20 mg/kg thereafter). At week 24, 83% of the study group (34 of 41 patients) reached the endpoint of a reduction of eye bulging by at least 2 mm, compared with 10% of patients (4 of 42) in the placebo group, which received infusions of saline solution.

Two millimeters is significant, Dr. Douglas said. “If you noticed someone’s eye was bulging 2 millimeters, you’d say, ‘Hey, I think something is wrong with your eye.’ ”

Initial study results were released in February 2019. New data about secondary endpoints were released at the AACE meeting: Researchers reported that the average reduction in proptosis (eye bulging) was 2.82 mm in the study group, compared with 0.54 mm in the placebo group (P less than .001).

Dr. Douglas said he can “achieve 3 mm of reduction through surgery to drill out the bone between the eye and the brain. [The patients in the study group] were able to achieve almost 3 millimeters of reduction by the drug alone. It’s a rather significant improvement.”

The new data also provided some insight into the timing of clinical improvements. According to Dr. Douglas, “most of the endpoints were met as early as 6 weeks or [after] two infusions of this drug.”

The adverse effects were relatively mild and included muscle spasms, said Dr. Douglas. The side effects seem to be “well tolerated,” he noted, and none led to cessation of therapy.

Participants with potential for motherhood or fatherhood during the trial had to agree to take precautions to avoid becoming pregnant or impregnating a partner.

Dr. Douglas didn’t provide cost information about the drug. However, it seems likely to be expensive. A writer with Seeking Alpha, a stock market analysis site, estimated that the cost could reach “$250,000 or $300,000 per patient per year, which translates to a $3.7 billion to $6 billion market in the United States alone (based on the estimated patient population in the 15,000-20,000 range).”

The drug’s manufacturer, Horizon Therapeutics, expects to apply to the Food and Drug Administration later this year for approval of the drug.

If it is approved, endocrinologists will have an opportunity to partner with eye surgeons to treat thyroid eye disease, Dr. Douglas said. “The crux will be the comanagement with the endocrinologist helping to control the thyroid function and manage some of the side effects of this medication, and the oculoplastic surgeon [working on] diagnosis, appropriate use, and management.”

Horizon Therapeutics funded the study. Dr. Douglas disclosed that he is a consultant with the company.
 

LOS ANGELES – A phase 3 clinical trial shows promising results for an experimental drug called teprotumumab, which treats thyroid eye disease, researchers reported at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists.

“For the first time, there appears to be a medicine that can be given during the active phase of the disease and can actually reverse not just the eyelid swelling and the clinical activity score, but also reduce the eye bulging and double vision and [improve] the [patient’s] quality of life. It could be a watershed moment in the treatment of the disease,” said ophthalmologist Raymond Douglas, MD, PhD, professor of surgery at Cedar-Sinai Medical Center Los Angeles and the study’s coprincipal investigator, in an interview at the meeting.

According to Dr. Douglas, thyroid eye disease, which is also known as Graves’ eye disease, is a severely disabling condition that causes swelling, pain, discomfort, and blindness. “The burden really is quite significant,” he said, with an impact that’s been compared with that of breast cancer in quality-of-life studies.

“Current treatments for thyroid eye disease are rather limited,” he said. “They really encompass just reducing the swelling and the short-term manifestations of the disease. Treatments such as IV steroids and radiation have been shown to not have any effect on long-term manifestations such as eye bulging and double vision.”

Teprotumumab is a fully human monoclonal antibody that targets the insulinlike growth factor I receptor (IGF-IR). It seems to downregulate thyroid eye disease, Dr. Douglas said.

Researchers studied the drug in a randomized, placebo-controlled study: 41 patients were designated to receive eight intravenous infusions of the drug over 21 weeks (10 mg/kg for the first infusion, then 20 mg/kg thereafter). At week 24, 83% of the study group (34 of 41 patients) reached the endpoint of a reduction of eye bulging by at least 2 mm, compared with 10% of patients (4 of 42) in the placebo group, which received infusions of saline solution.

Two millimeters is significant, Dr. Douglas said. “If you noticed someone’s eye was bulging 2 millimeters, you’d say, ‘Hey, I think something is wrong with your eye.’ ”

Initial study results were released in February 2019. New data about secondary endpoints were released at the AACE meeting: Researchers reported that the average reduction in proptosis (eye bulging) was 2.82 mm in the study group, compared with 0.54 mm in the placebo group (P less than .001).

Dr. Douglas said he can “achieve 3 mm of reduction through surgery to drill out the bone between the eye and the brain. [The patients in the study group] were able to achieve almost 3 millimeters of reduction by the drug alone. It’s a rather significant improvement.”

The new data also provided some insight into the timing of clinical improvements. According to Dr. Douglas, “most of the endpoints were met as early as 6 weeks or [after] two infusions of this drug.”

The adverse effects were relatively mild and included muscle spasms, said Dr. Douglas. The side effects seem to be “well tolerated,” he noted, and none led to cessation of therapy.

Participants with potential for motherhood or fatherhood during the trial had to agree to take precautions to avoid becoming pregnant or impregnating a partner.

Dr. Douglas didn’t provide cost information about the drug. However, it seems likely to be expensive. A writer with Seeking Alpha, a stock market analysis site, estimated that the cost could reach “$250,000 or $300,000 per patient per year, which translates to a $3.7 billion to $6 billion market in the United States alone (based on the estimated patient population in the 15,000-20,000 range).”

The drug’s manufacturer, Horizon Therapeutics, expects to apply to the Food and Drug Administration later this year for approval of the drug.

If it is approved, endocrinologists will have an opportunity to partner with eye surgeons to treat thyroid eye disease, Dr. Douglas said. “The crux will be the comanagement with the endocrinologist helping to control the thyroid function and manage some of the side effects of this medication, and the oculoplastic surgeon [working on] diagnosis, appropriate use, and management.”

Horizon Therapeutics funded the study. Dr. Douglas disclosed that he is a consultant with the company.
 

LOS ANGELES – A phase 3 clinical trial shows promising results for an experimental drug called teprotumumab, which treats thyroid eye disease, researchers reported at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists.

“For the first time, there appears to be a medicine that can be given during the active phase of the disease and can actually reverse not just the eyelid swelling and the clinical activity score, but also reduce the eye bulging and double vision and [improve] the [patient’s] quality of life. It could be a watershed moment in the treatment of the disease,” said ophthalmologist Raymond Douglas, MD, PhD, professor of surgery at Cedar-Sinai Medical Center Los Angeles and the study’s coprincipal investigator, in an interview at the meeting.

According to Dr. Douglas, thyroid eye disease, which is also known as Graves’ eye disease, is a severely disabling condition that causes swelling, pain, discomfort, and blindness. “The burden really is quite significant,” he said, with an impact that’s been compared with that of breast cancer in quality-of-life studies.

“Current treatments for thyroid eye disease are rather limited,” he said. “They really encompass just reducing the swelling and the short-term manifestations of the disease. Treatments such as IV steroids and radiation have been shown to not have any effect on long-term manifestations such as eye bulging and double vision.”

Teprotumumab is a fully human monoclonal antibody that targets the insulinlike growth factor I receptor (IGF-IR). It seems to downregulate thyroid eye disease, Dr. Douglas said.

Researchers studied the drug in a randomized, placebo-controlled study: 41 patients were designated to receive eight intravenous infusions of the drug over 21 weeks (10 mg/kg for the first infusion, then 20 mg/kg thereafter). At week 24, 83% of the study group (34 of 41 patients) reached the endpoint of a reduction of eye bulging by at least 2 mm, compared with 10% of patients (4 of 42) in the placebo group, which received infusions of saline solution.

Two millimeters is significant, Dr. Douglas said. “If you noticed someone’s eye was bulging 2 millimeters, you’d say, ‘Hey, I think something is wrong with your eye.’ ”

Initial study results were released in February 2019. New data about secondary endpoints were released at the AACE meeting: Researchers reported that the average reduction in proptosis (eye bulging) was 2.82 mm in the study group, compared with 0.54 mm in the placebo group (P less than .001).

Dr. Douglas said he can “achieve 3 mm of reduction through surgery to drill out the bone between the eye and the brain. [The patients in the study group] were able to achieve almost 3 millimeters of reduction by the drug alone. It’s a rather significant improvement.”

The new data also provided some insight into the timing of clinical improvements. According to Dr. Douglas, “most of the endpoints were met as early as 6 weeks or [after] two infusions of this drug.”

The adverse effects were relatively mild and included muscle spasms, said Dr. Douglas. The side effects seem to be “well tolerated,” he noted, and none led to cessation of therapy.

Participants with potential for motherhood or fatherhood during the trial had to agree to take precautions to avoid becoming pregnant or impregnating a partner.

Dr. Douglas didn’t provide cost information about the drug. However, it seems likely to be expensive. A writer with Seeking Alpha, a stock market analysis site, estimated that the cost could reach “$250,000 or $300,000 per patient per year, which translates to a $3.7 billion to $6 billion market in the United States alone (based on the estimated patient population in the 15,000-20,000 range).”

The drug’s manufacturer, Horizon Therapeutics, expects to apply to the Food and Drug Administration later this year for approval of the drug.

If it is approved, endocrinologists will have an opportunity to partner with eye surgeons to treat thyroid eye disease, Dr. Douglas said. “The crux will be the comanagement with the endocrinologist helping to control the thyroid function and manage some of the side effects of this medication, and the oculoplastic surgeon [working on] diagnosis, appropriate use, and management.”

Horizon Therapeutics funded the study. Dr. Douglas disclosed that he is a consultant with the company.
 

LOS ANGELES – There is no consistent evidence to suggest that subclinical hypothyroidism is linked to an increased risk of incident breast, prostate, or colon cancer. The condition, however, may be linked to an increased risk of thyroid malignancy and to an increased risk of overall cancer mortality.

These findings come from the first systematic review to examine the effect of subclinical hypothyroidism on the risk of incident cancer and cancer mortality.

“Subclinical hypothyroidism is very prevalent,” lead study author Oriana Yu, MD, MSc, said in an interview at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “It affects up to 10% of people, yet at this time we are uncertain as to whether or not [we should] treat them. Most studies have focused on cardiovascular outcomes, because we know that thyroid hormone is very important in lipid metabolism.”

Dr. Yu, an endocrinologist at McGill University, Montreal, and her colleagues searched the Ovid MEDLINE database for articles published from the date of its inception until Nov. 13, 2017, and combined words related to thyroid function and cancer in their search. They limited the analysis to randomized clinical trials and cohort and case-control studies in which the thyroid dysfunction chronologically preceded the cancer incidence or mortality by at least one year.

Of the 180 records screened, 51 full-text articles were assessed for eligibility. Of those, nine met the criteria for systematic review – seven related to cancer risk and two to cancer mortality. The studies were deemed to be of good to medium quality, but six of the nine were cohort studies, the rest case-control studies. “We had hoped to do a systematic review and meta-analysis, but there was high heterogeneity in the studies, especially in terms of different risk measures and outcomes reported,” Dr. Yu said. “As a result, we were not able to perform a meta-analysis.”

The researchers found that the studies had inconsistent findings when it came to the impact of subclinical hypothyroidism on the risk of breast, prostate, and colon cancer. For example, one prospective cohort study of 2,738 patients found no association between subclinical hypothyroidism and the risk of breast cancer (odds ratio, 1.9; 95% confidence interval, 0.8-4.9; Thyroid. 2005;15[11]:1253-9). Women with breast cancer, however, were more likely to have thyroid autoantibodies.

Meanwhile, a case-control study of 1,201 men found that those with elevated TSH levels had a decreased risk of prostate cancer (OR, 0.71; 95% CI, 0.47-1.06; PLoS One. 2012 Oct 30. doi: 10.1371/journal.pone.0047730). “That was a bit surprising to us,” Dr. Yu said. In addition, a nested case-control study of 103,044 patients found that subclinical hypothyroidism was linked to an increased risk for colon cancer (OR, 1.16; 95% CI, 1.08-1.24; J Natl Cancer Inst. 2015 Apr 8. doi: 10.1093/jnci/djv084).

Of the two studies that focused on cancer mortality, one retrospective cohort analysis of 4,735 patients showed that treatment of subclinical hypothyroidism was associated with a decreased risk of cancer mortality in those aged 40-70 years (hazard ratio, 0.59; 95% CI, 0.21-0.99; Arch Intern Med. 2012;172[10]:811-7). The other study, a retrospective cohort analysis of 115,746 patients, found that subclinical hypothyroidism was associated with an increased risk of cancer mortality (relative risk, 1.51; 95% CI, 1.06-2.15; PLoS One. 2015 Apr 1. doi: 10.1371/journal.pone.0122955).

“We need to interpret the cancer-related mortality findings with caution,” Dr. Yu said. “There’s concern about whether patients who are treated might be [generally] healthier or were less frail, compared with those who were not treated. Although these studies adjusted for a number of confounders, it may be difficult to measure and adjust for [those two] factors. That might explain the findings in the two studies on cancer-related mortality.”

Dr. Yu and two coauthors have received salary awards from the Fonds de recherche du Québec–Santé.

[email protected]

LOS ANGELES – There is no consistent evidence to suggest that subclinical hypothyroidism is linked to an increased risk of incident breast, prostate, or colon cancer. The condition, however, may be linked to an increased risk of thyroid malignancy and to an increased risk of overall cancer mortality.

These findings come from the first systematic review to examine the effect of subclinical hypothyroidism on the risk of incident cancer and cancer mortality.

“Subclinical hypothyroidism is very prevalent,” lead study author Oriana Yu, MD, MSc, said in an interview at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “It affects up to 10% of people, yet at this time we are uncertain as to whether or not [we should] treat them. Most studies have focused on cardiovascular outcomes, because we know that thyroid hormone is very important in lipid metabolism.”

Dr. Yu, an endocrinologist at McGill University, Montreal, and her colleagues searched the Ovid MEDLINE database for articles published from the date of its inception until Nov. 13, 2017, and combined words related to thyroid function and cancer in their search. They limited the analysis to randomized clinical trials and cohort and case-control studies in which the thyroid dysfunction chronologically preceded the cancer incidence or mortality by at least one year.

Of the 180 records screened, 51 full-text articles were assessed for eligibility. Of those, nine met the criteria for systematic review – seven related to cancer risk and two to cancer mortality. The studies were deemed to be of good to medium quality, but six of the nine were cohort studies, the rest case-control studies. “We had hoped to do a systematic review and meta-analysis, but there was high heterogeneity in the studies, especially in terms of different risk measures and outcomes reported,” Dr. Yu said. “As a result, we were not able to perform a meta-analysis.”

The researchers found that the studies had inconsistent findings when it came to the impact of subclinical hypothyroidism on the risk of breast, prostate, and colon cancer. For example, one prospective cohort study of 2,738 patients found no association between subclinical hypothyroidism and the risk of breast cancer (odds ratio, 1.9; 95% confidence interval, 0.8-4.9; Thyroid. 2005;15[11]:1253-9). Women with breast cancer, however, were more likely to have thyroid autoantibodies.

Meanwhile, a case-control study of 1,201 men found that those with elevated TSH levels had a decreased risk of prostate cancer (OR, 0.71; 95% CI, 0.47-1.06; PLoS One. 2012 Oct 30. doi: 10.1371/journal.pone.0047730). “That was a bit surprising to us,” Dr. Yu said. In addition, a nested case-control study of 103,044 patients found that subclinical hypothyroidism was linked to an increased risk for colon cancer (OR, 1.16; 95% CI, 1.08-1.24; J Natl Cancer Inst. 2015 Apr 8. doi: 10.1093/jnci/djv084).

Of the two studies that focused on cancer mortality, one retrospective cohort analysis of 4,735 patients showed that treatment of subclinical hypothyroidism was associated with a decreased risk of cancer mortality in those aged 40-70 years (hazard ratio, 0.59; 95% CI, 0.21-0.99; Arch Intern Med. 2012;172[10]:811-7). The other study, a retrospective cohort analysis of 115,746 patients, found that subclinical hypothyroidism was associated with an increased risk of cancer mortality (relative risk, 1.51; 95% CI, 1.06-2.15; PLoS One. 2015 Apr 1. doi: 10.1371/journal.pone.0122955).

“We need to interpret the cancer-related mortality findings with caution,” Dr. Yu said. “There’s concern about whether patients who are treated might be [generally] healthier or were less frail, compared with those who were not treated. Although these studies adjusted for a number of confounders, it may be difficult to measure and adjust for [those two] factors. That might explain the findings in the two studies on cancer-related mortality.”

Dr. Yu and two coauthors have received salary awards from the Fonds de recherche du Québec–Santé.

[email protected]

LOS ANGELES – There is no consistent evidence to suggest that subclinical hypothyroidism is linked to an increased risk of incident breast, prostate, or colon cancer. The condition, however, may be linked to an increased risk of thyroid malignancy and to an increased risk of overall cancer mortality.

These findings come from the first systematic review to examine the effect of subclinical hypothyroidism on the risk of incident cancer and cancer mortality.

“Subclinical hypothyroidism is very prevalent,” lead study author Oriana Yu, MD, MSc, said in an interview at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “It affects up to 10% of people, yet at this time we are uncertain as to whether or not [we should] treat them. Most studies have focused on cardiovascular outcomes, because we know that thyroid hormone is very important in lipid metabolism.”

Dr. Yu, an endocrinologist at McGill University, Montreal, and her colleagues searched the Ovid MEDLINE database for articles published from the date of its inception until Nov. 13, 2017, and combined words related to thyroid function and cancer in their search. They limited the analysis to randomized clinical trials and cohort and case-control studies in which the thyroid dysfunction chronologically preceded the cancer incidence or mortality by at least one year.

Of the 180 records screened, 51 full-text articles were assessed for eligibility. Of those, nine met the criteria for systematic review – seven related to cancer risk and two to cancer mortality. The studies were deemed to be of good to medium quality, but six of the nine were cohort studies, the rest case-control studies. “We had hoped to do a systematic review and meta-analysis, but there was high heterogeneity in the studies, especially in terms of different risk measures and outcomes reported,” Dr. Yu said. “As a result, we were not able to perform a meta-analysis.”

The researchers found that the studies had inconsistent findings when it came to the impact of subclinical hypothyroidism on the risk of breast, prostate, and colon cancer. For example, one prospective cohort study of 2,738 patients found no association between subclinical hypothyroidism and the risk of breast cancer (odds ratio, 1.9; 95% confidence interval, 0.8-4.9; Thyroid. 2005;15[11]:1253-9). Women with breast cancer, however, were more likely to have thyroid autoantibodies.

Meanwhile, a case-control study of 1,201 men found that those with elevated TSH levels had a decreased risk of prostate cancer (OR, 0.71; 95% CI, 0.47-1.06; PLoS One. 2012 Oct 30. doi: 10.1371/journal.pone.0047730). “That was a bit surprising to us,” Dr. Yu said. In addition, a nested case-control study of 103,044 patients found that subclinical hypothyroidism was linked to an increased risk for colon cancer (OR, 1.16; 95% CI, 1.08-1.24; J Natl Cancer Inst. 2015 Apr 8. doi: 10.1093/jnci/djv084).

Of the two studies that focused on cancer mortality, one retrospective cohort analysis of 4,735 patients showed that treatment of subclinical hypothyroidism was associated with a decreased risk of cancer mortality in those aged 40-70 years (hazard ratio, 0.59; 95% CI, 0.21-0.99; Arch Intern Med. 2012;172[10]:811-7). The other study, a retrospective cohort analysis of 115,746 patients, found that subclinical hypothyroidism was associated with an increased risk of cancer mortality (relative risk, 1.51; 95% CI, 1.06-2.15; PLoS One. 2015 Apr 1. doi: 10.1371/journal.pone.0122955).

“We need to interpret the cancer-related mortality findings with caution,” Dr. Yu said. “There’s concern about whether patients who are treated might be [generally] healthier or were less frail, compared with those who were not treated. Although these studies adjusted for a number of confounders, it may be difficult to measure and adjust for [those two] factors. That might explain the findings in the two studies on cancer-related mortality.”

Dr. Yu and two coauthors have received salary awards from the Fonds de recherche du Québec–Santé.

[email protected]

LOS ANGELES – The 69-year-old woman with a history of type 2 diabetes had persistent hypoglycemia despite treatment with hydrocortisone, dextrose, and glucagon. Doctors in South Carolina worried about insulinoma and planned to launch an intra-arterial calcium stimulation test. But the medical team wasn’t quite certain it had the correct diagnosis.

Then along came a suspicious nurse who uncovered the truth: The patient had used syringes and vials of insulin socked away in a cosmetics bag. The diagnosis? An unusual, but not entirely rare, case of factitious hypoglycemia. That doesn’t mean her condition was fictional. Instead, it means she created it herself.

Randy Dotinga/MDedge News

• In any case of hypoglycemia, consider the possibility that the patient has factitious hypoglycemia. In every patient, he said, do a drug screen for sulfonylureas. “Now that we have multiple classes of diabetes drugs, most of which have a risk for hypoglycemia, one has to have a lab capable of measuring all of them. And that is not easy. It’s not just ‘draw the blood and send to your corner lab.’ ”
• Patients with factitious hypoglycemia don’t tend to have predictable dips in blood sugar during fasting or after meals. Instead, their symptoms are chaotic. “It all depends on when they’re taking [insulin],” he said.
• Patients with factitious hypoglycemia don’t seem ill, but those with insulinomas do. “Patients with insulinomas are totally incapable of living normal lives. They’re incapacitated. Their lives are so disrupted that some of them need ‘babysitters’,” Dr. Service said. If they “get the tumor removed, they are cured. Then they are back to the normal life.”
• Beware that patients may not realize they’re taking a medication that causes factitious hypoglycemia. It’s common, Dr. Service said, for a patient to accidentally take his or her spouse’s medication because of a mix-up.

Ultimately, the goal is to catch factitious hypoglycemia in time. Some physicians haven’t been so fortunate. “They only get to the right answer,” he said, “after the patient has recovered from surgery.”

LOS ANGELES – The 69-year-old woman with a history of type 2 diabetes had persistent hypoglycemia despite treatment with hydrocortisone, dextrose, and glucagon. Doctors in South Carolina worried about insulinoma and planned to launch an intra-arterial calcium stimulation test. But the medical team wasn’t quite certain it had the correct diagnosis.

Then along came a suspicious nurse who uncovered the truth: The patient had used syringes and vials of insulin socked away in a cosmetics bag. The diagnosis? An unusual, but not entirely rare, case of factitious hypoglycemia. That doesn’t mean her condition was fictional. Instead, it means she created it herself.

Randy Dotinga/MDedge News

• In any case of hypoglycemia, consider the possibility that the patient has factitious hypoglycemia. In every patient, he said, do a drug screen for sulfonylureas. “Now that we have multiple classes of diabetes drugs, most of which have a risk for hypoglycemia, one has to have a lab capable of measuring all of them. And that is not easy. It’s not just ‘draw the blood and send to your corner lab.’ ”
• Patients with factitious hypoglycemia don’t tend to have predictable dips in blood sugar during fasting or after meals. Instead, their symptoms are chaotic. “It all depends on when they’re taking [insulin],” he said.
• Patients with factitious hypoglycemia don’t seem ill, but those with insulinomas do. “Patients with insulinomas are totally incapable of living normal lives. They’re incapacitated. Their lives are so disrupted that some of them need ‘babysitters’,” Dr. Service said. If they “get the tumor removed, they are cured. Then they are back to the normal life.”
• Beware that patients may not realize they’re taking a medication that causes factitious hypoglycemia. It’s common, Dr. Service said, for a patient to accidentally take his or her spouse’s medication because of a mix-up.

Ultimately, the goal is to catch factitious hypoglycemia in time. Some physicians haven’t been so fortunate. “They only get to the right answer,” he said, “after the patient has recovered from surgery.”

LOS ANGELES – The 69-year-old woman with a history of type 2 diabetes had persistent hypoglycemia despite treatment with hydrocortisone, dextrose, and glucagon. Doctors in South Carolina worried about insulinoma and planned to launch an intra-arterial calcium stimulation test. But the medical team wasn’t quite certain it had the correct diagnosis.

Then along came a suspicious nurse who uncovered the truth: The patient had used syringes and vials of insulin socked away in a cosmetics bag. The diagnosis? An unusual, but not entirely rare, case of factitious hypoglycemia. That doesn’t mean her condition was fictional. Instead, it means she created it herself.

Randy Dotinga/MDedge News

• In any case of hypoglycemia, consider the possibility that the patient has factitious hypoglycemia. In every patient, he said, do a drug screen for sulfonylureas. “Now that we have multiple classes of diabetes drugs, most of which have a risk for hypoglycemia, one has to have a lab capable of measuring all of them. And that is not easy. It’s not just ‘draw the blood and send to your corner lab.’ ”
• Patients with factitious hypoglycemia don’t tend to have predictable dips in blood sugar during fasting or after meals. Instead, their symptoms are chaotic. “It all depends on when they’re taking [insulin],” he said.
• Patients with factitious hypoglycemia don’t seem ill, but those with insulinomas do. “Patients with insulinomas are totally incapable of living normal lives. They’re incapacitated. Their lives are so disrupted that some of them need ‘babysitters’,” Dr. Service said. If they “get the tumor removed, they are cured. Then they are back to the normal life.”
• Beware that patients may not realize they’re taking a medication that causes factitious hypoglycemia. It’s common, Dr. Service said, for a patient to accidentally take his or her spouse’s medication because of a mix-up.

Ultimately, the goal is to catch factitious hypoglycemia in time. Some physicians haven’t been so fortunate. “They only get to the right answer,” he said, “after the patient has recovered from surgery.”

NEW ORLEANS – Patients who have type 2 diabetes and are taking a sodium-glucose cotransporter 2 (SGLT2) inhibitor have lower risks of heart failure hospitalization and all-cause mortality than patients on other glucose-lowering drugs regardless of whether their baseline left ventricular ejection fraction (LVEF) is preserved or reduced, based on data from a large real-world patient registry.

“The observed beneficial effects of SGLT2 inhibitors on heart failure may extend across the range of baseline ejection fractions,” Mikhail Kosiborod, MD, observed at the annual meeting of the American College of Cardiology.

This is an important new insight. The major randomized cardiovascular outcome trials that showed lower risks of heart failure hospitalization and all-cause mortality in type 2 diabetic patients on an SGLT2 inhibitor, such as EMPA-REG OUTCOME for empagliflozin (Jardiance) and CANVAS for canagliflozin (Invokana), didn’t include information on baseline LVEF. So until now it has been unclear whether the beneficial effects of the SGLT2 inhibitors preventing heart failure hospitalization vary depending upon LVEF, explained Dr. Kosiborod, a cardiologist at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.

He presented an analysis drawn from the patient database kept by Maccabi Healthcare Services in Israel. The study included 5,307 patients with type 2 diabetes and an LVEF measurement recorded in their chart at the time they started on either empagliflozin or dapagliflozin (Farxiga) and an equal number of propensity-matched type 2 diabetic controls who started on other glucose-lowering drugs, most commonly an oral dipeptidyl peptidase-4 inhibitor.

During roughly 16,000 person-years of follow-up, 239 deaths occurred. Compared with patients on another glucose-lowering drug, the risk of death from all causes was reduced by 47% among patients who were on an SGLT2 inhibitor and had a baseline LVEF of 50% or greater and by 62% among the 9% of subjects who had a baseline LVEF less than 50%.

Similarly, the risk of heart failure hospitalization was reduced by 29% in SGLT2 inhibitor users with a preserved LVEF and by 27% if they had a reduced LVEF.

For the composite endpoint of heart failure hospitalization or all-cause mortality, the risk reductions associated with SGLT2 inhibitor therapy were 45% with preserved and 39% with reduced LVEF.

Session comoderator Prakash C. Deedwania, MD, noted that there are ongoing major randomized trials of various SGLT2 inhibitors in patients with known heart failure, with cardiovascular death and heart failure hospitalization as primary endpoints. He asked Dr. Kosiborod whether, given that the results of these studies aren’t in yet, he thinks clinicians should be prescribing SGLT2 inhibitors to diabetic or prediabetic patients who don’t have clinical symptoms of heart failure but may have a marker of increased risk, such as an elevated B-type natriuretic peptide.

“At least in my mind, we have more than enough evidence at this point to say that SGLT2 inhibitors are effective in preventing heart failure,” Dr. Kosiborod replied.

“Obviously, if your risk for developing a condition is higher at baseline, then the absolute benefit that you’re going to get from using an agent that’s effective in preventing that event is going to be higher and the number needed to treat is going to be lower. So if you have a patient at high risk for heart failure by whatever risk predictor you’re using and the patient doesn’t yet have heart failure but does have diabetes, which is already a risk factor for heart failure, I think we have pretty solid data now that SGLT2 inhibitors will likely be effective in preventing heart failure in that kind of patient population. But I don’t think we have definitive data at this point to say that the drugs are effective in treating heart failure in people who already have a manifest clinical syndrome of heart failure, which is why we’re doing all these clinical trials now,” he continued.

Dr. Deedwania urged audience members to make the effort to become comfortable in prescribing SGLT2 inhibitors for their patients with type 2 diabetes.

“Many different surveys show that these drugs are not being utilized effectively by cardiologists,” noted Dr. Deedwania, professor of medicine at the University of California, San Francisco, and director of the heart failure program at the university’s Fresno campus.

“As cardiologists, we may not want to own diabetes, but we at least have to feel that we have the ownership of treating the diabetic patient with cardiovascular disease with appropriate drugs. We don’t need to depend on endocrinologists because if we do these patients may become lost,” he said.

Dr. Kosiborod concurred, citing evidence that diabetic patients with cardiovascular disease are much more likely to see a cardiologist than an endocrinologist in the course of usual care.

“There’s definitely a golden opportunity here to intervene to reduce risk,” he said.

Dr. Kosiborod reported serving as a consultant to roughly a dozen pharmaceutical companies.
 

[email protected]

SOURCE: Kosiborod M. ACC 19, Abstract #1024-07.

NEW ORLEANS – Patients who have type 2 diabetes and are taking a sodium-glucose cotransporter 2 (SGLT2) inhibitor have lower risks of heart failure hospitalization and all-cause mortality than patients on other glucose-lowering drugs regardless of whether their baseline left ventricular ejection fraction (LVEF) is preserved or reduced, based on data from a large real-world patient registry.

“The observed beneficial effects of SGLT2 inhibitors on heart failure may extend across the range of baseline ejection fractions,” Mikhail Kosiborod, MD, observed at the annual meeting of the American College of Cardiology.

This is an important new insight. The major randomized cardiovascular outcome trials that showed lower risks of heart failure hospitalization and all-cause mortality in type 2 diabetic patients on an SGLT2 inhibitor, such as EMPA-REG OUTCOME for empagliflozin (Jardiance) and CANVAS for canagliflozin (Invokana), didn’t include information on baseline LVEF. So until now it has been unclear whether the beneficial effects of the SGLT2 inhibitors preventing heart failure hospitalization vary depending upon LVEF, explained Dr. Kosiborod, a cardiologist at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.

He presented an analysis drawn from the patient database kept by Maccabi Healthcare Services in Israel. The study included 5,307 patients with type 2 diabetes and an LVEF measurement recorded in their chart at the time they started on either empagliflozin or dapagliflozin (Farxiga) and an equal number of propensity-matched type 2 diabetic controls who started on other glucose-lowering drugs, most commonly an oral dipeptidyl peptidase-4 inhibitor.

During roughly 16,000 person-years of follow-up, 239 deaths occurred. Compared with patients on another glucose-lowering drug, the risk of death from all causes was reduced by 47% among patients who were on an SGLT2 inhibitor and had a baseline LVEF of 50% or greater and by 62% among the 9% of subjects who had a baseline LVEF less than 50%.

Similarly, the risk of heart failure hospitalization was reduced by 29% in SGLT2 inhibitor users with a preserved LVEF and by 27% if they had a reduced LVEF.

For the composite endpoint of heart failure hospitalization or all-cause mortality, the risk reductions associated with SGLT2 inhibitor therapy were 45% with preserved and 39% with reduced LVEF.

Session comoderator Prakash C. Deedwania, MD, noted that there are ongoing major randomized trials of various SGLT2 inhibitors in patients with known heart failure, with cardiovascular death and heart failure hospitalization as primary endpoints. He asked Dr. Kosiborod whether, given that the results of these studies aren’t in yet, he thinks clinicians should be prescribing SGLT2 inhibitors to diabetic or prediabetic patients who don’t have clinical symptoms of heart failure but may have a marker of increased risk, such as an elevated B-type natriuretic peptide.

“At least in my mind, we have more than enough evidence at this point to say that SGLT2 inhibitors are effective in preventing heart failure,” Dr. Kosiborod replied.

“Obviously, if your risk for developing a condition is higher at baseline, then the absolute benefit that you’re going to get from using an agent that’s effective in preventing that event is going to be higher and the number needed to treat is going to be lower. So if you have a patient at high risk for heart failure by whatever risk predictor you’re using and the patient doesn’t yet have heart failure but does have diabetes, which is already a risk factor for heart failure, I think we have pretty solid data now that SGLT2 inhibitors will likely be effective in preventing heart failure in that kind of patient population. But I don’t think we have definitive data at this point to say that the drugs are effective in treating heart failure in people who already have a manifest clinical syndrome of heart failure, which is why we’re doing all these clinical trials now,” he continued.

Dr. Deedwania urged audience members to make the effort to become comfortable in prescribing SGLT2 inhibitors for their patients with type 2 diabetes.

“Many different surveys show that these drugs are not being utilized effectively by cardiologists,” noted Dr. Deedwania, professor of medicine at the University of California, San Francisco, and director of the heart failure program at the university’s Fresno campus.

“As cardiologists, we may not want to own diabetes, but we at least have to feel that we have the ownership of treating the diabetic patient with cardiovascular disease with appropriate drugs. We don’t need to depend on endocrinologists because if we do these patients may become lost,” he said.

Dr. Kosiborod concurred, citing evidence that diabetic patients with cardiovascular disease are much more likely to see a cardiologist than an endocrinologist in the course of usual care.

“There’s definitely a golden opportunity here to intervene to reduce risk,” he said.

Dr. Kosiborod reported serving as a consultant to roughly a dozen pharmaceutical companies.
 

[email protected]

SOURCE: Kosiborod M. ACC 19, Abstract #1024-07.

NEW ORLEANS – Patients who have type 2 diabetes and are taking a sodium-glucose cotransporter 2 (SGLT2) inhibitor have lower risks of heart failure hospitalization and all-cause mortality than patients on other glucose-lowering drugs regardless of whether their baseline left ventricular ejection fraction (LVEF) is preserved or reduced, based on data from a large real-world patient registry.

“The observed beneficial effects of SGLT2 inhibitors on heart failure may extend across the range of baseline ejection fractions,” Mikhail Kosiborod, MD, observed at the annual meeting of the American College of Cardiology.

This is an important new insight. The major randomized cardiovascular outcome trials that showed lower risks of heart failure hospitalization and all-cause mortality in type 2 diabetic patients on an SGLT2 inhibitor, such as EMPA-REG OUTCOME for empagliflozin (Jardiance) and CANVAS for canagliflozin (Invokana), didn’t include information on baseline LVEF. So until now it has been unclear whether the beneficial effects of the SGLT2 inhibitors preventing heart failure hospitalization vary depending upon LVEF, explained Dr. Kosiborod, a cardiologist at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.

He presented an analysis drawn from the patient database kept by Maccabi Healthcare Services in Israel. The study included 5,307 patients with type 2 diabetes and an LVEF measurement recorded in their chart at the time they started on either empagliflozin or dapagliflozin (Farxiga) and an equal number of propensity-matched type 2 diabetic controls who started on other glucose-lowering drugs, most commonly an oral dipeptidyl peptidase-4 inhibitor.

During roughly 16,000 person-years of follow-up, 239 deaths occurred. Compared with patients on another glucose-lowering drug, the risk of death from all causes was reduced by 47% among patients who were on an SGLT2 inhibitor and had a baseline LVEF of 50% or greater and by 62% among the 9% of subjects who had a baseline LVEF less than 50%.

Similarly, the risk of heart failure hospitalization was reduced by 29% in SGLT2 inhibitor users with a preserved LVEF and by 27% if they had a reduced LVEF.

For the composite endpoint of heart failure hospitalization or all-cause mortality, the risk reductions associated with SGLT2 inhibitor therapy were 45% with preserved and 39% with reduced LVEF.

Session comoderator Prakash C. Deedwania, MD, noted that there are ongoing major randomized trials of various SGLT2 inhibitors in patients with known heart failure, with cardiovascular death and heart failure hospitalization as primary endpoints. He asked Dr. Kosiborod whether, given that the results of these studies aren’t in yet, he thinks clinicians should be prescribing SGLT2 inhibitors to diabetic or prediabetic patients who don’t have clinical symptoms of heart failure but may have a marker of increased risk, such as an elevated B-type natriuretic peptide.

“At least in my mind, we have more than enough evidence at this point to say that SGLT2 inhibitors are effective in preventing heart failure,” Dr. Kosiborod replied.

“Obviously, if your risk for developing a condition is higher at baseline, then the absolute benefit that you’re going to get from using an agent that’s effective in preventing that event is going to be higher and the number needed to treat is going to be lower. So if you have a patient at high risk for heart failure by whatever risk predictor you’re using and the patient doesn’t yet have heart failure but does have diabetes, which is already a risk factor for heart failure, I think we have pretty solid data now that SGLT2 inhibitors will likely be effective in preventing heart failure in that kind of patient population. But I don’t think we have definitive data at this point to say that the drugs are effective in treating heart failure in people who already have a manifest clinical syndrome of heart failure, which is why we’re doing all these clinical trials now,” he continued.

Dr. Deedwania urged audience members to make the effort to become comfortable in prescribing SGLT2 inhibitors for their patients with type 2 diabetes.

“Many different surveys show that these drugs are not being utilized effectively by cardiologists,” noted Dr. Deedwania, professor of medicine at the University of California, San Francisco, and director of the heart failure program at the university’s Fresno campus.

“As cardiologists, we may not want to own diabetes, but we at least have to feel that we have the ownership of treating the diabetic patient with cardiovascular disease with appropriate drugs. We don’t need to depend on endocrinologists because if we do these patients may become lost,” he said.

Dr. Kosiborod concurred, citing evidence that diabetic patients with cardiovascular disease are much more likely to see a cardiologist than an endocrinologist in the course of usual care.

“There’s definitely a golden opportunity here to intervene to reduce risk,” he said.

Dr. Kosiborod reported serving as a consultant to roughly a dozen pharmaceutical companies.
 

[email protected]

SOURCE: Kosiborod M. ACC 19, Abstract #1024-07.