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Menstrual irregularity appears to be predictor of early death
than women with regular or short cycles, reported Yi-Xin Wang, PhD, of Harvard TH Chan School of Public Health, Boston, and associates. This is particularly true in the presence of cardiovascular disease and a history of smoking.
In a peer-reviewed observational study of 79,505 premenopausal women enrolled in the Nurses’ Health Study II, the researchers sought to determine whether a life-long history of irregular or long menstrual cycles was associated with premature death. Patients averaged a mean age of 37.7 years and had no history of cardiovascular disease, cancer, or diabetes at enrollment.
Although irregular and long menstrual cycles are common and frequently linked with an increased risk of major chronic diseases – such as ovarian cancer, coronary heart disease, type 2 diabetes, and mental health problems – in women of reproductive age, actual evidence linking irregular or long menstrual cycles with mortality is scant, the researchers noted in the BMJ.
During the study, participants checked in at ages 14-17 years, 18-22 years, and 29-46 years to report the usual length and regularity of their menstrual cycles. Over 24 years of follow-up, a total of 1,975 premature deaths were noted, including 894 from cancer and 172 from cardiovascular disease.
Irregular cycles appear to bring risks
After considering other possible factors of influence, including age, weight, lifestyle, and family medical history, Dr. Wang and associates noted higher rates of mortality among those consistently reporting irregular cycles than women in the same age ranges with very regular cycles. Specifically, women aged 18-22 years and 29-46 years with cycles of 40 days or more were at greater risk of dying prematurely than were those in the same age ranges with cycles of 26-31 days.
Cardiovascular disease was a stronger predictor of death than cancer or other causes. Also included in the higher-risk group were those who currently smoked.
Among women reporting very regular cycles and women reporting always irregular cycles, mortality rates per 1,000 person-years were 1.05 and 1.23 at ages 14-17 years, 1.00 and 1.37 at ages 18-22 years, and 1.00 and 1.68 at ages 29-46 years, respectively.
The study also found that women reporting irregular cycles or no periods had a higher body mass indexes (28.2 vs. 25.0 kg/m2); were more likely to have conditions including hypertension (13.2% vs. 6.2%), high blood cholesterol levels (23.9% vs. 14.9%), hirsutism (8.4%
vs. 1.8%), or endometriosis (5.9% vs. 4.5%); and uterine fibroids (10.0% vs. 7.8%); and a higher prevalence of family history of diabetes (19.4% vs. 15.8%).
Dr. Wang and associates also observed – using multivariable Cox models – a greater risk of premature death across all categories and all age ranges in women with decreasing menstrual cycle regularity. In models that were fully adjusted, cycle lengths that were 40 days or more or too irregular to estimate from ages 18-22 and 29-46 expressed hazard ratios for premature death at the time of follow-up of 1.34 and 1.40, compared with women in the same age ranges reporting cycle lengths of 26-31 days.
Of note, Dr. Wang and colleagues unexpectedly discovered an increased risk of premature death in women who had used contraceptives between 14-17 years. They suggested that a greater number of women self-reporting contraceptive use in adolescence may have been using contraceptives to manage symptoms of polycystic ovary syndrome (PCOS) and other conditions such as endometriosis.
Relying on the potential inaccuracy inherent in patient recall of their menstrual cycle characteristics, and the likelihood for other unmeasured factors, may have affected study results. Study strengths included the significant number of participants who had a high follow-up rate over many years, and the availability of menstrual cycle data at three different points across the reproductive lifespan.
Because the mechanisms underlying these associations are likely related to the disrupted hormonal environment, the study results “emphasize the need for primary care providers to include menstrual cycle characteristics throughout the reproductive life span as additional vital signs in assessing women’s general health status,” Dr. Wang and colleagues cautioned.
Expert suggests a probable underlying link
“Irregular menstrual cycles in women have long been known to be associated with significant morbidities, including the leading causes of mortality worldwide such as cardiovascular disease and cancer,” Reshef Tal, MD, PhD, assistant professor of obstetrics, gynecology & reproductive sciences at Yale University, New Haven, Conn., said in an interview. “The findings of this large study that irregular menstrual cycles are associated with premature death, most strongly from cardiovascular causes, are therefore not surprising.”
Dr. Tal acknowledged that one probable underlying link is PCOS, which is recognized as the most common hormonal disorder affecting women of reproductive age. The irregular periods that characterize PCOS are tied to a number of metabolic risk factors, including obesity, insulin resistance, dyslipidemia, and hypertension, which increase the long-term risk of cardiovascular disease and cancer of the uterus.
“The study did not have information on patients’ pelvic ultrasound findings and male hormone levels, which would have helped to establish PCOS diagnosis. However, women in this study who had irregular cycles tended to have more hirsutism, high cholesterol, hypertension as well as higher BMI, suggesting that PCOS is at least partly responsible for the observed association with cardiovascular disease. Interestingly, the association between irregular cycles and early mortality was independent of BMI, indicating that mechanisms other than metabolic factors may also play a role,” observed Dr. Tal, who was asked to comment on the study.
“Irregular periods are a symptom and not a disease, so it is important to identify underlying metabolic risk factors. Furthermore, physicians are advised to counsel patients experiencing menstrual irregularity, [to advise them to] maintain a healthy lifestyle and be alert to health changes,” Dr. Tal suggested.
The study was funded by the National Institutes of Health. The investigators had no relevant financial disclosures. Dr. Tal said he had no relevant financial disclosures.
SOURCE: Chavarro J et al. BMJ. 2020. doi: 10.1136/bmj.m3464.
than women with regular or short cycles, reported Yi-Xin Wang, PhD, of Harvard TH Chan School of Public Health, Boston, and associates. This is particularly true in the presence of cardiovascular disease and a history of smoking.
In a peer-reviewed observational study of 79,505 premenopausal women enrolled in the Nurses’ Health Study II, the researchers sought to determine whether a life-long history of irregular or long menstrual cycles was associated with premature death. Patients averaged a mean age of 37.7 years and had no history of cardiovascular disease, cancer, or diabetes at enrollment.
Although irregular and long menstrual cycles are common and frequently linked with an increased risk of major chronic diseases – such as ovarian cancer, coronary heart disease, type 2 diabetes, and mental health problems – in women of reproductive age, actual evidence linking irregular or long menstrual cycles with mortality is scant, the researchers noted in the BMJ.
During the study, participants checked in at ages 14-17 years, 18-22 years, and 29-46 years to report the usual length and regularity of their menstrual cycles. Over 24 years of follow-up, a total of 1,975 premature deaths were noted, including 894 from cancer and 172 from cardiovascular disease.
Irregular cycles appear to bring risks
After considering other possible factors of influence, including age, weight, lifestyle, and family medical history, Dr. Wang and associates noted higher rates of mortality among those consistently reporting irregular cycles than women in the same age ranges with very regular cycles. Specifically, women aged 18-22 years and 29-46 years with cycles of 40 days or more were at greater risk of dying prematurely than were those in the same age ranges with cycles of 26-31 days.
Cardiovascular disease was a stronger predictor of death than cancer or other causes. Also included in the higher-risk group were those who currently smoked.
Among women reporting very regular cycles and women reporting always irregular cycles, mortality rates per 1,000 person-years were 1.05 and 1.23 at ages 14-17 years, 1.00 and 1.37 at ages 18-22 years, and 1.00 and 1.68 at ages 29-46 years, respectively.
The study also found that women reporting irregular cycles or no periods had a higher body mass indexes (28.2 vs. 25.0 kg/m2); were more likely to have conditions including hypertension (13.2% vs. 6.2%), high blood cholesterol levels (23.9% vs. 14.9%), hirsutism (8.4%
vs. 1.8%), or endometriosis (5.9% vs. 4.5%); and uterine fibroids (10.0% vs. 7.8%); and a higher prevalence of family history of diabetes (19.4% vs. 15.8%).
Dr. Wang and associates also observed – using multivariable Cox models – a greater risk of premature death across all categories and all age ranges in women with decreasing menstrual cycle regularity. In models that were fully adjusted, cycle lengths that were 40 days or more or too irregular to estimate from ages 18-22 and 29-46 expressed hazard ratios for premature death at the time of follow-up of 1.34 and 1.40, compared with women in the same age ranges reporting cycle lengths of 26-31 days.
Of note, Dr. Wang and colleagues unexpectedly discovered an increased risk of premature death in women who had used contraceptives between 14-17 years. They suggested that a greater number of women self-reporting contraceptive use in adolescence may have been using contraceptives to manage symptoms of polycystic ovary syndrome (PCOS) and other conditions such as endometriosis.
Relying on the potential inaccuracy inherent in patient recall of their menstrual cycle characteristics, and the likelihood for other unmeasured factors, may have affected study results. Study strengths included the significant number of participants who had a high follow-up rate over many years, and the availability of menstrual cycle data at three different points across the reproductive lifespan.
Because the mechanisms underlying these associations are likely related to the disrupted hormonal environment, the study results “emphasize the need for primary care providers to include menstrual cycle characteristics throughout the reproductive life span as additional vital signs in assessing women’s general health status,” Dr. Wang and colleagues cautioned.
Expert suggests a probable underlying link
“Irregular menstrual cycles in women have long been known to be associated with significant morbidities, including the leading causes of mortality worldwide such as cardiovascular disease and cancer,” Reshef Tal, MD, PhD, assistant professor of obstetrics, gynecology & reproductive sciences at Yale University, New Haven, Conn., said in an interview. “The findings of this large study that irregular menstrual cycles are associated with premature death, most strongly from cardiovascular causes, are therefore not surprising.”
Dr. Tal acknowledged that one probable underlying link is PCOS, which is recognized as the most common hormonal disorder affecting women of reproductive age. The irregular periods that characterize PCOS are tied to a number of metabolic risk factors, including obesity, insulin resistance, dyslipidemia, and hypertension, which increase the long-term risk of cardiovascular disease and cancer of the uterus.
“The study did not have information on patients’ pelvic ultrasound findings and male hormone levels, which would have helped to establish PCOS diagnosis. However, women in this study who had irregular cycles tended to have more hirsutism, high cholesterol, hypertension as well as higher BMI, suggesting that PCOS is at least partly responsible for the observed association with cardiovascular disease. Interestingly, the association between irregular cycles and early mortality was independent of BMI, indicating that mechanisms other than metabolic factors may also play a role,” observed Dr. Tal, who was asked to comment on the study.
“Irregular periods are a symptom and not a disease, so it is important to identify underlying metabolic risk factors. Furthermore, physicians are advised to counsel patients experiencing menstrual irregularity, [to advise them to] maintain a healthy lifestyle and be alert to health changes,” Dr. Tal suggested.
The study was funded by the National Institutes of Health. The investigators had no relevant financial disclosures. Dr. Tal said he had no relevant financial disclosures.
SOURCE: Chavarro J et al. BMJ. 2020. doi: 10.1136/bmj.m3464.
than women with regular or short cycles, reported Yi-Xin Wang, PhD, of Harvard TH Chan School of Public Health, Boston, and associates. This is particularly true in the presence of cardiovascular disease and a history of smoking.
In a peer-reviewed observational study of 79,505 premenopausal women enrolled in the Nurses’ Health Study II, the researchers sought to determine whether a life-long history of irregular or long menstrual cycles was associated with premature death. Patients averaged a mean age of 37.7 years and had no history of cardiovascular disease, cancer, or diabetes at enrollment.
Although irregular and long menstrual cycles are common and frequently linked with an increased risk of major chronic diseases – such as ovarian cancer, coronary heart disease, type 2 diabetes, and mental health problems – in women of reproductive age, actual evidence linking irregular or long menstrual cycles with mortality is scant, the researchers noted in the BMJ.
During the study, participants checked in at ages 14-17 years, 18-22 years, and 29-46 years to report the usual length and regularity of their menstrual cycles. Over 24 years of follow-up, a total of 1,975 premature deaths were noted, including 894 from cancer and 172 from cardiovascular disease.
Irregular cycles appear to bring risks
After considering other possible factors of influence, including age, weight, lifestyle, and family medical history, Dr. Wang and associates noted higher rates of mortality among those consistently reporting irregular cycles than women in the same age ranges with very regular cycles. Specifically, women aged 18-22 years and 29-46 years with cycles of 40 days or more were at greater risk of dying prematurely than were those in the same age ranges with cycles of 26-31 days.
Cardiovascular disease was a stronger predictor of death than cancer or other causes. Also included in the higher-risk group were those who currently smoked.
Among women reporting very regular cycles and women reporting always irregular cycles, mortality rates per 1,000 person-years were 1.05 and 1.23 at ages 14-17 years, 1.00 and 1.37 at ages 18-22 years, and 1.00 and 1.68 at ages 29-46 years, respectively.
The study also found that women reporting irregular cycles or no periods had a higher body mass indexes (28.2 vs. 25.0 kg/m2); were more likely to have conditions including hypertension (13.2% vs. 6.2%), high blood cholesterol levels (23.9% vs. 14.9%), hirsutism (8.4%
vs. 1.8%), or endometriosis (5.9% vs. 4.5%); and uterine fibroids (10.0% vs. 7.8%); and a higher prevalence of family history of diabetes (19.4% vs. 15.8%).
Dr. Wang and associates also observed – using multivariable Cox models – a greater risk of premature death across all categories and all age ranges in women with decreasing menstrual cycle regularity. In models that were fully adjusted, cycle lengths that were 40 days or more or too irregular to estimate from ages 18-22 and 29-46 expressed hazard ratios for premature death at the time of follow-up of 1.34 and 1.40, compared with women in the same age ranges reporting cycle lengths of 26-31 days.
Of note, Dr. Wang and colleagues unexpectedly discovered an increased risk of premature death in women who had used contraceptives between 14-17 years. They suggested that a greater number of women self-reporting contraceptive use in adolescence may have been using contraceptives to manage symptoms of polycystic ovary syndrome (PCOS) and other conditions such as endometriosis.
Relying on the potential inaccuracy inherent in patient recall of their menstrual cycle characteristics, and the likelihood for other unmeasured factors, may have affected study results. Study strengths included the significant number of participants who had a high follow-up rate over many years, and the availability of menstrual cycle data at three different points across the reproductive lifespan.
Because the mechanisms underlying these associations are likely related to the disrupted hormonal environment, the study results “emphasize the need for primary care providers to include menstrual cycle characteristics throughout the reproductive life span as additional vital signs in assessing women’s general health status,” Dr. Wang and colleagues cautioned.
Expert suggests a probable underlying link
“Irregular menstrual cycles in women have long been known to be associated with significant morbidities, including the leading causes of mortality worldwide such as cardiovascular disease and cancer,” Reshef Tal, MD, PhD, assistant professor of obstetrics, gynecology & reproductive sciences at Yale University, New Haven, Conn., said in an interview. “The findings of this large study that irregular menstrual cycles are associated with premature death, most strongly from cardiovascular causes, are therefore not surprising.”
Dr. Tal acknowledged that one probable underlying link is PCOS, which is recognized as the most common hormonal disorder affecting women of reproductive age. The irregular periods that characterize PCOS are tied to a number of metabolic risk factors, including obesity, insulin resistance, dyslipidemia, and hypertension, which increase the long-term risk of cardiovascular disease and cancer of the uterus.
“The study did not have information on patients’ pelvic ultrasound findings and male hormone levels, which would have helped to establish PCOS diagnosis. However, women in this study who had irregular cycles tended to have more hirsutism, high cholesterol, hypertension as well as higher BMI, suggesting that PCOS is at least partly responsible for the observed association with cardiovascular disease. Interestingly, the association between irregular cycles and early mortality was independent of BMI, indicating that mechanisms other than metabolic factors may also play a role,” observed Dr. Tal, who was asked to comment on the study.
“Irregular periods are a symptom and not a disease, so it is important to identify underlying metabolic risk factors. Furthermore, physicians are advised to counsel patients experiencing menstrual irregularity, [to advise them to] maintain a healthy lifestyle and be alert to health changes,” Dr. Tal suggested.
The study was funded by the National Institutes of Health. The investigators had no relevant financial disclosures. Dr. Tal said he had no relevant financial disclosures.
SOURCE: Chavarro J et al. BMJ. 2020. doi: 10.1136/bmj.m3464.
FROM THE BMJ
No mortality benefit after intensive glucose control once Hb A1c curves equalize
Background: A previous study reported that a median of 5.6 years of intensive versus standard glucose lowering in veterans with type 2 diabetes resulted in significantly reduced risk of major cardiovascular events after 10 years of combined intervention and observational follow-up.
Study design: Prospective cohort.
Setting: Veterans Affairs Healthcare System.
Synopsis: In the original trial, 1,791 veterans were randomly assigned to receive either intensive or standard glucose control therapy. After conclusion of that study, 1,655 participants were followed using central databases, and 1,391 also provided data via surveys and chart review. Initially the difference in the glycated hemoglobin (Hb A1c) curves between the two groups averaged 1.5%, but it declined to 0.2%-0.3% 3 years after the trial ended. The median Hb A1c then stabilized to 8% in both groups.
Over a period of 15 years of combined intervention and posttrial follow-up, the risks of major cardiovascular events or death were not lower in the intensive-therapy group (hazard ratio for composite outcome, 0.91; 95% confidence interval, 0.78-1.06; P = .23; HR for death, 1.02; 95% CI, 0.88-1.18). The risk of major cardiovascular disease outcomes was reduced during the approximately 10-year interval of separation of the Hb A1c curves (HR, 0.83; 95% CI, 0.70-0.99), but it did not persist after equalization of Hb A1c levels (HR, 1.26; 95% CI, 0.90-1.75). Limitations include the observational study design, the study population of mostly older men, and reliance on administrative data for outcomes.
Bottom line: More than 5 years of intensive glucose lowering, compared with standard therapy, did not show significantly lower risks of cardiovascular events or mortality once the glycated hemoglobin curves equalized during follow-up in years 11-15.
Citation: Reaven PD et al. Intensive glucose control in patients with type 2 diabetes – 15-year follow-up. New Engl J Med. 2019 Jun 6;380(23):2215-24.
Dr. Burke is a hospitalist at Vanderbilt University Medical Center, Nashville, Tenn.
Background: A previous study reported that a median of 5.6 years of intensive versus standard glucose lowering in veterans with type 2 diabetes resulted in significantly reduced risk of major cardiovascular events after 10 years of combined intervention and observational follow-up.
Study design: Prospective cohort.
Setting: Veterans Affairs Healthcare System.
Synopsis: In the original trial, 1,791 veterans were randomly assigned to receive either intensive or standard glucose control therapy. After conclusion of that study, 1,655 participants were followed using central databases, and 1,391 also provided data via surveys and chart review. Initially the difference in the glycated hemoglobin (Hb A1c) curves between the two groups averaged 1.5%, but it declined to 0.2%-0.3% 3 years after the trial ended. The median Hb A1c then stabilized to 8% in both groups.
Over a period of 15 years of combined intervention and posttrial follow-up, the risks of major cardiovascular events or death were not lower in the intensive-therapy group (hazard ratio for composite outcome, 0.91; 95% confidence interval, 0.78-1.06; P = .23; HR for death, 1.02; 95% CI, 0.88-1.18). The risk of major cardiovascular disease outcomes was reduced during the approximately 10-year interval of separation of the Hb A1c curves (HR, 0.83; 95% CI, 0.70-0.99), but it did not persist after equalization of Hb A1c levels (HR, 1.26; 95% CI, 0.90-1.75). Limitations include the observational study design, the study population of mostly older men, and reliance on administrative data for outcomes.
Bottom line: More than 5 years of intensive glucose lowering, compared with standard therapy, did not show significantly lower risks of cardiovascular events or mortality once the glycated hemoglobin curves equalized during follow-up in years 11-15.
Citation: Reaven PD et al. Intensive glucose control in patients with type 2 diabetes – 15-year follow-up. New Engl J Med. 2019 Jun 6;380(23):2215-24.
Dr. Burke is a hospitalist at Vanderbilt University Medical Center, Nashville, Tenn.
Background: A previous study reported that a median of 5.6 years of intensive versus standard glucose lowering in veterans with type 2 diabetes resulted in significantly reduced risk of major cardiovascular events after 10 years of combined intervention and observational follow-up.
Study design: Prospective cohort.
Setting: Veterans Affairs Healthcare System.
Synopsis: In the original trial, 1,791 veterans were randomly assigned to receive either intensive or standard glucose control therapy. After conclusion of that study, 1,655 participants were followed using central databases, and 1,391 also provided data via surveys and chart review. Initially the difference in the glycated hemoglobin (Hb A1c) curves between the two groups averaged 1.5%, but it declined to 0.2%-0.3% 3 years after the trial ended. The median Hb A1c then stabilized to 8% in both groups.
Over a period of 15 years of combined intervention and posttrial follow-up, the risks of major cardiovascular events or death were not lower in the intensive-therapy group (hazard ratio for composite outcome, 0.91; 95% confidence interval, 0.78-1.06; P = .23; HR for death, 1.02; 95% CI, 0.88-1.18). The risk of major cardiovascular disease outcomes was reduced during the approximately 10-year interval of separation of the Hb A1c curves (HR, 0.83; 95% CI, 0.70-0.99), but it did not persist after equalization of Hb A1c levels (HR, 1.26; 95% CI, 0.90-1.75). Limitations include the observational study design, the study population of mostly older men, and reliance on administrative data for outcomes.
Bottom line: More than 5 years of intensive glucose lowering, compared with standard therapy, did not show significantly lower risks of cardiovascular events or mortality once the glycated hemoglobin curves equalized during follow-up in years 11-15.
Citation: Reaven PD et al. Intensive glucose control in patients with type 2 diabetes – 15-year follow-up. New Engl J Med. 2019 Jun 6;380(23):2215-24.
Dr. Burke is a hospitalist at Vanderbilt University Medical Center, Nashville, Tenn.
Genitourinary syndrome of menopause statement stresses treatment options
It’s important for clinicians to ask women whether they are experiencing symptoms of genitourinary syndrome of menopause (GSM) before and after menopause, according to a new statement from the North American Menopause Society.
Stephanie Faubion, MD, MBA, medical director of NAMS, presented the updated statement at the virtual annual meeting of the North American Menopause Society.
“The one thing we tried to emphasize is proactive counseling and proactive inquiry, educating women when they hit perimenopause that this is a thing and that there are treatments,” Dr. Faubion said in an interview.
There’s the misperception that it’s just part of getting old, which it’s not,” said Dr. Faubion, who is also director of the Mayo Clinic Center for Women’s Health in Rochester, Minn., and chair of the department of medicine at the Mayo Clinic in Jacksonville, Fla.
Changes from previous statement
The GSM statement describes the symptoms and signs resulting from estrogen deficiency on the genitourinary tract, Dr. Faubion explained. The biggest change from the earlier version, published in 2013, is the condition’s new name. Formerly known as vulvovaginal atrophy, the condition’s new term was developed in 2014 and is now preferred by NAMS and the American College of Obstetricians and Gynecologists because it’s more comprehensive. Rather than just a physical description of the condition, GSM encompasses the many related symptoms and the urinary tract changes that occur, and it clearly associates the condition with menopause.
“Women don’t always associate these changes with menopause and don’t recognize that there’s something that can be done about it,” Dr. Faubion said. “We like to emphasize that sex should never be painful, but it’s not just about sex. It’s about comfort.”
Other changes include a review of evidence related to vaginal laser therapy for GSM and the availability of Imvexxy vaginal inserts with lower doses (4 mcg and 10 mpg) of estrogen.
Etiology and diagnosis of GSM
The presence of endogenous estrogen keeps the vaginal lining thick, rugated, well vascularized, and lubricated. As estrogen levels decline during postmenopause, the epithelial lining becomes thinner, with reduced blood supply and loss of glycogen.
The most common symptoms of GSM include irritation of the vulva, inadequate vaginal lubrication, burning, dysuria, dyspareunia, and vaginal discharge, but the symptoms may not always correlate with physical findings. In women with surgical menopause, the symptoms tend to be more severe. The most distressing symptoms to women are often those that affect sexual function.
“Clinicians must be proactive in asking menopausal women if GSM symptoms are present, even before menopause begins,” Dr. Faubion said.
Taking a women’s history during evaluation may help identify contributing factors, other causes, or potentially effective treatments based on what has worked in the past. History should include a description of symptoms, their onset and duration, how distressing they are, and their effect on the woman’s quality of life. A sexual history, such as lubricants the woman has used, can also be useful in determining management strategies.
Signs of GSM include labial atrophy, vaginal dryness, introital stenosis, clitoral atrophy, phimosis of the prepuce, reduced mons pubis and labia majora bulk, reduced labia minora tissue and pigmentation, and changes in the urethra, including erythema of the urethral meatus and commonly a urethral caruncle, a benign outgrown of inflammatory tissue that likely results from low estrogen levels and can be treated effectively with topical hormonal therapies.
A diagnosis of GSM requires both physical findings and bothersome symptoms, though not necessarily specific vaginal maturation index or vaginal pH values. The differential diagnosis speaks to the importance of taking a good history: allergic or inflammatory conditions, infection, trauma, presence of a foreign body, malignancy, vulvodynia, chronic pelvic pain, or provoked pelvic floor hypertonia.
If first-line therapies of over-the-counter lubricants do not sufficiently treat GSM, other effective treatments include low-dose vaginal estrogen therapy, systemic estrogen therapy if other menopause symptoms are present, vaginal dehydroepiandrosterone (DHEA), and ospemifene.
Management of GSM
First-line therapy of GSM involves over-the-counter lubricants and moisturizers, which are often adequate to alleviate or eliminate women’s symptoms. However, the panel that developed the statement found no evidence that hyaluronic acid was any more effective than other lubricants or moisturizers, and no herbal products were found to effectively treat GSM.
While emerging evidence suggests that energy-based therapies, such as treatments with vaginal laser or radiofrequency devices, show some promise, more evidence is needed to show safety and efficacy before the panel can recommend routine use.
When over-the-counter therapies are not effective, vaginal estrogen usually relieves GSM with little absorption and is preferred over systemic therapy if GSM is the only bothersome menopausal symptom. Options include topical creams, a slow-release estradiol intravaginal ring, and estradiol vaginal tablets and inserts.
“However, when systemic hormone therapy is needed to treat other menopause symptoms, usually a woman will derive benefit and resolution of the GSM at the same time,” Dr. Faubion said. “However, for some women, additional low-dose vaginal estrogen may be added to systemic estrogen if needed, and that could include vaginal DHEA.”
All the approved vaginal products have shown efficacy, compared with placebo in clinical trials, and a Cochrane review comparing the different therapies found them to be similarly efficacious in treating vaginal dryness and dyspareunia with no significant differences in adverse events.
Preparing patients for the boxed warning
As vaginal estrogen doses are significantly lower than systemic estrogen, their safety profile is better, with serum estrogen levels remaining within the postmenopausal range when low-dose vaginal estrogen therapy is used. That said, some studies have shown that vaginal estrogen cream can be a large enough dose to involve systemic absorption and lead to symptoms such as vaginal bleeding, breast pain, and nausea.
However, package inserts for vaginal estrogen have the same boxed warning as seen in systemic hormone therapy inserts regarding risk of endometrial cancer, breast cancer, cardiovascular disorders, and “probable dementia” despite these conditions not being linked to vaginal estrogen in trials. Neither has venous thromboembolism been linked to vaginal estrogen.
“The panel felt it was very important that women be educated about the differences between low-dose vaginal estrogen and systemic estrogen therapy and be prepared for this boxed warning,” Dr. Faubion told attendees. “It’s really important to say: ‘You’re going to get this, it’s going to look scary, and there’s no evidence these same warnings apply to the low-dose vaginal estrogen products.’ ”
This point particularly resonated with NAMS attendee Juliana (Jewel) Kling, MD, MPH, an associate professor of medicine at the Mayo Clinic Arizona, Scottsdale.
“The point about educating women about the differences between low-dose vaginal estrogen products and systemic treatments and being prepared for the boxed warning is important and I hope reaches many practitioners,” Dr. Kling said in an interview.
The panel did not recommend using progestogen with low-dose vaginal estrogen therapy or doing routine endometrial surveillance in women using vaginal estrogen. But endometrial surveillance may be worth considering in women with increased risk of endometrial cancer.
Estrogen insufficiency from premature menopause or primary ovarian insufficiency is linked to more severe sexual dysfunction, which can be particularly upsetting for younger women with vaginal atrophy and dyspareunia. A meta-analysis showed that vaginal estrogen appeared to slightly outperform over-the-counter lubricants in bringing back sexual function.
Undiagnosed vaginal or uterine bleeding is a contraindication for vaginal estrogen until the cause has been determined, and providers should use caution in prescribing vaginal estrogen to women with estrogen-dependent neoplasia. Dr. Faubion noted that GSM is common in women with breast cancer, especially if they are receiving endocrine treatments or aromatase inhibitors.
“For women with a hormone-dependent cancer, GSM management depends on each woman’s preference in consultants with her oncologist,” she said. GSM management in women with a nonhormone-dependent cancer, however, is no different than in women without cancer.
DHEA is a steroid that effectively improves vaginal maturation index, vaginal pH, dyspareunia, and vaginal dryness. The most common side effect is vaginal discharge.
Ospemifene, an estrogen agonist available in the United States but not in Canada, is the only oral product approved to treat vaginal dryness and dyspareunia. An observational study also found it effective in reducing recurrent UTIs. The most common side effect is vasomotor symptoms, and it should not be used in patients with breast cancer because it hasn’t been studied in this population.
“This updated information and position statement was needed and will be very clinically relevant in treating midlife women,” Dr. Kling said in an interview. “Dr. Faubion presented a high-level overview of the position statement with clinically relevant points, including treatment for sexual dysfunction related to GSM, GSM treatment in cancer patients, and emphasized the efficacy and low-risk safety profile of low-dose vaginal estrogen, compared to systemic [hormone therapy], for treatment of GSM.”
Dr. Faubion and Dr. Kling disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
It’s important for clinicians to ask women whether they are experiencing symptoms of genitourinary syndrome of menopause (GSM) before and after menopause, according to a new statement from the North American Menopause Society.
Stephanie Faubion, MD, MBA, medical director of NAMS, presented the updated statement at the virtual annual meeting of the North American Menopause Society.
“The one thing we tried to emphasize is proactive counseling and proactive inquiry, educating women when they hit perimenopause that this is a thing and that there are treatments,” Dr. Faubion said in an interview.
There’s the misperception that it’s just part of getting old, which it’s not,” said Dr. Faubion, who is also director of the Mayo Clinic Center for Women’s Health in Rochester, Minn., and chair of the department of medicine at the Mayo Clinic in Jacksonville, Fla.
Changes from previous statement
The GSM statement describes the symptoms and signs resulting from estrogen deficiency on the genitourinary tract, Dr. Faubion explained. The biggest change from the earlier version, published in 2013, is the condition’s new name. Formerly known as vulvovaginal atrophy, the condition’s new term was developed in 2014 and is now preferred by NAMS and the American College of Obstetricians and Gynecologists because it’s more comprehensive. Rather than just a physical description of the condition, GSM encompasses the many related symptoms and the urinary tract changes that occur, and it clearly associates the condition with menopause.
“Women don’t always associate these changes with menopause and don’t recognize that there’s something that can be done about it,” Dr. Faubion said. “We like to emphasize that sex should never be painful, but it’s not just about sex. It’s about comfort.”
Other changes include a review of evidence related to vaginal laser therapy for GSM and the availability of Imvexxy vaginal inserts with lower doses (4 mcg and 10 mpg) of estrogen.
Etiology and diagnosis of GSM
The presence of endogenous estrogen keeps the vaginal lining thick, rugated, well vascularized, and lubricated. As estrogen levels decline during postmenopause, the epithelial lining becomes thinner, with reduced blood supply and loss of glycogen.
The most common symptoms of GSM include irritation of the vulva, inadequate vaginal lubrication, burning, dysuria, dyspareunia, and vaginal discharge, but the symptoms may not always correlate with physical findings. In women with surgical menopause, the symptoms tend to be more severe. The most distressing symptoms to women are often those that affect sexual function.
“Clinicians must be proactive in asking menopausal women if GSM symptoms are present, even before menopause begins,” Dr. Faubion said.
Taking a women’s history during evaluation may help identify contributing factors, other causes, or potentially effective treatments based on what has worked in the past. History should include a description of symptoms, their onset and duration, how distressing they are, and their effect on the woman’s quality of life. A sexual history, such as lubricants the woman has used, can also be useful in determining management strategies.
Signs of GSM include labial atrophy, vaginal dryness, introital stenosis, clitoral atrophy, phimosis of the prepuce, reduced mons pubis and labia majora bulk, reduced labia minora tissue and pigmentation, and changes in the urethra, including erythema of the urethral meatus and commonly a urethral caruncle, a benign outgrown of inflammatory tissue that likely results from low estrogen levels and can be treated effectively with topical hormonal therapies.
A diagnosis of GSM requires both physical findings and bothersome symptoms, though not necessarily specific vaginal maturation index or vaginal pH values. The differential diagnosis speaks to the importance of taking a good history: allergic or inflammatory conditions, infection, trauma, presence of a foreign body, malignancy, vulvodynia, chronic pelvic pain, or provoked pelvic floor hypertonia.
If first-line therapies of over-the-counter lubricants do not sufficiently treat GSM, other effective treatments include low-dose vaginal estrogen therapy, systemic estrogen therapy if other menopause symptoms are present, vaginal dehydroepiandrosterone (DHEA), and ospemifene.
Management of GSM
First-line therapy of GSM involves over-the-counter lubricants and moisturizers, which are often adequate to alleviate or eliminate women’s symptoms. However, the panel that developed the statement found no evidence that hyaluronic acid was any more effective than other lubricants or moisturizers, and no herbal products were found to effectively treat GSM.
While emerging evidence suggests that energy-based therapies, such as treatments with vaginal laser or radiofrequency devices, show some promise, more evidence is needed to show safety and efficacy before the panel can recommend routine use.
When over-the-counter therapies are not effective, vaginal estrogen usually relieves GSM with little absorption and is preferred over systemic therapy if GSM is the only bothersome menopausal symptom. Options include topical creams, a slow-release estradiol intravaginal ring, and estradiol vaginal tablets and inserts.
“However, when systemic hormone therapy is needed to treat other menopause symptoms, usually a woman will derive benefit and resolution of the GSM at the same time,” Dr. Faubion said. “However, for some women, additional low-dose vaginal estrogen may be added to systemic estrogen if needed, and that could include vaginal DHEA.”
All the approved vaginal products have shown efficacy, compared with placebo in clinical trials, and a Cochrane review comparing the different therapies found them to be similarly efficacious in treating vaginal dryness and dyspareunia with no significant differences in adverse events.
Preparing patients for the boxed warning
As vaginal estrogen doses are significantly lower than systemic estrogen, their safety profile is better, with serum estrogen levels remaining within the postmenopausal range when low-dose vaginal estrogen therapy is used. That said, some studies have shown that vaginal estrogen cream can be a large enough dose to involve systemic absorption and lead to symptoms such as vaginal bleeding, breast pain, and nausea.
However, package inserts for vaginal estrogen have the same boxed warning as seen in systemic hormone therapy inserts regarding risk of endometrial cancer, breast cancer, cardiovascular disorders, and “probable dementia” despite these conditions not being linked to vaginal estrogen in trials. Neither has venous thromboembolism been linked to vaginal estrogen.
“The panel felt it was very important that women be educated about the differences between low-dose vaginal estrogen and systemic estrogen therapy and be prepared for this boxed warning,” Dr. Faubion told attendees. “It’s really important to say: ‘You’re going to get this, it’s going to look scary, and there’s no evidence these same warnings apply to the low-dose vaginal estrogen products.’ ”
This point particularly resonated with NAMS attendee Juliana (Jewel) Kling, MD, MPH, an associate professor of medicine at the Mayo Clinic Arizona, Scottsdale.
“The point about educating women about the differences between low-dose vaginal estrogen products and systemic treatments and being prepared for the boxed warning is important and I hope reaches many practitioners,” Dr. Kling said in an interview.
The panel did not recommend using progestogen with low-dose vaginal estrogen therapy or doing routine endometrial surveillance in women using vaginal estrogen. But endometrial surveillance may be worth considering in women with increased risk of endometrial cancer.
Estrogen insufficiency from premature menopause or primary ovarian insufficiency is linked to more severe sexual dysfunction, which can be particularly upsetting for younger women with vaginal atrophy and dyspareunia. A meta-analysis showed that vaginal estrogen appeared to slightly outperform over-the-counter lubricants in bringing back sexual function.
Undiagnosed vaginal or uterine bleeding is a contraindication for vaginal estrogen until the cause has been determined, and providers should use caution in prescribing vaginal estrogen to women with estrogen-dependent neoplasia. Dr. Faubion noted that GSM is common in women with breast cancer, especially if they are receiving endocrine treatments or aromatase inhibitors.
“For women with a hormone-dependent cancer, GSM management depends on each woman’s preference in consultants with her oncologist,” she said. GSM management in women with a nonhormone-dependent cancer, however, is no different than in women without cancer.
DHEA is a steroid that effectively improves vaginal maturation index, vaginal pH, dyspareunia, and vaginal dryness. The most common side effect is vaginal discharge.
Ospemifene, an estrogen agonist available in the United States but not in Canada, is the only oral product approved to treat vaginal dryness and dyspareunia. An observational study also found it effective in reducing recurrent UTIs. The most common side effect is vasomotor symptoms, and it should not be used in patients with breast cancer because it hasn’t been studied in this population.
“This updated information and position statement was needed and will be very clinically relevant in treating midlife women,” Dr. Kling said in an interview. “Dr. Faubion presented a high-level overview of the position statement with clinically relevant points, including treatment for sexual dysfunction related to GSM, GSM treatment in cancer patients, and emphasized the efficacy and low-risk safety profile of low-dose vaginal estrogen, compared to systemic [hormone therapy], for treatment of GSM.”
Dr. Faubion and Dr. Kling disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
It’s important for clinicians to ask women whether they are experiencing symptoms of genitourinary syndrome of menopause (GSM) before and after menopause, according to a new statement from the North American Menopause Society.
Stephanie Faubion, MD, MBA, medical director of NAMS, presented the updated statement at the virtual annual meeting of the North American Menopause Society.
“The one thing we tried to emphasize is proactive counseling and proactive inquiry, educating women when they hit perimenopause that this is a thing and that there are treatments,” Dr. Faubion said in an interview.
There’s the misperception that it’s just part of getting old, which it’s not,” said Dr. Faubion, who is also director of the Mayo Clinic Center for Women’s Health in Rochester, Minn., and chair of the department of medicine at the Mayo Clinic in Jacksonville, Fla.
Changes from previous statement
The GSM statement describes the symptoms and signs resulting from estrogen deficiency on the genitourinary tract, Dr. Faubion explained. The biggest change from the earlier version, published in 2013, is the condition’s new name. Formerly known as vulvovaginal atrophy, the condition’s new term was developed in 2014 and is now preferred by NAMS and the American College of Obstetricians and Gynecologists because it’s more comprehensive. Rather than just a physical description of the condition, GSM encompasses the many related symptoms and the urinary tract changes that occur, and it clearly associates the condition with menopause.
“Women don’t always associate these changes with menopause and don’t recognize that there’s something that can be done about it,” Dr. Faubion said. “We like to emphasize that sex should never be painful, but it’s not just about sex. It’s about comfort.”
Other changes include a review of evidence related to vaginal laser therapy for GSM and the availability of Imvexxy vaginal inserts with lower doses (4 mcg and 10 mpg) of estrogen.
Etiology and diagnosis of GSM
The presence of endogenous estrogen keeps the vaginal lining thick, rugated, well vascularized, and lubricated. As estrogen levels decline during postmenopause, the epithelial lining becomes thinner, with reduced blood supply and loss of glycogen.
The most common symptoms of GSM include irritation of the vulva, inadequate vaginal lubrication, burning, dysuria, dyspareunia, and vaginal discharge, but the symptoms may not always correlate with physical findings. In women with surgical menopause, the symptoms tend to be more severe. The most distressing symptoms to women are often those that affect sexual function.
“Clinicians must be proactive in asking menopausal women if GSM symptoms are present, even before menopause begins,” Dr. Faubion said.
Taking a women’s history during evaluation may help identify contributing factors, other causes, or potentially effective treatments based on what has worked in the past. History should include a description of symptoms, their onset and duration, how distressing they are, and their effect on the woman’s quality of life. A sexual history, such as lubricants the woman has used, can also be useful in determining management strategies.
Signs of GSM include labial atrophy, vaginal dryness, introital stenosis, clitoral atrophy, phimosis of the prepuce, reduced mons pubis and labia majora bulk, reduced labia minora tissue and pigmentation, and changes in the urethra, including erythema of the urethral meatus and commonly a urethral caruncle, a benign outgrown of inflammatory tissue that likely results from low estrogen levels and can be treated effectively with topical hormonal therapies.
A diagnosis of GSM requires both physical findings and bothersome symptoms, though not necessarily specific vaginal maturation index or vaginal pH values. The differential diagnosis speaks to the importance of taking a good history: allergic or inflammatory conditions, infection, trauma, presence of a foreign body, malignancy, vulvodynia, chronic pelvic pain, or provoked pelvic floor hypertonia.
If first-line therapies of over-the-counter lubricants do not sufficiently treat GSM, other effective treatments include low-dose vaginal estrogen therapy, systemic estrogen therapy if other menopause symptoms are present, vaginal dehydroepiandrosterone (DHEA), and ospemifene.
Management of GSM
First-line therapy of GSM involves over-the-counter lubricants and moisturizers, which are often adequate to alleviate or eliminate women’s symptoms. However, the panel that developed the statement found no evidence that hyaluronic acid was any more effective than other lubricants or moisturizers, and no herbal products were found to effectively treat GSM.
While emerging evidence suggests that energy-based therapies, such as treatments with vaginal laser or radiofrequency devices, show some promise, more evidence is needed to show safety and efficacy before the panel can recommend routine use.
When over-the-counter therapies are not effective, vaginal estrogen usually relieves GSM with little absorption and is preferred over systemic therapy if GSM is the only bothersome menopausal symptom. Options include topical creams, a slow-release estradiol intravaginal ring, and estradiol vaginal tablets and inserts.
“However, when systemic hormone therapy is needed to treat other menopause symptoms, usually a woman will derive benefit and resolution of the GSM at the same time,” Dr. Faubion said. “However, for some women, additional low-dose vaginal estrogen may be added to systemic estrogen if needed, and that could include vaginal DHEA.”
All the approved vaginal products have shown efficacy, compared with placebo in clinical trials, and a Cochrane review comparing the different therapies found them to be similarly efficacious in treating vaginal dryness and dyspareunia with no significant differences in adverse events.
Preparing patients for the boxed warning
As vaginal estrogen doses are significantly lower than systemic estrogen, their safety profile is better, with serum estrogen levels remaining within the postmenopausal range when low-dose vaginal estrogen therapy is used. That said, some studies have shown that vaginal estrogen cream can be a large enough dose to involve systemic absorption and lead to symptoms such as vaginal bleeding, breast pain, and nausea.
However, package inserts for vaginal estrogen have the same boxed warning as seen in systemic hormone therapy inserts regarding risk of endometrial cancer, breast cancer, cardiovascular disorders, and “probable dementia” despite these conditions not being linked to vaginal estrogen in trials. Neither has venous thromboembolism been linked to vaginal estrogen.
“The panel felt it was very important that women be educated about the differences between low-dose vaginal estrogen and systemic estrogen therapy and be prepared for this boxed warning,” Dr. Faubion told attendees. “It’s really important to say: ‘You’re going to get this, it’s going to look scary, and there’s no evidence these same warnings apply to the low-dose vaginal estrogen products.’ ”
This point particularly resonated with NAMS attendee Juliana (Jewel) Kling, MD, MPH, an associate professor of medicine at the Mayo Clinic Arizona, Scottsdale.
“The point about educating women about the differences between low-dose vaginal estrogen products and systemic treatments and being prepared for the boxed warning is important and I hope reaches many practitioners,” Dr. Kling said in an interview.
The panel did not recommend using progestogen with low-dose vaginal estrogen therapy or doing routine endometrial surveillance in women using vaginal estrogen. But endometrial surveillance may be worth considering in women with increased risk of endometrial cancer.
Estrogen insufficiency from premature menopause or primary ovarian insufficiency is linked to more severe sexual dysfunction, which can be particularly upsetting for younger women with vaginal atrophy and dyspareunia. A meta-analysis showed that vaginal estrogen appeared to slightly outperform over-the-counter lubricants in bringing back sexual function.
Undiagnosed vaginal or uterine bleeding is a contraindication for vaginal estrogen until the cause has been determined, and providers should use caution in prescribing vaginal estrogen to women with estrogen-dependent neoplasia. Dr. Faubion noted that GSM is common in women with breast cancer, especially if they are receiving endocrine treatments or aromatase inhibitors.
“For women with a hormone-dependent cancer, GSM management depends on each woman’s preference in consultants with her oncologist,” she said. GSM management in women with a nonhormone-dependent cancer, however, is no different than in women without cancer.
DHEA is a steroid that effectively improves vaginal maturation index, vaginal pH, dyspareunia, and vaginal dryness. The most common side effect is vaginal discharge.
Ospemifene, an estrogen agonist available in the United States but not in Canada, is the only oral product approved to treat vaginal dryness and dyspareunia. An observational study also found it effective in reducing recurrent UTIs. The most common side effect is vasomotor symptoms, and it should not be used in patients with breast cancer because it hasn’t been studied in this population.
“This updated information and position statement was needed and will be very clinically relevant in treating midlife women,” Dr. Kling said in an interview. “Dr. Faubion presented a high-level overview of the position statement with clinically relevant points, including treatment for sexual dysfunction related to GSM, GSM treatment in cancer patients, and emphasized the efficacy and low-risk safety profile of low-dose vaginal estrogen, compared to systemic [hormone therapy], for treatment of GSM.”
Dr. Faubion and Dr. Kling disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Fetal estrogens show promise for safer therapy for menopause
Hormone therapy for menopausal symptoms has come a long way in the past decade, but some low risks remain, particularly for certain groups of women. But new naturally occurring estrogens are on the horizon and may provide safer options with similar efficacy for treating hot flashes and other symptoms, researchers report.
“Unfortunately, there is no such thing as the perfect estrogen that has all the things that makes it favorable and none of the negative,” Hugh S. Taylor, MD, told attendees at the virtual annual meeting of the North American Menopause Society. “It probably doesn’t exist. But there’s an opportunity for us to design better estrogens or take advantage of other naturally occurring estrogens that come closer to that goal of the ideal estrogen,” said Dr. Taylor, professor and chair of ob.gyn. and reproductive sciences at Yale University, New Haven, Conn.
Those naturally occurring estrogens are the fetal estrogens, estetrol and estriol, which are produced almost exclusively during pregnancy. Only estetrol has been investigated in clinical trials, and it does show some promise, Dr. Taylor said.
“If there’s a better cardiovascular effect without the breast cancer risk, this could be something everyone would want to take,” Dr. Taylor said in an interview. We’ve never really been able to get a synthetic estrogen [that works].”
Hormone therapy still most effective for vasomotor symptoms
The primary benefits of hormone therapy for postmenopausal women are decreased hot flashes and night sweats and the prevention of bone loss, vaginal dryness, and vaginal atrophy. But as women age, particularly past age 70 years, the risks for stroke, heart disease, and breast cancer associated with hormone therapy begin to outweigh the benefits.
That leaves women who are still experiencing those symptoms in a quandary.
“Some people will take on substantial risks because they want to continue taking hormones,” Nanette F. Santoro, MD, a professor of ob.gyn. at the University of Colorado at Denver, Aurora, said in an interview. “If they understand what they’re doing and they tell me that they are that miserable, then I will continue their hormones.”
Dr. Santoro, who was not involved in Taylor’s work, said some patients have seen her because their primary care providers refused to continue prescribing them hormones at their age, despite serious vasomotor symptoms that interfered with their daily life.
“Women are sometimes not taken seriously, and I think that’s a problem,” Dr. Santoro said. “Women need to be able to make an informed choice about what kinds of risk they’re taking on. Many physicians’ rationales are that hot flashes never killed anybody. Well, they can sure make you miserable.”
Dr. Taylor echoed the importance of taking women’s symptoms seriously and helping them choose the most effective treatments to manage their symptoms.
“The rush of adrenaline, the anxiety, the palpitations, the heart racing, the sweating, all the night sweats [that mean] you can’t sleep at night, and the lack of adequate REM sleep – all these things add up and can really be disruptive to someone’s life,” Dr. Taylor said in an interview. “I think it’s important that we raise awareness of how severe it can be, about just how low the risks [of hormone therapy] are, and get people more comfortable using hormone therapy, but also continue to search for safer, better products that will eliminate even those low risks.”
A major development toward that goal in the past decade has been therapies that combine an estrogen with a selective estrogen receptor modulator (SERM), which have antiestrogen effects in the endometrium and breast without blocking estrogen in the bones and brain.
One such tissue-selective estrogen complex (TSEC) is the combination of bazedoxifene (20 mg) and conjugated estrogens (0.45 mg). Clinical trials showed that this TSEC reduced the frequency of hot flashes by 74%, compared with 47% with placebo. In addition, TSEC reduced the severity of hot flashes by 39%, compared with 13% with placebo. The combination also improved bone density at the spine and hip without promoting endometrial hyperplasia.
“It looks like it does exactly what we want,” Dr. Taylor told NAMS attendees. “The SERM is antagonizing the effects of the estrogens in the endometrium but not in the bone or brain.” It also led to a decrease in total cholesterol, and there was no increase in breast stimulation or density.
Another advance in recent years has been more choices and more precision with dosing, Dr. Santoro said.
“Where inroads have been made is in having women be aware of all the options they have and in getting the most convenient compounds to people,” she said, despite the confusion and misinformation that have arisen from the proliferation of bioidenticals. “You can dial in a dose for just about anybody.”
New estrogens in the pipeline
Neither of these developments, however, have eliminated the risks associated with hormone therapy for women of older age or for women at high risk for breast cancer. Although total elimination of risk may not be possible, recent research suggests that the naturally occurring fetal estrogens estriol and estetrol appear to have SERM-like properties, Dr. Taylor said. These estrogens are made only in pregnancy and appear to have evolved for a purpose different from that of estrone and estradiol.
“While both are weak estrogens by traditional standards, both have unique properties that make them very interesting for therapeutic use,” Dr. Taylor said. In particular, estetrol has a much longer half-life than estriol, making it more appropriate for therapeutic investigation.
A study of estetrol that was published in Menopause in August 2020 showed encouraging results. Despite a fairly sizable placebo effect, there was also a dose-response effect from estetrol on vasomotor symptoms. Low doses did not have much effect, but with higher doses (15 mg), there was a robust, significant improvement in the frequency and severity of hot flashes. So far, Dr. Taylor said, it looks like estetrol can be a highly effective treatment for vasomotor symptoms.
In addition, preclinical research suggests that estetrol may have a better safety profile than currently available therapies, though much more work is needed to know for sure. For example, a 2015 study found that it requires extremely high doses – well above therapeutic levels – for tumor growth to occur. Similarly, a 2019 study found that very high doses of estetrol or estriol were needed before it would stimulate breast cancer cell growth, likely because these are such weak estrogens, compared with estradiol, Dr. Taylor said.
There is currently less information on estetrol’s potential cardiovascular effects, but an animal model suggests positive effects, he said. Giving a mouse estetrol led to an increase in blood vessel dilation with increased blood flow.
The reason these estrogens appear to pose less risk yet still show therapeutic effects appears related to how they bind to the estrogen receptor and what their purpose is, Dr. Taylor told attendees.
“These fetal estrogens are really there probably for developmental programming,” he said. “It’s no wonder they may have some unique and favorable properties for therapeutic use. I’m really enthusiastic to see this explored further as a potential new hormonal therapy.”
Dr. Taylor disclosed no relevant financial relationships. Dr. Santoro reported stock ownership in Menogenix and consulting or advising for Ansh Labs, Menogenix, and Ogeda/Astellas.
A version of this article originally appeared on Medscape.com.
Hormone therapy for menopausal symptoms has come a long way in the past decade, but some low risks remain, particularly for certain groups of women. But new naturally occurring estrogens are on the horizon and may provide safer options with similar efficacy for treating hot flashes and other symptoms, researchers report.
“Unfortunately, there is no such thing as the perfect estrogen that has all the things that makes it favorable and none of the negative,” Hugh S. Taylor, MD, told attendees at the virtual annual meeting of the North American Menopause Society. “It probably doesn’t exist. But there’s an opportunity for us to design better estrogens or take advantage of other naturally occurring estrogens that come closer to that goal of the ideal estrogen,” said Dr. Taylor, professor and chair of ob.gyn. and reproductive sciences at Yale University, New Haven, Conn.
Those naturally occurring estrogens are the fetal estrogens, estetrol and estriol, which are produced almost exclusively during pregnancy. Only estetrol has been investigated in clinical trials, and it does show some promise, Dr. Taylor said.
“If there’s a better cardiovascular effect without the breast cancer risk, this could be something everyone would want to take,” Dr. Taylor said in an interview. We’ve never really been able to get a synthetic estrogen [that works].”
Hormone therapy still most effective for vasomotor symptoms
The primary benefits of hormone therapy for postmenopausal women are decreased hot flashes and night sweats and the prevention of bone loss, vaginal dryness, and vaginal atrophy. But as women age, particularly past age 70 years, the risks for stroke, heart disease, and breast cancer associated with hormone therapy begin to outweigh the benefits.
That leaves women who are still experiencing those symptoms in a quandary.
“Some people will take on substantial risks because they want to continue taking hormones,” Nanette F. Santoro, MD, a professor of ob.gyn. at the University of Colorado at Denver, Aurora, said in an interview. “If they understand what they’re doing and they tell me that they are that miserable, then I will continue their hormones.”
Dr. Santoro, who was not involved in Taylor’s work, said some patients have seen her because their primary care providers refused to continue prescribing them hormones at their age, despite serious vasomotor symptoms that interfered with their daily life.
“Women are sometimes not taken seriously, and I think that’s a problem,” Dr. Santoro said. “Women need to be able to make an informed choice about what kinds of risk they’re taking on. Many physicians’ rationales are that hot flashes never killed anybody. Well, they can sure make you miserable.”
Dr. Taylor echoed the importance of taking women’s symptoms seriously and helping them choose the most effective treatments to manage their symptoms.
“The rush of adrenaline, the anxiety, the palpitations, the heart racing, the sweating, all the night sweats [that mean] you can’t sleep at night, and the lack of adequate REM sleep – all these things add up and can really be disruptive to someone’s life,” Dr. Taylor said in an interview. “I think it’s important that we raise awareness of how severe it can be, about just how low the risks [of hormone therapy] are, and get people more comfortable using hormone therapy, but also continue to search for safer, better products that will eliminate even those low risks.”
A major development toward that goal in the past decade has been therapies that combine an estrogen with a selective estrogen receptor modulator (SERM), which have antiestrogen effects in the endometrium and breast without blocking estrogen in the bones and brain.
One such tissue-selective estrogen complex (TSEC) is the combination of bazedoxifene (20 mg) and conjugated estrogens (0.45 mg). Clinical trials showed that this TSEC reduced the frequency of hot flashes by 74%, compared with 47% with placebo. In addition, TSEC reduced the severity of hot flashes by 39%, compared with 13% with placebo. The combination also improved bone density at the spine and hip without promoting endometrial hyperplasia.
“It looks like it does exactly what we want,” Dr. Taylor told NAMS attendees. “The SERM is antagonizing the effects of the estrogens in the endometrium but not in the bone or brain.” It also led to a decrease in total cholesterol, and there was no increase in breast stimulation or density.
Another advance in recent years has been more choices and more precision with dosing, Dr. Santoro said.
“Where inroads have been made is in having women be aware of all the options they have and in getting the most convenient compounds to people,” she said, despite the confusion and misinformation that have arisen from the proliferation of bioidenticals. “You can dial in a dose for just about anybody.”
New estrogens in the pipeline
Neither of these developments, however, have eliminated the risks associated with hormone therapy for women of older age or for women at high risk for breast cancer. Although total elimination of risk may not be possible, recent research suggests that the naturally occurring fetal estrogens estriol and estetrol appear to have SERM-like properties, Dr. Taylor said. These estrogens are made only in pregnancy and appear to have evolved for a purpose different from that of estrone and estradiol.
“While both are weak estrogens by traditional standards, both have unique properties that make them very interesting for therapeutic use,” Dr. Taylor said. In particular, estetrol has a much longer half-life than estriol, making it more appropriate for therapeutic investigation.
A study of estetrol that was published in Menopause in August 2020 showed encouraging results. Despite a fairly sizable placebo effect, there was also a dose-response effect from estetrol on vasomotor symptoms. Low doses did not have much effect, but with higher doses (15 mg), there was a robust, significant improvement in the frequency and severity of hot flashes. So far, Dr. Taylor said, it looks like estetrol can be a highly effective treatment for vasomotor symptoms.
In addition, preclinical research suggests that estetrol may have a better safety profile than currently available therapies, though much more work is needed to know for sure. For example, a 2015 study found that it requires extremely high doses – well above therapeutic levels – for tumor growth to occur. Similarly, a 2019 study found that very high doses of estetrol or estriol were needed before it would stimulate breast cancer cell growth, likely because these are such weak estrogens, compared with estradiol, Dr. Taylor said.
There is currently less information on estetrol’s potential cardiovascular effects, but an animal model suggests positive effects, he said. Giving a mouse estetrol led to an increase in blood vessel dilation with increased blood flow.
The reason these estrogens appear to pose less risk yet still show therapeutic effects appears related to how they bind to the estrogen receptor and what their purpose is, Dr. Taylor told attendees.
“These fetal estrogens are really there probably for developmental programming,” he said. “It’s no wonder they may have some unique and favorable properties for therapeutic use. I’m really enthusiastic to see this explored further as a potential new hormonal therapy.”
Dr. Taylor disclosed no relevant financial relationships. Dr. Santoro reported stock ownership in Menogenix and consulting or advising for Ansh Labs, Menogenix, and Ogeda/Astellas.
A version of this article originally appeared on Medscape.com.
Hormone therapy for menopausal symptoms has come a long way in the past decade, but some low risks remain, particularly for certain groups of women. But new naturally occurring estrogens are on the horizon and may provide safer options with similar efficacy for treating hot flashes and other symptoms, researchers report.
“Unfortunately, there is no such thing as the perfect estrogen that has all the things that makes it favorable and none of the negative,” Hugh S. Taylor, MD, told attendees at the virtual annual meeting of the North American Menopause Society. “It probably doesn’t exist. But there’s an opportunity for us to design better estrogens or take advantage of other naturally occurring estrogens that come closer to that goal of the ideal estrogen,” said Dr. Taylor, professor and chair of ob.gyn. and reproductive sciences at Yale University, New Haven, Conn.
Those naturally occurring estrogens are the fetal estrogens, estetrol and estriol, which are produced almost exclusively during pregnancy. Only estetrol has been investigated in clinical trials, and it does show some promise, Dr. Taylor said.
“If there’s a better cardiovascular effect without the breast cancer risk, this could be something everyone would want to take,” Dr. Taylor said in an interview. We’ve never really been able to get a synthetic estrogen [that works].”
Hormone therapy still most effective for vasomotor symptoms
The primary benefits of hormone therapy for postmenopausal women are decreased hot flashes and night sweats and the prevention of bone loss, vaginal dryness, and vaginal atrophy. But as women age, particularly past age 70 years, the risks for stroke, heart disease, and breast cancer associated with hormone therapy begin to outweigh the benefits.
That leaves women who are still experiencing those symptoms in a quandary.
“Some people will take on substantial risks because they want to continue taking hormones,” Nanette F. Santoro, MD, a professor of ob.gyn. at the University of Colorado at Denver, Aurora, said in an interview. “If they understand what they’re doing and they tell me that they are that miserable, then I will continue their hormones.”
Dr. Santoro, who was not involved in Taylor’s work, said some patients have seen her because their primary care providers refused to continue prescribing them hormones at their age, despite serious vasomotor symptoms that interfered with their daily life.
“Women are sometimes not taken seriously, and I think that’s a problem,” Dr. Santoro said. “Women need to be able to make an informed choice about what kinds of risk they’re taking on. Many physicians’ rationales are that hot flashes never killed anybody. Well, they can sure make you miserable.”
Dr. Taylor echoed the importance of taking women’s symptoms seriously and helping them choose the most effective treatments to manage their symptoms.
“The rush of adrenaline, the anxiety, the palpitations, the heart racing, the sweating, all the night sweats [that mean] you can’t sleep at night, and the lack of adequate REM sleep – all these things add up and can really be disruptive to someone’s life,” Dr. Taylor said in an interview. “I think it’s important that we raise awareness of how severe it can be, about just how low the risks [of hormone therapy] are, and get people more comfortable using hormone therapy, but also continue to search for safer, better products that will eliminate even those low risks.”
A major development toward that goal in the past decade has been therapies that combine an estrogen with a selective estrogen receptor modulator (SERM), which have antiestrogen effects in the endometrium and breast without blocking estrogen in the bones and brain.
One such tissue-selective estrogen complex (TSEC) is the combination of bazedoxifene (20 mg) and conjugated estrogens (0.45 mg). Clinical trials showed that this TSEC reduced the frequency of hot flashes by 74%, compared with 47% with placebo. In addition, TSEC reduced the severity of hot flashes by 39%, compared with 13% with placebo. The combination also improved bone density at the spine and hip without promoting endometrial hyperplasia.
“It looks like it does exactly what we want,” Dr. Taylor told NAMS attendees. “The SERM is antagonizing the effects of the estrogens in the endometrium but not in the bone or brain.” It also led to a decrease in total cholesterol, and there was no increase in breast stimulation or density.
Another advance in recent years has been more choices and more precision with dosing, Dr. Santoro said.
“Where inroads have been made is in having women be aware of all the options they have and in getting the most convenient compounds to people,” she said, despite the confusion and misinformation that have arisen from the proliferation of bioidenticals. “You can dial in a dose for just about anybody.”
New estrogens in the pipeline
Neither of these developments, however, have eliminated the risks associated with hormone therapy for women of older age or for women at high risk for breast cancer. Although total elimination of risk may not be possible, recent research suggests that the naturally occurring fetal estrogens estriol and estetrol appear to have SERM-like properties, Dr. Taylor said. These estrogens are made only in pregnancy and appear to have evolved for a purpose different from that of estrone and estradiol.
“While both are weak estrogens by traditional standards, both have unique properties that make them very interesting for therapeutic use,” Dr. Taylor said. In particular, estetrol has a much longer half-life than estriol, making it more appropriate for therapeutic investigation.
A study of estetrol that was published in Menopause in August 2020 showed encouraging results. Despite a fairly sizable placebo effect, there was also a dose-response effect from estetrol on vasomotor symptoms. Low doses did not have much effect, but with higher doses (15 mg), there was a robust, significant improvement in the frequency and severity of hot flashes. So far, Dr. Taylor said, it looks like estetrol can be a highly effective treatment for vasomotor symptoms.
In addition, preclinical research suggests that estetrol may have a better safety profile than currently available therapies, though much more work is needed to know for sure. For example, a 2015 study found that it requires extremely high doses – well above therapeutic levels – for tumor growth to occur. Similarly, a 2019 study found that very high doses of estetrol or estriol were needed before it would stimulate breast cancer cell growth, likely because these are such weak estrogens, compared with estradiol, Dr. Taylor said.
There is currently less information on estetrol’s potential cardiovascular effects, but an animal model suggests positive effects, he said. Giving a mouse estetrol led to an increase in blood vessel dilation with increased blood flow.
The reason these estrogens appear to pose less risk yet still show therapeutic effects appears related to how they bind to the estrogen receptor and what their purpose is, Dr. Taylor told attendees.
“These fetal estrogens are really there probably for developmental programming,” he said. “It’s no wonder they may have some unique and favorable properties for therapeutic use. I’m really enthusiastic to see this explored further as a potential new hormonal therapy.”
Dr. Taylor disclosed no relevant financial relationships. Dr. Santoro reported stock ownership in Menogenix and consulting or advising for Ansh Labs, Menogenix, and Ogeda/Astellas.
A version of this article originally appeared on Medscape.com.
‘Modest’ benefit for post-MI T2D glucose monitoring
Following a heart attack, there appears to be a “modest” benefit of using flash glucose monitoring over fingerstick testing to monitor blood glucose levels in patients with type 2 diabetes being treated with insulin or a sulfonylurea, according to investigators of the LIBERATES trial.
The results showed a nonsignificant increase in the time that subjects’ blood glucose was spent in the target range of 3.9-10.00 mmol/L (70-180 mg/dL) 3 months after experiencing an acute coronary syndrome (ACS).
At best, flash monitoring using Abbott’s Freestyle Libre system was associated with an increase in time spent in range (TIR) of 17-28 or 48 minutes per day over self-monitoring of blood glucose (SMBG), depending on the type of statistical analysis used. There was no difference in glycated hemoglobin A1c levels between the two groups, but there was a trend for less time spent in hypoglycemia in the flash monitoring arm.
Viewers underwhelmed
“My overall impression is that the effects were less pronounced than anticipated,” Kare Birkeland, MD, PhD, a specialist in internal medicine and endocrinology at Oslo University Hospital, Rikshospitalet, Norway, observed after the findings were presented at the virtual annual meeting of the European Association for the Study of Diabetes.
Others who had watched the live session seemed similarly underwhelmed by the findings, with one viewer questioning the value of devoting an hour-and-a-half session to the phase 2 trial.
However, the session chair Simon Heller, BA, MB, BChir, DM, professor of clinical diabetes at the University of Sheffield, and trial coinvestigator, defended the detailed look at the trial’s findings, noting that it was worthwhile to present the data from the trial as it “really helps explain why we do phase 2 and phase 3 trials.”
Strong rationale for monitoring post-MI
There is a strong rationale for ensuring that blood glucose is well controlled in type 2 diabetes patients who have experienced a myocardial infarction, observed Robert Storey, BSc, BM, DM, professor of cardiology at the University of Sheffield. One way to do that potentially is through improved glucose monitoring.
“There’s clearly a close link between diabetes and the risk of MI: Both high and low HbA1c are associated with adverse outcome, and high and low glucose levels following MI are also associated with adverse outcome,” he observed, noting also that hypoglycemia was not given enough attention in post-ACS patients.
“The hypothesis of the LIBERATES study was that a modern glycemic monitoring strategy can optimize blood glucose levels in type 2 diabetes patients following MI with the potential to reduce mortality and morbidity and improve quality of life,” Dr. Storey said. “The main research question of LIBERATES says, ‘Do new approaches in glucose monitoring increase the time in range and reduce hypoglycemia?’ ”
Pragmatic trial design
LIBERATES was a prospective, multicenter, parallel group, randomized controlled trial, explained the study’s statistician Deborah Stocken, PhD, professor of clinical trials research at the University of Leeds. There was “limited ability to blind the interventions,” so it was an open-label design.
“The patient population in LIBERATES was kept as inclusive and as pragmatic as possible to ensure that the results at the end of the trial are generalizable,” said Dr. Stocken. Patients with type 2 diabetes were recruited within 5 days of hospital admission for ACS, which could include both ST- and non-ST elevation MI. In all, 141 of a calculated 150 patients that would be needed were recruited and randomized to the flash monitoring (69) or SMBG (72) arm.
Dr. Stocken noted that early in the recruitment phase, the trials oversight committee recommended that Bayesian methodology should be used as the most robust analytical approach.
“Essentially, a Bayesian approach would avoid a hypothesis test, and instead would provide a probability of there being a treatment benefit for continuous monitoring. And if this probability was high enough, this would warrant further research in the phase 3 setting,” Dr. Stocken said.
What else was shown?
“We had a number of prespecified secondary endpoints, which to me are equally important,” said Ramzi Ajjan, MD, MMed.Sci, PhD, associate professor and consultant in diabetes and endocrinology at Leeds University and Leeds Teaching Hospitals Trust.
Among these was the TIR at days 16-30, which showed a 90-minute increase per day in favor of flash monitoring over SMBG. This “seems to be driven by those who are an insulin,” Dr. Ajjan said, adding that “you get almost a 3-hour increase in time in range in people who are on insulin at baseline, and you don’t see that in people who are on sulfonylurea.”
Conversely, sulfonylurea treatment seemed to drive the reduction in the time spent in hypoglycemia defined as 3.9 mmol/L (70 g/dL) at 3 months. For the whole group, there was a 1.3-hour reduction in hypoglycemia per day with flash monitoring versus SMBG, which increased to 2 hours for those on sulfonylureas.
There also was a “pattern of reduction” in time spent in hypoglycemia defined as less than 3.0 mmol/L (54 g/dL) both early on and becoming more pronounced with time.
“Flash glucose monitoring is associated with higher treatment satisfaction score, compared with SMBG,” Dr. Ajjan said.
Although A1c dropped in both groups to a similar extent, he noted that the reduction seen in the flash monitoring group was associated with a decrease in hypoglycemia.
There was a huge amount of data collected during the trial and there are many more analyses that could be done, Dr. Ajjan said. The outcome of those may determine whether a phase 3 trial is likely, assuming sponsorship can be secured.
The LIBERATES Trial was funded by grants from the UK National Institute for Health Research and Abbott Diabetes Care. None of the investigators were additionally compensated for their work within the trial. Dr. Stocken had no disclosures in relation to this trial. Dr. Ajjan has received research funding and other financial support from Abbott, Bayer, Eli Lilly, Johnson & Johnson, and Novo Nordisk.
SOURCE: Ajjan R et al. EASD 2020. S11 – The LIBERATES Trial.
Following a heart attack, there appears to be a “modest” benefit of using flash glucose monitoring over fingerstick testing to monitor blood glucose levels in patients with type 2 diabetes being treated with insulin or a sulfonylurea, according to investigators of the LIBERATES trial.
The results showed a nonsignificant increase in the time that subjects’ blood glucose was spent in the target range of 3.9-10.00 mmol/L (70-180 mg/dL) 3 months after experiencing an acute coronary syndrome (ACS).
At best, flash monitoring using Abbott’s Freestyle Libre system was associated with an increase in time spent in range (TIR) of 17-28 or 48 minutes per day over self-monitoring of blood glucose (SMBG), depending on the type of statistical analysis used. There was no difference in glycated hemoglobin A1c levels between the two groups, but there was a trend for less time spent in hypoglycemia in the flash monitoring arm.
Viewers underwhelmed
“My overall impression is that the effects were less pronounced than anticipated,” Kare Birkeland, MD, PhD, a specialist in internal medicine and endocrinology at Oslo University Hospital, Rikshospitalet, Norway, observed after the findings were presented at the virtual annual meeting of the European Association for the Study of Diabetes.
Others who had watched the live session seemed similarly underwhelmed by the findings, with one viewer questioning the value of devoting an hour-and-a-half session to the phase 2 trial.
However, the session chair Simon Heller, BA, MB, BChir, DM, professor of clinical diabetes at the University of Sheffield, and trial coinvestigator, defended the detailed look at the trial’s findings, noting that it was worthwhile to present the data from the trial as it “really helps explain why we do phase 2 and phase 3 trials.”
Strong rationale for monitoring post-MI
There is a strong rationale for ensuring that blood glucose is well controlled in type 2 diabetes patients who have experienced a myocardial infarction, observed Robert Storey, BSc, BM, DM, professor of cardiology at the University of Sheffield. One way to do that potentially is through improved glucose monitoring.
“There’s clearly a close link between diabetes and the risk of MI: Both high and low HbA1c are associated with adverse outcome, and high and low glucose levels following MI are also associated with adverse outcome,” he observed, noting also that hypoglycemia was not given enough attention in post-ACS patients.
“The hypothesis of the LIBERATES study was that a modern glycemic monitoring strategy can optimize blood glucose levels in type 2 diabetes patients following MI with the potential to reduce mortality and morbidity and improve quality of life,” Dr. Storey said. “The main research question of LIBERATES says, ‘Do new approaches in glucose monitoring increase the time in range and reduce hypoglycemia?’ ”
Pragmatic trial design
LIBERATES was a prospective, multicenter, parallel group, randomized controlled trial, explained the study’s statistician Deborah Stocken, PhD, professor of clinical trials research at the University of Leeds. There was “limited ability to blind the interventions,” so it was an open-label design.
“The patient population in LIBERATES was kept as inclusive and as pragmatic as possible to ensure that the results at the end of the trial are generalizable,” said Dr. Stocken. Patients with type 2 diabetes were recruited within 5 days of hospital admission for ACS, which could include both ST- and non-ST elevation MI. In all, 141 of a calculated 150 patients that would be needed were recruited and randomized to the flash monitoring (69) or SMBG (72) arm.
Dr. Stocken noted that early in the recruitment phase, the trials oversight committee recommended that Bayesian methodology should be used as the most robust analytical approach.
“Essentially, a Bayesian approach would avoid a hypothesis test, and instead would provide a probability of there being a treatment benefit for continuous monitoring. And if this probability was high enough, this would warrant further research in the phase 3 setting,” Dr. Stocken said.
What else was shown?
“We had a number of prespecified secondary endpoints, which to me are equally important,” said Ramzi Ajjan, MD, MMed.Sci, PhD, associate professor and consultant in diabetes and endocrinology at Leeds University and Leeds Teaching Hospitals Trust.
Among these was the TIR at days 16-30, which showed a 90-minute increase per day in favor of flash monitoring over SMBG. This “seems to be driven by those who are an insulin,” Dr. Ajjan said, adding that “you get almost a 3-hour increase in time in range in people who are on insulin at baseline, and you don’t see that in people who are on sulfonylurea.”
Conversely, sulfonylurea treatment seemed to drive the reduction in the time spent in hypoglycemia defined as 3.9 mmol/L (70 g/dL) at 3 months. For the whole group, there was a 1.3-hour reduction in hypoglycemia per day with flash monitoring versus SMBG, which increased to 2 hours for those on sulfonylureas.
There also was a “pattern of reduction” in time spent in hypoglycemia defined as less than 3.0 mmol/L (54 g/dL) both early on and becoming more pronounced with time.
“Flash glucose monitoring is associated with higher treatment satisfaction score, compared with SMBG,” Dr. Ajjan said.
Although A1c dropped in both groups to a similar extent, he noted that the reduction seen in the flash monitoring group was associated with a decrease in hypoglycemia.
There was a huge amount of data collected during the trial and there are many more analyses that could be done, Dr. Ajjan said. The outcome of those may determine whether a phase 3 trial is likely, assuming sponsorship can be secured.
The LIBERATES Trial was funded by grants from the UK National Institute for Health Research and Abbott Diabetes Care. None of the investigators were additionally compensated for their work within the trial. Dr. Stocken had no disclosures in relation to this trial. Dr. Ajjan has received research funding and other financial support from Abbott, Bayer, Eli Lilly, Johnson & Johnson, and Novo Nordisk.
SOURCE: Ajjan R et al. EASD 2020. S11 – The LIBERATES Trial.
Following a heart attack, there appears to be a “modest” benefit of using flash glucose monitoring over fingerstick testing to monitor blood glucose levels in patients with type 2 diabetes being treated with insulin or a sulfonylurea, according to investigators of the LIBERATES trial.
The results showed a nonsignificant increase in the time that subjects’ blood glucose was spent in the target range of 3.9-10.00 mmol/L (70-180 mg/dL) 3 months after experiencing an acute coronary syndrome (ACS).
At best, flash monitoring using Abbott’s Freestyle Libre system was associated with an increase in time spent in range (TIR) of 17-28 or 48 minutes per day over self-monitoring of blood glucose (SMBG), depending on the type of statistical analysis used. There was no difference in glycated hemoglobin A1c levels between the two groups, but there was a trend for less time spent in hypoglycemia in the flash monitoring arm.
Viewers underwhelmed
“My overall impression is that the effects were less pronounced than anticipated,” Kare Birkeland, MD, PhD, a specialist in internal medicine and endocrinology at Oslo University Hospital, Rikshospitalet, Norway, observed after the findings were presented at the virtual annual meeting of the European Association for the Study of Diabetes.
Others who had watched the live session seemed similarly underwhelmed by the findings, with one viewer questioning the value of devoting an hour-and-a-half session to the phase 2 trial.
However, the session chair Simon Heller, BA, MB, BChir, DM, professor of clinical diabetes at the University of Sheffield, and trial coinvestigator, defended the detailed look at the trial’s findings, noting that it was worthwhile to present the data from the trial as it “really helps explain why we do phase 2 and phase 3 trials.”
Strong rationale for monitoring post-MI
There is a strong rationale for ensuring that blood glucose is well controlled in type 2 diabetes patients who have experienced a myocardial infarction, observed Robert Storey, BSc, BM, DM, professor of cardiology at the University of Sheffield. One way to do that potentially is through improved glucose monitoring.
“There’s clearly a close link between diabetes and the risk of MI: Both high and low HbA1c are associated with adverse outcome, and high and low glucose levels following MI are also associated with adverse outcome,” he observed, noting also that hypoglycemia was not given enough attention in post-ACS patients.
“The hypothesis of the LIBERATES study was that a modern glycemic monitoring strategy can optimize blood glucose levels in type 2 diabetes patients following MI with the potential to reduce mortality and morbidity and improve quality of life,” Dr. Storey said. “The main research question of LIBERATES says, ‘Do new approaches in glucose monitoring increase the time in range and reduce hypoglycemia?’ ”
Pragmatic trial design
LIBERATES was a prospective, multicenter, parallel group, randomized controlled trial, explained the study’s statistician Deborah Stocken, PhD, professor of clinical trials research at the University of Leeds. There was “limited ability to blind the interventions,” so it was an open-label design.
“The patient population in LIBERATES was kept as inclusive and as pragmatic as possible to ensure that the results at the end of the trial are generalizable,” said Dr. Stocken. Patients with type 2 diabetes were recruited within 5 days of hospital admission for ACS, which could include both ST- and non-ST elevation MI. In all, 141 of a calculated 150 patients that would be needed were recruited and randomized to the flash monitoring (69) or SMBG (72) arm.
Dr. Stocken noted that early in the recruitment phase, the trials oversight committee recommended that Bayesian methodology should be used as the most robust analytical approach.
“Essentially, a Bayesian approach would avoid a hypothesis test, and instead would provide a probability of there being a treatment benefit for continuous monitoring. And if this probability was high enough, this would warrant further research in the phase 3 setting,” Dr. Stocken said.
What else was shown?
“We had a number of prespecified secondary endpoints, which to me are equally important,” said Ramzi Ajjan, MD, MMed.Sci, PhD, associate professor and consultant in diabetes and endocrinology at Leeds University and Leeds Teaching Hospitals Trust.
Among these was the TIR at days 16-30, which showed a 90-minute increase per day in favor of flash monitoring over SMBG. This “seems to be driven by those who are an insulin,” Dr. Ajjan said, adding that “you get almost a 3-hour increase in time in range in people who are on insulin at baseline, and you don’t see that in people who are on sulfonylurea.”
Conversely, sulfonylurea treatment seemed to drive the reduction in the time spent in hypoglycemia defined as 3.9 mmol/L (70 g/dL) at 3 months. For the whole group, there was a 1.3-hour reduction in hypoglycemia per day with flash monitoring versus SMBG, which increased to 2 hours for those on sulfonylureas.
There also was a “pattern of reduction” in time spent in hypoglycemia defined as less than 3.0 mmol/L (54 g/dL) both early on and becoming more pronounced with time.
“Flash glucose monitoring is associated with higher treatment satisfaction score, compared with SMBG,” Dr. Ajjan said.
Although A1c dropped in both groups to a similar extent, he noted that the reduction seen in the flash monitoring group was associated with a decrease in hypoglycemia.
There was a huge amount of data collected during the trial and there are many more analyses that could be done, Dr. Ajjan said. The outcome of those may determine whether a phase 3 trial is likely, assuming sponsorship can be secured.
The LIBERATES Trial was funded by grants from the UK National Institute for Health Research and Abbott Diabetes Care. None of the investigators were additionally compensated for their work within the trial. Dr. Stocken had no disclosures in relation to this trial. Dr. Ajjan has received research funding and other financial support from Abbott, Bayer, Eli Lilly, Johnson & Johnson, and Novo Nordisk.
SOURCE: Ajjan R et al. EASD 2020. S11 – The LIBERATES Trial.
FROM EASD 2020
COVID-19 antibody response not reduced with diabetes
Neither diabetes per se nor hyperglycemia appear to impair the antibody response to SARS-CoV-2, suggesting that a COVID-19 vaccine would be just as effective in people with diabetes as in those without, new research finds.
Results from a study involving 480 patients with confirmed COVID-19 seen at an Italian hospital between February 25 and April 19 were published online October 8 in Diabetologia by Vito Lampasona, MD, and colleagues.
Antibody responses against multiple SARS-CoV-2 antigens among the 27% of patients with COVID-19 and diabetes (preexisting and newly diagnosed) were similar with regard to timing, titers, and classes to those of patients with COVID-19 and without diabetes, and the results did not differ by glucose levels.
Moreover, positivity for immunoglobulin G (IgG) against the SARS-CoV-2 spike receptor-binding domain (RBD) was associated with improved survival regardless of diabetes status.
And as previously shown, high blood glucose levels were strongly associated with greater COVID-19 mortality even in those without diabetes.
This is the first study of the immunologic humoral response against SARS-CoV-2 in patients with hyperglycemia, the authors say.
“The immunological response to a future SARS-CoV-2 vaccine will be assessed when the vaccine becomes available. However, our data allow a cautious optimism regarding effective immunization in individuals with diabetes, as well as in the general population,” wrote Dr. Lampasona of San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele in Milan, and colleagues.
Diabetes and hyperglycemia worsen COVID-19 outcomes
The investigators analyzed the presence of three types of antibody to multiple SARS-CoV-2 antigens in 509 participants: IgG, which is evidence of past infection; IgM, which indicates more recent or current infection; and IgA, which is involved in the mucosal immune response, for example, in the nose where the virus enters the body.
Overall, 452 (88.8%) patients were hospitalized, 79 (15.5%) patients were admitted to intensive care, and 93 (18.3%) patients died during follow-up.
Of the 139 patients with diabetes, 90 (17.7% of the study cohort) already had a diagnosis of diabetes, and 49 (9.6%) were newly diagnosed.
Those with diabetes were older, had a higher body mass index (BMI), and were more likely to have cardiovascular comorbidities, hypertension, and chronic kidney disease. As has been previously reported for diabetes and COVID-19, diabetes was also associated with increased levels of inflammatory biomarkers, hypercoagulopathy, leukocytosis, and neutrophilia.
In multivariate analysis, diabetes status (hazard ratio, 2.32; P = .001), mean fasting plasma glucose (P < .001), and glucose variability (P = .002) were all independently associated with increased mortality and ICU admission. And fasting plasma glucose was associated with increased mortality risk even among those without diabetes (P < .001).
Antibody response similar in patients with and without diabetes
The humoral response against SARS-CoV-2 in patients with diabetes was present and superimposable in terms of timing and antibody titers to that of patients without diabetes, with marginal differences, and was not influenced by glucose levels.
After adjustment for sex, age, and diabetes status and stratification by symptom duration at time of sampling, the development of SARS-CoV-2 RBD IgG antibodies was associated with improved survival, with an HR for time to death of 0.4 (P = .002).
“Of the measured antibody responses, positivity for IgG against the SARS-CoV-2 spike RBD was predictive of survival rate, both in the presence or absence of diabetes,” the authors stressed, with similar HRs for those with diabetes (0.37; P = .013) and without diabetes (0.43; P = .038).
These data confirm “the relevance for patient survival rate of the specific antigen response against spike RBD even in the presence of diabetes, and it underlines how the mechanism explaining the worse clinical outcome in patients with diabetes is unrelated to the antibody response,” they explain.
They added, “This, together with evidence that increased blood glucose levels do predict a poor prognosis even in nondiabetic individuals and the association with increased levels of inflammatory biomarkers and hypercoagulopathy, as well as leukocytosis and neutrophilia, support the speculation that glucose per se could be an independent biological negative factor, acting as a direct regulator of innate immunity.”
“The observed increased severity and mortality risk of COVID-19 pneumonia in patients with hyperglycemia was not the result of an impaired humoral response against SARS-CoV-2.”
“RBD IgG positivity was associated with a remarkable protective effect, allowing for a cautious optimism about the efficacy of future vaccines against SARS-COV-2 in people with diabetes,” they reiterated.
The authors have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Neither diabetes per se nor hyperglycemia appear to impair the antibody response to SARS-CoV-2, suggesting that a COVID-19 vaccine would be just as effective in people with diabetes as in those without, new research finds.
Results from a study involving 480 patients with confirmed COVID-19 seen at an Italian hospital between February 25 and April 19 were published online October 8 in Diabetologia by Vito Lampasona, MD, and colleagues.
Antibody responses against multiple SARS-CoV-2 antigens among the 27% of patients with COVID-19 and diabetes (preexisting and newly diagnosed) were similar with regard to timing, titers, and classes to those of patients with COVID-19 and without diabetes, and the results did not differ by glucose levels.
Moreover, positivity for immunoglobulin G (IgG) against the SARS-CoV-2 spike receptor-binding domain (RBD) was associated with improved survival regardless of diabetes status.
And as previously shown, high blood glucose levels were strongly associated with greater COVID-19 mortality even in those without diabetes.
This is the first study of the immunologic humoral response against SARS-CoV-2 in patients with hyperglycemia, the authors say.
“The immunological response to a future SARS-CoV-2 vaccine will be assessed when the vaccine becomes available. However, our data allow a cautious optimism regarding effective immunization in individuals with diabetes, as well as in the general population,” wrote Dr. Lampasona of San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele in Milan, and colleagues.
Diabetes and hyperglycemia worsen COVID-19 outcomes
The investigators analyzed the presence of three types of antibody to multiple SARS-CoV-2 antigens in 509 participants: IgG, which is evidence of past infection; IgM, which indicates more recent or current infection; and IgA, which is involved in the mucosal immune response, for example, in the nose where the virus enters the body.
Overall, 452 (88.8%) patients were hospitalized, 79 (15.5%) patients were admitted to intensive care, and 93 (18.3%) patients died during follow-up.
Of the 139 patients with diabetes, 90 (17.7% of the study cohort) already had a diagnosis of diabetes, and 49 (9.6%) were newly diagnosed.
Those with diabetes were older, had a higher body mass index (BMI), and were more likely to have cardiovascular comorbidities, hypertension, and chronic kidney disease. As has been previously reported for diabetes and COVID-19, diabetes was also associated with increased levels of inflammatory biomarkers, hypercoagulopathy, leukocytosis, and neutrophilia.
In multivariate analysis, diabetes status (hazard ratio, 2.32; P = .001), mean fasting plasma glucose (P < .001), and glucose variability (P = .002) were all independently associated with increased mortality and ICU admission. And fasting plasma glucose was associated with increased mortality risk even among those without diabetes (P < .001).
Antibody response similar in patients with and without diabetes
The humoral response against SARS-CoV-2 in patients with diabetes was present and superimposable in terms of timing and antibody titers to that of patients without diabetes, with marginal differences, and was not influenced by glucose levels.
After adjustment for sex, age, and diabetes status and stratification by symptom duration at time of sampling, the development of SARS-CoV-2 RBD IgG antibodies was associated with improved survival, with an HR for time to death of 0.4 (P = .002).
“Of the measured antibody responses, positivity for IgG against the SARS-CoV-2 spike RBD was predictive of survival rate, both in the presence or absence of diabetes,” the authors stressed, with similar HRs for those with diabetes (0.37; P = .013) and without diabetes (0.43; P = .038).
These data confirm “the relevance for patient survival rate of the specific antigen response against spike RBD even in the presence of diabetes, and it underlines how the mechanism explaining the worse clinical outcome in patients with diabetes is unrelated to the antibody response,” they explain.
They added, “This, together with evidence that increased blood glucose levels do predict a poor prognosis even in nondiabetic individuals and the association with increased levels of inflammatory biomarkers and hypercoagulopathy, as well as leukocytosis and neutrophilia, support the speculation that glucose per se could be an independent biological negative factor, acting as a direct regulator of innate immunity.”
“The observed increased severity and mortality risk of COVID-19 pneumonia in patients with hyperglycemia was not the result of an impaired humoral response against SARS-CoV-2.”
“RBD IgG positivity was associated with a remarkable protective effect, allowing for a cautious optimism about the efficacy of future vaccines against SARS-COV-2 in people with diabetes,” they reiterated.
The authors have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Neither diabetes per se nor hyperglycemia appear to impair the antibody response to SARS-CoV-2, suggesting that a COVID-19 vaccine would be just as effective in people with diabetes as in those without, new research finds.
Results from a study involving 480 patients with confirmed COVID-19 seen at an Italian hospital between February 25 and April 19 were published online October 8 in Diabetologia by Vito Lampasona, MD, and colleagues.
Antibody responses against multiple SARS-CoV-2 antigens among the 27% of patients with COVID-19 and diabetes (preexisting and newly diagnosed) were similar with regard to timing, titers, and classes to those of patients with COVID-19 and without diabetes, and the results did not differ by glucose levels.
Moreover, positivity for immunoglobulin G (IgG) against the SARS-CoV-2 spike receptor-binding domain (RBD) was associated with improved survival regardless of diabetes status.
And as previously shown, high blood glucose levels were strongly associated with greater COVID-19 mortality even in those without diabetes.
This is the first study of the immunologic humoral response against SARS-CoV-2 in patients with hyperglycemia, the authors say.
“The immunological response to a future SARS-CoV-2 vaccine will be assessed when the vaccine becomes available. However, our data allow a cautious optimism regarding effective immunization in individuals with diabetes, as well as in the general population,” wrote Dr. Lampasona of San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele in Milan, and colleagues.
Diabetes and hyperglycemia worsen COVID-19 outcomes
The investigators analyzed the presence of three types of antibody to multiple SARS-CoV-2 antigens in 509 participants: IgG, which is evidence of past infection; IgM, which indicates more recent or current infection; and IgA, which is involved in the mucosal immune response, for example, in the nose where the virus enters the body.
Overall, 452 (88.8%) patients were hospitalized, 79 (15.5%) patients were admitted to intensive care, and 93 (18.3%) patients died during follow-up.
Of the 139 patients with diabetes, 90 (17.7% of the study cohort) already had a diagnosis of diabetes, and 49 (9.6%) were newly diagnosed.
Those with diabetes were older, had a higher body mass index (BMI), and were more likely to have cardiovascular comorbidities, hypertension, and chronic kidney disease. As has been previously reported for diabetes and COVID-19, diabetes was also associated with increased levels of inflammatory biomarkers, hypercoagulopathy, leukocytosis, and neutrophilia.
In multivariate analysis, diabetes status (hazard ratio, 2.32; P = .001), mean fasting plasma glucose (P < .001), and glucose variability (P = .002) were all independently associated with increased mortality and ICU admission. And fasting plasma glucose was associated with increased mortality risk even among those without diabetes (P < .001).
Antibody response similar in patients with and without diabetes
The humoral response against SARS-CoV-2 in patients with diabetes was present and superimposable in terms of timing and antibody titers to that of patients without diabetes, with marginal differences, and was not influenced by glucose levels.
After adjustment for sex, age, and diabetes status and stratification by symptom duration at time of sampling, the development of SARS-CoV-2 RBD IgG antibodies was associated with improved survival, with an HR for time to death of 0.4 (P = .002).
“Of the measured antibody responses, positivity for IgG against the SARS-CoV-2 spike RBD was predictive of survival rate, both in the presence or absence of diabetes,” the authors stressed, with similar HRs for those with diabetes (0.37; P = .013) and without diabetes (0.43; P = .038).
These data confirm “the relevance for patient survival rate of the specific antigen response against spike RBD even in the presence of diabetes, and it underlines how the mechanism explaining the worse clinical outcome in patients with diabetes is unrelated to the antibody response,” they explain.
They added, “This, together with evidence that increased blood glucose levels do predict a poor prognosis even in nondiabetic individuals and the association with increased levels of inflammatory biomarkers and hypercoagulopathy, as well as leukocytosis and neutrophilia, support the speculation that glucose per se could be an independent biological negative factor, acting as a direct regulator of innate immunity.”
“The observed increased severity and mortality risk of COVID-19 pneumonia in patients with hyperglycemia was not the result of an impaired humoral response against SARS-CoV-2.”
“RBD IgG positivity was associated with a remarkable protective effect, allowing for a cautious optimism about the efficacy of future vaccines against SARS-COV-2 in people with diabetes,” they reiterated.
The authors have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Recall widens for diabetes drug metformin
The recall of extended-release metformin continues this month as 76 more lots have been flagged for a possible cancer-causing ingredient.
The Food and Drug Administration announced the latest recall, involving Marksans Pharma Limited and Sun Pharmaceutical Industries products, on Oct. 5. It involves the 500-mg and 700-mg tablets. More than 175 different drug combinations have been recalled since late May.
Consumers can see all the recalled metformin products at this FDA website. The agency says that immediate-release metformin does not appear to have the same contamination problem.
The FDA has been investigating the presence of nitrosamines, known to be possible carcinogens, in the popular diabetes medications since December, when they were first discovered in drugs in other countries. The agency said this month they still do not know the source of nitrosamines in the medications.
The investigation and subsequent recalls follow similar ones for contamination of popular heartburn and blood pressure drugs also for nitrosamines, such as N-Nitrosodimethylamine (NDMA).
The FDA says patients taking metformin products that have been recalled should continue taking the medication until a doctor or pharmacist gives them a replacement or a different treatment option. It could be dangerous for patients with type 2 diabetes to stop taking the medication without first talking to their doctor.
The agency has asked drug manufacturers to test products before batches are released into the market. The companies must tell the FDA if any product shows levels of nitrosamines above the acceptable limit.
The risk from nitrosamines is not clear. The FDA says they may increase the risk of cancer in people who are exposed to high levels over a long period of time, “but we do not anticipate that shorter-term exposure at levels above the acceptable intake limit would lead to an increase in the risk of cancer.”
This article first appeared on WebMD.com.
The recall of extended-release metformin continues this month as 76 more lots have been flagged for a possible cancer-causing ingredient.
The Food and Drug Administration announced the latest recall, involving Marksans Pharma Limited and Sun Pharmaceutical Industries products, on Oct. 5. It involves the 500-mg and 700-mg tablets. More than 175 different drug combinations have been recalled since late May.
Consumers can see all the recalled metformin products at this FDA website. The agency says that immediate-release metformin does not appear to have the same contamination problem.
The FDA has been investigating the presence of nitrosamines, known to be possible carcinogens, in the popular diabetes medications since December, when they were first discovered in drugs in other countries. The agency said this month they still do not know the source of nitrosamines in the medications.
The investigation and subsequent recalls follow similar ones for contamination of popular heartburn and blood pressure drugs also for nitrosamines, such as N-Nitrosodimethylamine (NDMA).
The FDA says patients taking metformin products that have been recalled should continue taking the medication until a doctor or pharmacist gives them a replacement or a different treatment option. It could be dangerous for patients with type 2 diabetes to stop taking the medication without first talking to their doctor.
The agency has asked drug manufacturers to test products before batches are released into the market. The companies must tell the FDA if any product shows levels of nitrosamines above the acceptable limit.
The risk from nitrosamines is not clear. The FDA says they may increase the risk of cancer in people who are exposed to high levels over a long period of time, “but we do not anticipate that shorter-term exposure at levels above the acceptable intake limit would lead to an increase in the risk of cancer.”
This article first appeared on WebMD.com.
The recall of extended-release metformin continues this month as 76 more lots have been flagged for a possible cancer-causing ingredient.
The Food and Drug Administration announced the latest recall, involving Marksans Pharma Limited and Sun Pharmaceutical Industries products, on Oct. 5. It involves the 500-mg and 700-mg tablets. More than 175 different drug combinations have been recalled since late May.
Consumers can see all the recalled metformin products at this FDA website. The agency says that immediate-release metformin does not appear to have the same contamination problem.
The FDA has been investigating the presence of nitrosamines, known to be possible carcinogens, in the popular diabetes medications since December, when they were first discovered in drugs in other countries. The agency said this month they still do not know the source of nitrosamines in the medications.
The investigation and subsequent recalls follow similar ones for contamination of popular heartburn and blood pressure drugs also for nitrosamines, such as N-Nitrosodimethylamine (NDMA).
The FDA says patients taking metformin products that have been recalled should continue taking the medication until a doctor or pharmacist gives them a replacement or a different treatment option. It could be dangerous for patients with type 2 diabetes to stop taking the medication without first talking to their doctor.
The agency has asked drug manufacturers to test products before batches are released into the market. The companies must tell the FDA if any product shows levels of nitrosamines above the acceptable limit.
The risk from nitrosamines is not clear. The FDA says they may increase the risk of cancer in people who are exposed to high levels over a long period of time, “but we do not anticipate that shorter-term exposure at levels above the acceptable intake limit would lead to an increase in the risk of cancer.”
This article first appeared on WebMD.com.
Entresto halves renal events in preserved EF heart failure patients
Patients with heart failure with preserved ejection fraction (HFpEF) who received sacubitril/valsartan in the PARAGON-HF trial had significant protection against progression of renal dysfunction in a prespecified secondary analysis.
The 2,419 patients with HFpEF who received sacubitril/valsartan (Entresto) had half the rate of the primary adverse renal outcome, compared with the 2,403 patients randomized to valsartan alone in the comparator group, a significant difference, according to the results published online Sept. 29 in Circulation by Finnian R. McCausland, MBBCh, and colleagues.
In absolute terms, sacubitril/valsartan treatment, an angiotensin-receptor/neprilysin inhibitor (ARNI), cut the incidence of the combined renal endpoint – renal death, end-stage renal disease, or at least a 50% drop in estimated glomerular filtration rate (eGFR) – from 2.7% in the control group to 1.4% in the sacubitril/valsartan group during a median follow-up of 35 months.
The absolute difference of 1.3% equated to a number needed to treat of 51 to prevent one of these events.
Also notable was that renal protection from sacubitril/valsartan was equally robust across the range of baseline kidney function.
‘An important therapeutic option’
The efficacy “across the spectrum of baseline renal function” indicates treatment with sacubitril/valsartan is “an important therapeutic option to slow renal-function decline in patients with heart failure,” wrote Dr. McCausland, a nephrologist at Brigham and Women’s Hospital in Boston, and colleagues.
The authors’ conclusion is striking because currently no drug class has produced clear evidence for efficacy in HFpEF.
On the other hand, the PARAGON-HF trial that provided the data for this new analysis was statistically neutral for its primary endpoint – a reduction in the combined rate of cardiovascular death and hospitalizations for heart failure – with a P value of .06 and 95% confidence interval of 0.75-1.01.
“Because this difference [in the primary endpoint incidence between the two study group] did not meet the predetermined level of statistical significance, subsequent analyses were considered to be exploratory,” noted the authors of the primary analysis of PARAGON-HF, as reported by Medscape Medical News.
Despite this limitation in interpreting secondary outcomes from the trial, the new report of a significant renal benefit “opens the potential to provide evidence-based treatment for patients with HFpEF,” commented Sheldon W. Tobe, MD, and Stephanie Poon, MD, in an editorial accompanying the latest analysis.
“At the very least, these results are certainly intriguing and suggest that there may be important patient subgroups with HFpEF who might benefit from using sacubitril/valsartan,” they emphasized.
First large trial to show renal improvement in HFpEF
The editorialists’ enthusiasm for the implications of the new findings relate in part to the fact that “PARAGON-HF is the first large trial to demonstrate improvement in renal parameters in HFpEF,” they noted.
“The finding that the composite renal outcome did not differ according to baseline eGFR is significant and suggests that the beneficial effect on renal function was indirect, possibly linked to improved cardiac function,” say Dr. Tobe, a nephrologist, and Dr. Poon, a cardiologist, both at Sunnybrook Health Sciences Centre in Toronto.
PARAGON-HF enrolled 4,822 HFpEF patients at 848 centers in 43 countries, and the efficacy analysis included 4,796 patients.
The composite renal outcome was mainly driven by the incidence of a 50% or greater drop from baseline in eGFR, which occurred in 27 patients (1.1%) in the sacubitril/valsartan group and 60 patients (2.5%) who received valsartan alone.
The annual average drop in eGFR during the study was 2.0 mL/min per 1.73m2 in the sacubitril/valsartan group and 2.7 mL/min per 1.73m2 in the control group.
Although the heart failure community was disappointed that sacubitril/valsartan failed to show a significant benefit for the study’s primary outcome in HFpEF, the combination has become a mainstay of treatment for patients with HFpEF based on its performance in the PARADIGM-HF trial.
And despite the unqualified support sacubitril/valsartan now receives in guidelines and its label as a foundational treatment for HFpEF, the formulation has had a hard time gaining traction in U.S. practice, often because of barriers placed by third-party payers.
PARAGON-HF was sponsored by Novartis, which markets sacubitril/valsartan (Entresto). Dr. McCausland has reported no relevant financial relationships. Dr. Tobe has reported participating on a steering committee for Bayer Fidelio/Figaro studies and being a speaker on behalf of Pfizer and Servier. Dr. Poon has reported being an adviser to Novartis, Boehringer Ingelheim, and Servier.
A version of this article originally appeared on Medscape.com.
Patients with heart failure with preserved ejection fraction (HFpEF) who received sacubitril/valsartan in the PARAGON-HF trial had significant protection against progression of renal dysfunction in a prespecified secondary analysis.
The 2,419 patients with HFpEF who received sacubitril/valsartan (Entresto) had half the rate of the primary adverse renal outcome, compared with the 2,403 patients randomized to valsartan alone in the comparator group, a significant difference, according to the results published online Sept. 29 in Circulation by Finnian R. McCausland, MBBCh, and colleagues.
In absolute terms, sacubitril/valsartan treatment, an angiotensin-receptor/neprilysin inhibitor (ARNI), cut the incidence of the combined renal endpoint – renal death, end-stage renal disease, or at least a 50% drop in estimated glomerular filtration rate (eGFR) – from 2.7% in the control group to 1.4% in the sacubitril/valsartan group during a median follow-up of 35 months.
The absolute difference of 1.3% equated to a number needed to treat of 51 to prevent one of these events.
Also notable was that renal protection from sacubitril/valsartan was equally robust across the range of baseline kidney function.
‘An important therapeutic option’
The efficacy “across the spectrum of baseline renal function” indicates treatment with sacubitril/valsartan is “an important therapeutic option to slow renal-function decline in patients with heart failure,” wrote Dr. McCausland, a nephrologist at Brigham and Women’s Hospital in Boston, and colleagues.
The authors’ conclusion is striking because currently no drug class has produced clear evidence for efficacy in HFpEF.
On the other hand, the PARAGON-HF trial that provided the data for this new analysis was statistically neutral for its primary endpoint – a reduction in the combined rate of cardiovascular death and hospitalizations for heart failure – with a P value of .06 and 95% confidence interval of 0.75-1.01.
“Because this difference [in the primary endpoint incidence between the two study group] did not meet the predetermined level of statistical significance, subsequent analyses were considered to be exploratory,” noted the authors of the primary analysis of PARAGON-HF, as reported by Medscape Medical News.
Despite this limitation in interpreting secondary outcomes from the trial, the new report of a significant renal benefit “opens the potential to provide evidence-based treatment for patients with HFpEF,” commented Sheldon W. Tobe, MD, and Stephanie Poon, MD, in an editorial accompanying the latest analysis.
“At the very least, these results are certainly intriguing and suggest that there may be important patient subgroups with HFpEF who might benefit from using sacubitril/valsartan,” they emphasized.
First large trial to show renal improvement in HFpEF
The editorialists’ enthusiasm for the implications of the new findings relate in part to the fact that “PARAGON-HF is the first large trial to demonstrate improvement in renal parameters in HFpEF,” they noted.
“The finding that the composite renal outcome did not differ according to baseline eGFR is significant and suggests that the beneficial effect on renal function was indirect, possibly linked to improved cardiac function,” say Dr. Tobe, a nephrologist, and Dr. Poon, a cardiologist, both at Sunnybrook Health Sciences Centre in Toronto.
PARAGON-HF enrolled 4,822 HFpEF patients at 848 centers in 43 countries, and the efficacy analysis included 4,796 patients.
The composite renal outcome was mainly driven by the incidence of a 50% or greater drop from baseline in eGFR, which occurred in 27 patients (1.1%) in the sacubitril/valsartan group and 60 patients (2.5%) who received valsartan alone.
The annual average drop in eGFR during the study was 2.0 mL/min per 1.73m2 in the sacubitril/valsartan group and 2.7 mL/min per 1.73m2 in the control group.
Although the heart failure community was disappointed that sacubitril/valsartan failed to show a significant benefit for the study’s primary outcome in HFpEF, the combination has become a mainstay of treatment for patients with HFpEF based on its performance in the PARADIGM-HF trial.
And despite the unqualified support sacubitril/valsartan now receives in guidelines and its label as a foundational treatment for HFpEF, the formulation has had a hard time gaining traction in U.S. practice, often because of barriers placed by third-party payers.
PARAGON-HF was sponsored by Novartis, which markets sacubitril/valsartan (Entresto). Dr. McCausland has reported no relevant financial relationships. Dr. Tobe has reported participating on a steering committee for Bayer Fidelio/Figaro studies and being a speaker on behalf of Pfizer and Servier. Dr. Poon has reported being an adviser to Novartis, Boehringer Ingelheim, and Servier.
A version of this article originally appeared on Medscape.com.
Patients with heart failure with preserved ejection fraction (HFpEF) who received sacubitril/valsartan in the PARAGON-HF trial had significant protection against progression of renal dysfunction in a prespecified secondary analysis.
The 2,419 patients with HFpEF who received sacubitril/valsartan (Entresto) had half the rate of the primary adverse renal outcome, compared with the 2,403 patients randomized to valsartan alone in the comparator group, a significant difference, according to the results published online Sept. 29 in Circulation by Finnian R. McCausland, MBBCh, and colleagues.
In absolute terms, sacubitril/valsartan treatment, an angiotensin-receptor/neprilysin inhibitor (ARNI), cut the incidence of the combined renal endpoint – renal death, end-stage renal disease, or at least a 50% drop in estimated glomerular filtration rate (eGFR) – from 2.7% in the control group to 1.4% in the sacubitril/valsartan group during a median follow-up of 35 months.
The absolute difference of 1.3% equated to a number needed to treat of 51 to prevent one of these events.
Also notable was that renal protection from sacubitril/valsartan was equally robust across the range of baseline kidney function.
‘An important therapeutic option’
The efficacy “across the spectrum of baseline renal function” indicates treatment with sacubitril/valsartan is “an important therapeutic option to slow renal-function decline in patients with heart failure,” wrote Dr. McCausland, a nephrologist at Brigham and Women’s Hospital in Boston, and colleagues.
The authors’ conclusion is striking because currently no drug class has produced clear evidence for efficacy in HFpEF.
On the other hand, the PARAGON-HF trial that provided the data for this new analysis was statistically neutral for its primary endpoint – a reduction in the combined rate of cardiovascular death and hospitalizations for heart failure – with a P value of .06 and 95% confidence interval of 0.75-1.01.
“Because this difference [in the primary endpoint incidence between the two study group] did not meet the predetermined level of statistical significance, subsequent analyses were considered to be exploratory,” noted the authors of the primary analysis of PARAGON-HF, as reported by Medscape Medical News.
Despite this limitation in interpreting secondary outcomes from the trial, the new report of a significant renal benefit “opens the potential to provide evidence-based treatment for patients with HFpEF,” commented Sheldon W. Tobe, MD, and Stephanie Poon, MD, in an editorial accompanying the latest analysis.
“At the very least, these results are certainly intriguing and suggest that there may be important patient subgroups with HFpEF who might benefit from using sacubitril/valsartan,” they emphasized.
First large trial to show renal improvement in HFpEF
The editorialists’ enthusiasm for the implications of the new findings relate in part to the fact that “PARAGON-HF is the first large trial to demonstrate improvement in renal parameters in HFpEF,” they noted.
“The finding that the composite renal outcome did not differ according to baseline eGFR is significant and suggests that the beneficial effect on renal function was indirect, possibly linked to improved cardiac function,” say Dr. Tobe, a nephrologist, and Dr. Poon, a cardiologist, both at Sunnybrook Health Sciences Centre in Toronto.
PARAGON-HF enrolled 4,822 HFpEF patients at 848 centers in 43 countries, and the efficacy analysis included 4,796 patients.
The composite renal outcome was mainly driven by the incidence of a 50% or greater drop from baseline in eGFR, which occurred in 27 patients (1.1%) in the sacubitril/valsartan group and 60 patients (2.5%) who received valsartan alone.
The annual average drop in eGFR during the study was 2.0 mL/min per 1.73m2 in the sacubitril/valsartan group and 2.7 mL/min per 1.73m2 in the control group.
Although the heart failure community was disappointed that sacubitril/valsartan failed to show a significant benefit for the study’s primary outcome in HFpEF, the combination has become a mainstay of treatment for patients with HFpEF based on its performance in the PARADIGM-HF trial.
And despite the unqualified support sacubitril/valsartan now receives in guidelines and its label as a foundational treatment for HFpEF, the formulation has had a hard time gaining traction in U.S. practice, often because of barriers placed by third-party payers.
PARAGON-HF was sponsored by Novartis, which markets sacubitril/valsartan (Entresto). Dr. McCausland has reported no relevant financial relationships. Dr. Tobe has reported participating on a steering committee for Bayer Fidelio/Figaro studies and being a speaker on behalf of Pfizer and Servier. Dr. Poon has reported being an adviser to Novartis, Boehringer Ingelheim, and Servier.
A version of this article originally appeared on Medscape.com.
T2D treatments create tension between glycemic and cardiovascular goals
It was no surprise that updated guidelines recently published by the European Society of Cardiology for managing cardiovascular disease in patients with diabetes highlighted optimized treatment from a cardiovascular disease perspective, while a nearly concurrent update from two major diabetes societies saw the same issue from a more glycemic point of view.
This difference led to divergent approaches to managing hyperglycemia in patients with type 2 diabetes (T2D). The two diabetes societies that wrote one set of recommendations, the American Diabetes Association and the European Association for the Study of Diabetes, put metformin at the pinnacle of their drug hierarchy. Patients with T2D and established atherosclerotic cardiovascular disease (CVD), chronic kidney disease, or heart failure should all receive metformin first unless contraindicated or not tolerated, their updated consensus report said.
Once metformin is on board, a clinician can then add a second diabetes agent from among the two drug classes recently proven to also reduce cardiovascular and renal events, either the SGLT2 (sodium-glucose transporter 2) inhibitors, or GLP-1 (glucagonlike peptide–1) receptor agonists, they advised.
Cardiovascular disease focus represents a ‘major paradigm shift’
In contrast, the ESC guidelines called for upfront, systematic assessment of CVD risk in patients with T2D before treatment starts, and for patients in high- or very high–risk strata, the guidelines recommended starting the patient first on an SGLT2 inhibitor or a GLP-1 receptor agonist, and only adding metformin in patients who need additional glycemic control.
The guidelines also recommended starting treatment-naive patients with moderate CVD risk on metformin. For patients already on metformin, the new ESC guidelines called for adding an agent from at least one of these two drug classes with proven CVD benefits for those at high or very high CVD risk. The guidelines also note that the CVD benefits of the two newer drug classes differ and hence require further individualization depending on the risks faced by each patient, such as the risk for heart failure hospitalizations.
It’s an approach “driven by data from the cardiovascular outcome trials,” that showed several drugs from both the SGLT2 inhibitor and GLP-1 receptor agonist classes have substantial benefit for preventing cardiovascular events, renal events, hospitalizations for heart failure, and in some studies all-cause mortality, said Francesco Cosentino, MD, during a discussion of the guideline differences at the virtual annual meeting of the European Association for the Study of Diabetes.
The ESC approach also represents “a major paradigm shift,” a “change from a glucose-centric approach to an approach driven by cardiovascular disease events,” summed up Dr. Cosentino, professor of cardiology at the Karolinska Institute in Stockholm and chair of the task force that wrote the ESC’s 2019 updated guidelines. The ESC approach advocates initiating drugs for treating patients with T2D “based on cardiovascular disease risk classification,” he highlighted. Results from some SGLT2 inhibitor cardiovascular outcome trials showed that the CVD benefit was similar regardless of whether or not patients also received metformin.
ADA, EASD call for ‘a different emphasis’
“There is a different emphasis” in the statement issued by the diabetologists of the ADA and EASD, admitted Peter J. Grant, MD, a professor of diabetes and endocrinology at the University of Leeds (England) and cochair of the ESC guidelines task force. Dr. Grant represented the EASD on the task force, and the Association collaborated with the ESC in producing its guidelines.
“The ADA and EASD recommendations “look primarily at glucose control, with cardiovascular disease management as secondary.” In contrast, the ESC guidelines “are primarily cardiovascular disease risk guidelines, with a glucose interest,” Dr. Grant declared.
Despite his involvement in writing the ESC guidelines, Dr. Grant tilted toward the ADA/EASD statement as more globally relevant.
“There is much more to vasculopathy in diabetes than just macrovascular disease. Many patients with type 2 diabetes without macrovascular complications have microvascular disease,” including the potential for retinopathy, nephropathy, and neuropathy, he said. These complications can also have a strong impact on psychological well being and treatment satisfaction.
“It’s important that we’re not glucocentric any more, but it’s equally important that we treat glucose because it has such a benefit for microvascular disease.” Dr. Grant also cited metformin’s long history of safety and good tolerance, clinician comfort prescribing it, and its low price. Heavier reliance on SGLT2 inhibitors and GLP-1 receptor agonists will be expensive for the short term while the cost of these drugs remains high, which places a higher burden on “knowing we’re doing it right,” said Dr. Grant.
Dr. Cosentino pointed out that the higher cost of the drugs in the two classes shown to exert important cardiovascular and renal effects needs to be considered in a cost-effectiveness context, not just by cost alone.
‘Clinical inertia’ could be a danger
Dr. Cosentino played down a major disagreement between the two guidelines, suggesting that “focusing on the differences leads to clinical inertia” by the practicing community when they are unsure how to reconcile the two positions.
Dr. Grant agreed that adding a second drug to metformin right away made sense in at least selected patients. “Look at each patient and decide whether they need glycemic control. If so, and if they also have cardiovascular disease, use both drugs,” metformin, plus one agent from one of the two newer classes.
Something both experts agreed on is that it’s time to generally steer clear of sulfonylurea drugs. “We have evidence for harmful effects from sulfonylureas,” Dr. Cosentino said.
“I’d dump sulfonylureas,” was Dr. Grant’s assessment, but he added that they still have a role for patients who need additional glycemic control but can’t afford the newer drugs.
Dr. Cosentino has had financial relationships with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Mundipharma, Novo Nordisk, and Pfizer, Dr. Grant has lectured on behalf of AstraZeneca, GlaxoSmithKline, Merck, Novo Nordisk, the Medicines Company, and Takeda, and he has been an adviser to Amgen, AstraZeneca, Novartis, Novo Nordisk, and Synexus.
It was no surprise that updated guidelines recently published by the European Society of Cardiology for managing cardiovascular disease in patients with diabetes highlighted optimized treatment from a cardiovascular disease perspective, while a nearly concurrent update from two major diabetes societies saw the same issue from a more glycemic point of view.
This difference led to divergent approaches to managing hyperglycemia in patients with type 2 diabetes (T2D). The two diabetes societies that wrote one set of recommendations, the American Diabetes Association and the European Association for the Study of Diabetes, put metformin at the pinnacle of their drug hierarchy. Patients with T2D and established atherosclerotic cardiovascular disease (CVD), chronic kidney disease, or heart failure should all receive metformin first unless contraindicated or not tolerated, their updated consensus report said.
Once metformin is on board, a clinician can then add a second diabetes agent from among the two drug classes recently proven to also reduce cardiovascular and renal events, either the SGLT2 (sodium-glucose transporter 2) inhibitors, or GLP-1 (glucagonlike peptide–1) receptor agonists, they advised.
Cardiovascular disease focus represents a ‘major paradigm shift’
In contrast, the ESC guidelines called for upfront, systematic assessment of CVD risk in patients with T2D before treatment starts, and for patients in high- or very high–risk strata, the guidelines recommended starting the patient first on an SGLT2 inhibitor or a GLP-1 receptor agonist, and only adding metformin in patients who need additional glycemic control.
The guidelines also recommended starting treatment-naive patients with moderate CVD risk on metformin. For patients already on metformin, the new ESC guidelines called for adding an agent from at least one of these two drug classes with proven CVD benefits for those at high or very high CVD risk. The guidelines also note that the CVD benefits of the two newer drug classes differ and hence require further individualization depending on the risks faced by each patient, such as the risk for heart failure hospitalizations.
It’s an approach “driven by data from the cardiovascular outcome trials,” that showed several drugs from both the SGLT2 inhibitor and GLP-1 receptor agonist classes have substantial benefit for preventing cardiovascular events, renal events, hospitalizations for heart failure, and in some studies all-cause mortality, said Francesco Cosentino, MD, during a discussion of the guideline differences at the virtual annual meeting of the European Association for the Study of Diabetes.
The ESC approach also represents “a major paradigm shift,” a “change from a glucose-centric approach to an approach driven by cardiovascular disease events,” summed up Dr. Cosentino, professor of cardiology at the Karolinska Institute in Stockholm and chair of the task force that wrote the ESC’s 2019 updated guidelines. The ESC approach advocates initiating drugs for treating patients with T2D “based on cardiovascular disease risk classification,” he highlighted. Results from some SGLT2 inhibitor cardiovascular outcome trials showed that the CVD benefit was similar regardless of whether or not patients also received metformin.
ADA, EASD call for ‘a different emphasis’
“There is a different emphasis” in the statement issued by the diabetologists of the ADA and EASD, admitted Peter J. Grant, MD, a professor of diabetes and endocrinology at the University of Leeds (England) and cochair of the ESC guidelines task force. Dr. Grant represented the EASD on the task force, and the Association collaborated with the ESC in producing its guidelines.
“The ADA and EASD recommendations “look primarily at glucose control, with cardiovascular disease management as secondary.” In contrast, the ESC guidelines “are primarily cardiovascular disease risk guidelines, with a glucose interest,” Dr. Grant declared.
Despite his involvement in writing the ESC guidelines, Dr. Grant tilted toward the ADA/EASD statement as more globally relevant.
“There is much more to vasculopathy in diabetes than just macrovascular disease. Many patients with type 2 diabetes without macrovascular complications have microvascular disease,” including the potential for retinopathy, nephropathy, and neuropathy, he said. These complications can also have a strong impact on psychological well being and treatment satisfaction.
“It’s important that we’re not glucocentric any more, but it’s equally important that we treat glucose because it has such a benefit for microvascular disease.” Dr. Grant also cited metformin’s long history of safety and good tolerance, clinician comfort prescribing it, and its low price. Heavier reliance on SGLT2 inhibitors and GLP-1 receptor agonists will be expensive for the short term while the cost of these drugs remains high, which places a higher burden on “knowing we’re doing it right,” said Dr. Grant.
Dr. Cosentino pointed out that the higher cost of the drugs in the two classes shown to exert important cardiovascular and renal effects needs to be considered in a cost-effectiveness context, not just by cost alone.
‘Clinical inertia’ could be a danger
Dr. Cosentino played down a major disagreement between the two guidelines, suggesting that “focusing on the differences leads to clinical inertia” by the practicing community when they are unsure how to reconcile the two positions.
Dr. Grant agreed that adding a second drug to metformin right away made sense in at least selected patients. “Look at each patient and decide whether they need glycemic control. If so, and if they also have cardiovascular disease, use both drugs,” metformin, plus one agent from one of the two newer classes.
Something both experts agreed on is that it’s time to generally steer clear of sulfonylurea drugs. “We have evidence for harmful effects from sulfonylureas,” Dr. Cosentino said.
“I’d dump sulfonylureas,” was Dr. Grant’s assessment, but he added that they still have a role for patients who need additional glycemic control but can’t afford the newer drugs.
Dr. Cosentino has had financial relationships with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Mundipharma, Novo Nordisk, and Pfizer, Dr. Grant has lectured on behalf of AstraZeneca, GlaxoSmithKline, Merck, Novo Nordisk, the Medicines Company, and Takeda, and he has been an adviser to Amgen, AstraZeneca, Novartis, Novo Nordisk, and Synexus.
It was no surprise that updated guidelines recently published by the European Society of Cardiology for managing cardiovascular disease in patients with diabetes highlighted optimized treatment from a cardiovascular disease perspective, while a nearly concurrent update from two major diabetes societies saw the same issue from a more glycemic point of view.
This difference led to divergent approaches to managing hyperglycemia in patients with type 2 diabetes (T2D). The two diabetes societies that wrote one set of recommendations, the American Diabetes Association and the European Association for the Study of Diabetes, put metformin at the pinnacle of their drug hierarchy. Patients with T2D and established atherosclerotic cardiovascular disease (CVD), chronic kidney disease, or heart failure should all receive metformin first unless contraindicated or not tolerated, their updated consensus report said.
Once metformin is on board, a clinician can then add a second diabetes agent from among the two drug classes recently proven to also reduce cardiovascular and renal events, either the SGLT2 (sodium-glucose transporter 2) inhibitors, or GLP-1 (glucagonlike peptide–1) receptor agonists, they advised.
Cardiovascular disease focus represents a ‘major paradigm shift’
In contrast, the ESC guidelines called for upfront, systematic assessment of CVD risk in patients with T2D before treatment starts, and for patients in high- or very high–risk strata, the guidelines recommended starting the patient first on an SGLT2 inhibitor or a GLP-1 receptor agonist, and only adding metformin in patients who need additional glycemic control.
The guidelines also recommended starting treatment-naive patients with moderate CVD risk on metformin. For patients already on metformin, the new ESC guidelines called for adding an agent from at least one of these two drug classes with proven CVD benefits for those at high or very high CVD risk. The guidelines also note that the CVD benefits of the two newer drug classes differ and hence require further individualization depending on the risks faced by each patient, such as the risk for heart failure hospitalizations.
It’s an approach “driven by data from the cardiovascular outcome trials,” that showed several drugs from both the SGLT2 inhibitor and GLP-1 receptor agonist classes have substantial benefit for preventing cardiovascular events, renal events, hospitalizations for heart failure, and in some studies all-cause mortality, said Francesco Cosentino, MD, during a discussion of the guideline differences at the virtual annual meeting of the European Association for the Study of Diabetes.
The ESC approach also represents “a major paradigm shift,” a “change from a glucose-centric approach to an approach driven by cardiovascular disease events,” summed up Dr. Cosentino, professor of cardiology at the Karolinska Institute in Stockholm and chair of the task force that wrote the ESC’s 2019 updated guidelines. The ESC approach advocates initiating drugs for treating patients with T2D “based on cardiovascular disease risk classification,” he highlighted. Results from some SGLT2 inhibitor cardiovascular outcome trials showed that the CVD benefit was similar regardless of whether or not patients also received metformin.
ADA, EASD call for ‘a different emphasis’
“There is a different emphasis” in the statement issued by the diabetologists of the ADA and EASD, admitted Peter J. Grant, MD, a professor of diabetes and endocrinology at the University of Leeds (England) and cochair of the ESC guidelines task force. Dr. Grant represented the EASD on the task force, and the Association collaborated with the ESC in producing its guidelines.
“The ADA and EASD recommendations “look primarily at glucose control, with cardiovascular disease management as secondary.” In contrast, the ESC guidelines “are primarily cardiovascular disease risk guidelines, with a glucose interest,” Dr. Grant declared.
Despite his involvement in writing the ESC guidelines, Dr. Grant tilted toward the ADA/EASD statement as more globally relevant.
“There is much more to vasculopathy in diabetes than just macrovascular disease. Many patients with type 2 diabetes without macrovascular complications have microvascular disease,” including the potential for retinopathy, nephropathy, and neuropathy, he said. These complications can also have a strong impact on psychological well being and treatment satisfaction.
“It’s important that we’re not glucocentric any more, but it’s equally important that we treat glucose because it has such a benefit for microvascular disease.” Dr. Grant also cited metformin’s long history of safety and good tolerance, clinician comfort prescribing it, and its low price. Heavier reliance on SGLT2 inhibitors and GLP-1 receptor agonists will be expensive for the short term while the cost of these drugs remains high, which places a higher burden on “knowing we’re doing it right,” said Dr. Grant.
Dr. Cosentino pointed out that the higher cost of the drugs in the two classes shown to exert important cardiovascular and renal effects needs to be considered in a cost-effectiveness context, not just by cost alone.
‘Clinical inertia’ could be a danger
Dr. Cosentino played down a major disagreement between the two guidelines, suggesting that “focusing on the differences leads to clinical inertia” by the practicing community when they are unsure how to reconcile the two positions.
Dr. Grant agreed that adding a second drug to metformin right away made sense in at least selected patients. “Look at each patient and decide whether they need glycemic control. If so, and if they also have cardiovascular disease, use both drugs,” metformin, plus one agent from one of the two newer classes.
Something both experts agreed on is that it’s time to generally steer clear of sulfonylurea drugs. “We have evidence for harmful effects from sulfonylureas,” Dr. Cosentino said.
“I’d dump sulfonylureas,” was Dr. Grant’s assessment, but he added that they still have a role for patients who need additional glycemic control but can’t afford the newer drugs.
Dr. Cosentino has had financial relationships with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Mundipharma, Novo Nordisk, and Pfizer, Dr. Grant has lectured on behalf of AstraZeneca, GlaxoSmithKline, Merck, Novo Nordisk, the Medicines Company, and Takeda, and he has been an adviser to Amgen, AstraZeneca, Novartis, Novo Nordisk, and Synexus.
FROM EASD 2020
Adrenal vein sampling looms as choke point for aldosteronism assessment of hypertensives
At a time when new evidence strongly suggests that roughly a fifth of patents with hypertension have primary aldosteronism as the cause, other recent findings suggest that many of these possibly tens of millions of patients with aldosterone-driven high blood pressure may as a consequence need an expensive and not-widely-available diagnostic test – adrenal vein sampling – to determine whether they are candidates for a definitive surgical cure to their aldosteronism.
Some endocrinologists worry the worldwide infrastructure for running adrenal vein sampling (AVS) isn’t close to being in place to deliver on this looming need for patients with primary aldosteronism (PA), especially given the burgeoning numbers now being cited for PA prevalence.
“The system could be overwhelmed,” warned Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville. “Right now, adrenal vein sampling [AVS] is the gold standard,” for distinguishing unilateral and bilateral excess aldosterone secretion, “but not every radiologist can do AVS. Until we find a surrogate biomarker that can distinguish unilateral and bilateral PA” many patients will need AVS, Dr. Carey said in an interview.
“AVS is important for accurate lateralization of aldosterone excess in patients, but it may not be feasible for all patients with PA to undergo AVS. If the prevalence of PA truly is on the order of 15% [of all patients with hypertension] then health systems would be stretched to offer all of them AVS, which is technically challenging and requires dedicated training and is therefore limited to expert centers,” commented Jun Yang, MBBS, a cardiovascular endocrinologist at the Hudson Institute of Medical Research and a hypertension researcher at Monash University, both in Melbourne. “At Monash, our interventional radiologists have increased their [AVS] success rate from 40% to more than 90% during the past 10 years, and our waiting list for patients scheduled for AVS is now 3-4 months long,” Dr. Yang said in an interview.
Finding a unilateral adrenal nodule as the cause of PA means that surgical removal is an option, a step that often fully resolves the PA and normalizes blood pressure. Patients with a bilateral source of the aldosterone are not candidates for surgical cure and must be managed with medical treatment, usually a mineralocorticoid receptor antagonist such as spironolactone that can neutralize or at least reduce the impact of hyperaldosteronism.
AVS finds unilateral adenomas when imaging can’t
The evidence that raised concerns about the reliability of imaging as an easier and noninvasive means to identify hypertensive patients with PA and a unilateral adrenal nodule that makes them candidates for surgical removal to resolve their PA and hypertension came out in May 2020 in a review of 174 PA patients who underwent AVS at a single center in Calgary, Alta., during 2006-2018.
The review included 366 patients with PA referred to the University of Calgary for assessment, of whom 179 had no adrenal nodule visible with either CT or MRI imaging, with 174 of these patients also undergoing successful AVS. The procedure revealed 70 patients (40%) had unilateral aldosterone secretion (Can J Cardiol. 2020 May 16. doi: 10.1016/j.cjca.2020.05.013).
In an editorial about this report that appeared a few weeks later, Ross D. Feldman, MD, a hypertension-management researcher and professor of medicine at the University of Manitoba in Winnipeg, Man., said the finding was “amazing,” and “confirms that lateralization of aldosterone secretion in a patient with PA but without an identifiable mass on that side is not a zebra,” but instead a presentation that “occurs in almost half of patients with PA and no discernible adenoma on the side that lateralizes.” (Can J. Cardiol. 2020 Jul 3. doi: 10.1016/j.cjca.2020.06.022).
Although this was just one center’s experience, the authors are not alone in making this finding, although prior reports seem to have been largely forgotten or ignored until now.
“The discordance between AVS and adrenal imaging has been documented by numerous groups, and in our own experience [in Melbourne] around 40% of patients with unilateral aldosterone excess do not have a distinct unilateral adenoma on CT,” said Dr. Yang.
“Here’s the problem,” summed up Dr. Feldman in an interview. “Nearly half of patients with hyperaldosteronism don’t localize based on a CT or MRI, so you have to do AVS, but AVS is not generally available; it’s only at tertiary centers; and you have to do a lot of them,” to do them well. “It’s a half-day procedure, and you have to hit the correct adrenal vein.”
AVS for millions?
Compounding the challenge is the other bit of bombshell news recently dropped on the endocrinology and hypertension communities: PA may be much more prevalent that previously suspected, occurring in roughly 20% of patients with hypertension, according to study results that also came out in 2020 (Ann Int Med. 2020 Jul 7;173[1]:10-20).
The upshot, according to Dr. Feldman and others, is that researchers will need to find reliable criteria besides imaging for identifying PA patients with an increased likelihood of having a lateralized source for their excess aldosterone production. That’s “the only hope,” said Dr. Feldman, “so we won’t have to do AVS on 20 million Americans.”
Unfortunately, the path toward a successful screen to winnow down candidates for AVS has been long and not especially fruitful, with efforts dating back at least 50 years, and with one of the most recent efforts at stratifying PA patients by certain laboratory measures getting dismissed as producing a benefit that “might not be substantial,” wrote Michael Stowasser, MBBS, in a published commentary (J Hypertension. 2020 Jul;38[7]:1259-61).
In contrast to Dr. Feldman, Dr. Stowasser was more optimistic about the prospects for avoiding an immediate crisis in AVS assessment of PA patients, mostly because so few patients with PA are now identified by clinicians. Given the poor record clinicians have historically rung up diagnosing PA, “it would seem unlikely that we are going to be flooded with AVS requests any time soon,” he wrote. There is also reason to hope that increased demand for AVS will help broaden availability, and innovative testing methods promise to speed up the procedure, said Dr. Stowasser, a professor of medicine at the University of Queensland in Brisbane, Australia and director of the Endocrine Hypertension Research Centre at Greenslopes and Princess Alexandra Hospitals in Brisbane, in an interview.
But regardless of whether AVS testing becomes more available or streamlined, recent events suggest there will be little way to avoid eventually having to run millions of these diagnostic procedures.
Patients with PA “who decide they will not want surgery do not need AVS. For all other patients with PA, you need AVS. The medical system will just have to respond,” Dr. Carey concluded.
Dr. Carey, Dr. Yang, Dr. Feldman, and Dr. Stowasser had no relevant disclosures.
At a time when new evidence strongly suggests that roughly a fifth of patents with hypertension have primary aldosteronism as the cause, other recent findings suggest that many of these possibly tens of millions of patients with aldosterone-driven high blood pressure may as a consequence need an expensive and not-widely-available diagnostic test – adrenal vein sampling – to determine whether they are candidates for a definitive surgical cure to their aldosteronism.
Some endocrinologists worry the worldwide infrastructure for running adrenal vein sampling (AVS) isn’t close to being in place to deliver on this looming need for patients with primary aldosteronism (PA), especially given the burgeoning numbers now being cited for PA prevalence.
“The system could be overwhelmed,” warned Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville. “Right now, adrenal vein sampling [AVS] is the gold standard,” for distinguishing unilateral and bilateral excess aldosterone secretion, “but not every radiologist can do AVS. Until we find a surrogate biomarker that can distinguish unilateral and bilateral PA” many patients will need AVS, Dr. Carey said in an interview.
“AVS is important for accurate lateralization of aldosterone excess in patients, but it may not be feasible for all patients with PA to undergo AVS. If the prevalence of PA truly is on the order of 15% [of all patients with hypertension] then health systems would be stretched to offer all of them AVS, which is technically challenging and requires dedicated training and is therefore limited to expert centers,” commented Jun Yang, MBBS, a cardiovascular endocrinologist at the Hudson Institute of Medical Research and a hypertension researcher at Monash University, both in Melbourne. “At Monash, our interventional radiologists have increased their [AVS] success rate from 40% to more than 90% during the past 10 years, and our waiting list for patients scheduled for AVS is now 3-4 months long,” Dr. Yang said in an interview.
Finding a unilateral adrenal nodule as the cause of PA means that surgical removal is an option, a step that often fully resolves the PA and normalizes blood pressure. Patients with a bilateral source of the aldosterone are not candidates for surgical cure and must be managed with medical treatment, usually a mineralocorticoid receptor antagonist such as spironolactone that can neutralize or at least reduce the impact of hyperaldosteronism.
AVS finds unilateral adenomas when imaging can’t
The evidence that raised concerns about the reliability of imaging as an easier and noninvasive means to identify hypertensive patients with PA and a unilateral adrenal nodule that makes them candidates for surgical removal to resolve their PA and hypertension came out in May 2020 in a review of 174 PA patients who underwent AVS at a single center in Calgary, Alta., during 2006-2018.
The review included 366 patients with PA referred to the University of Calgary for assessment, of whom 179 had no adrenal nodule visible with either CT or MRI imaging, with 174 of these patients also undergoing successful AVS. The procedure revealed 70 patients (40%) had unilateral aldosterone secretion (Can J Cardiol. 2020 May 16. doi: 10.1016/j.cjca.2020.05.013).
In an editorial about this report that appeared a few weeks later, Ross D. Feldman, MD, a hypertension-management researcher and professor of medicine at the University of Manitoba in Winnipeg, Man., said the finding was “amazing,” and “confirms that lateralization of aldosterone secretion in a patient with PA but without an identifiable mass on that side is not a zebra,” but instead a presentation that “occurs in almost half of patients with PA and no discernible adenoma on the side that lateralizes.” (Can J. Cardiol. 2020 Jul 3. doi: 10.1016/j.cjca.2020.06.022).
Although this was just one center’s experience, the authors are not alone in making this finding, although prior reports seem to have been largely forgotten or ignored until now.
“The discordance between AVS and adrenal imaging has been documented by numerous groups, and in our own experience [in Melbourne] around 40% of patients with unilateral aldosterone excess do not have a distinct unilateral adenoma on CT,” said Dr. Yang.
“Here’s the problem,” summed up Dr. Feldman in an interview. “Nearly half of patients with hyperaldosteronism don’t localize based on a CT or MRI, so you have to do AVS, but AVS is not generally available; it’s only at tertiary centers; and you have to do a lot of them,” to do them well. “It’s a half-day procedure, and you have to hit the correct adrenal vein.”
AVS for millions?
Compounding the challenge is the other bit of bombshell news recently dropped on the endocrinology and hypertension communities: PA may be much more prevalent that previously suspected, occurring in roughly 20% of patients with hypertension, according to study results that also came out in 2020 (Ann Int Med. 2020 Jul 7;173[1]:10-20).
The upshot, according to Dr. Feldman and others, is that researchers will need to find reliable criteria besides imaging for identifying PA patients with an increased likelihood of having a lateralized source for their excess aldosterone production. That’s “the only hope,” said Dr. Feldman, “so we won’t have to do AVS on 20 million Americans.”
Unfortunately, the path toward a successful screen to winnow down candidates for AVS has been long and not especially fruitful, with efforts dating back at least 50 years, and with one of the most recent efforts at stratifying PA patients by certain laboratory measures getting dismissed as producing a benefit that “might not be substantial,” wrote Michael Stowasser, MBBS, in a published commentary (J Hypertension. 2020 Jul;38[7]:1259-61).
In contrast to Dr. Feldman, Dr. Stowasser was more optimistic about the prospects for avoiding an immediate crisis in AVS assessment of PA patients, mostly because so few patients with PA are now identified by clinicians. Given the poor record clinicians have historically rung up diagnosing PA, “it would seem unlikely that we are going to be flooded with AVS requests any time soon,” he wrote. There is also reason to hope that increased demand for AVS will help broaden availability, and innovative testing methods promise to speed up the procedure, said Dr. Stowasser, a professor of medicine at the University of Queensland in Brisbane, Australia and director of the Endocrine Hypertension Research Centre at Greenslopes and Princess Alexandra Hospitals in Brisbane, in an interview.
But regardless of whether AVS testing becomes more available or streamlined, recent events suggest there will be little way to avoid eventually having to run millions of these diagnostic procedures.
Patients with PA “who decide they will not want surgery do not need AVS. For all other patients with PA, you need AVS. The medical system will just have to respond,” Dr. Carey concluded.
Dr. Carey, Dr. Yang, Dr. Feldman, and Dr. Stowasser had no relevant disclosures.
At a time when new evidence strongly suggests that roughly a fifth of patents with hypertension have primary aldosteronism as the cause, other recent findings suggest that many of these possibly tens of millions of patients with aldosterone-driven high blood pressure may as a consequence need an expensive and not-widely-available diagnostic test – adrenal vein sampling – to determine whether they are candidates for a definitive surgical cure to their aldosteronism.
Some endocrinologists worry the worldwide infrastructure for running adrenal vein sampling (AVS) isn’t close to being in place to deliver on this looming need for patients with primary aldosteronism (PA), especially given the burgeoning numbers now being cited for PA prevalence.
“The system could be overwhelmed,” warned Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville. “Right now, adrenal vein sampling [AVS] is the gold standard,” for distinguishing unilateral and bilateral excess aldosterone secretion, “but not every radiologist can do AVS. Until we find a surrogate biomarker that can distinguish unilateral and bilateral PA” many patients will need AVS, Dr. Carey said in an interview.
“AVS is important for accurate lateralization of aldosterone excess in patients, but it may not be feasible for all patients with PA to undergo AVS. If the prevalence of PA truly is on the order of 15% [of all patients with hypertension] then health systems would be stretched to offer all of them AVS, which is technically challenging and requires dedicated training and is therefore limited to expert centers,” commented Jun Yang, MBBS, a cardiovascular endocrinologist at the Hudson Institute of Medical Research and a hypertension researcher at Monash University, both in Melbourne. “At Monash, our interventional radiologists have increased their [AVS] success rate from 40% to more than 90% during the past 10 years, and our waiting list for patients scheduled for AVS is now 3-4 months long,” Dr. Yang said in an interview.
Finding a unilateral adrenal nodule as the cause of PA means that surgical removal is an option, a step that often fully resolves the PA and normalizes blood pressure. Patients with a bilateral source of the aldosterone are not candidates for surgical cure and must be managed with medical treatment, usually a mineralocorticoid receptor antagonist such as spironolactone that can neutralize or at least reduce the impact of hyperaldosteronism.
AVS finds unilateral adenomas when imaging can’t
The evidence that raised concerns about the reliability of imaging as an easier and noninvasive means to identify hypertensive patients with PA and a unilateral adrenal nodule that makes them candidates for surgical removal to resolve their PA and hypertension came out in May 2020 in a review of 174 PA patients who underwent AVS at a single center in Calgary, Alta., during 2006-2018.
The review included 366 patients with PA referred to the University of Calgary for assessment, of whom 179 had no adrenal nodule visible with either CT or MRI imaging, with 174 of these patients also undergoing successful AVS. The procedure revealed 70 patients (40%) had unilateral aldosterone secretion (Can J Cardiol. 2020 May 16. doi: 10.1016/j.cjca.2020.05.013).
In an editorial about this report that appeared a few weeks later, Ross D. Feldman, MD, a hypertension-management researcher and professor of medicine at the University of Manitoba in Winnipeg, Man., said the finding was “amazing,” and “confirms that lateralization of aldosterone secretion in a patient with PA but without an identifiable mass on that side is not a zebra,” but instead a presentation that “occurs in almost half of patients with PA and no discernible adenoma on the side that lateralizes.” (Can J. Cardiol. 2020 Jul 3. doi: 10.1016/j.cjca.2020.06.022).
Although this was just one center’s experience, the authors are not alone in making this finding, although prior reports seem to have been largely forgotten or ignored until now.
“The discordance between AVS and adrenal imaging has been documented by numerous groups, and in our own experience [in Melbourne] around 40% of patients with unilateral aldosterone excess do not have a distinct unilateral adenoma on CT,” said Dr. Yang.
“Here’s the problem,” summed up Dr. Feldman in an interview. “Nearly half of patients with hyperaldosteronism don’t localize based on a CT or MRI, so you have to do AVS, but AVS is not generally available; it’s only at tertiary centers; and you have to do a lot of them,” to do them well. “It’s a half-day procedure, and you have to hit the correct adrenal vein.”
AVS for millions?
Compounding the challenge is the other bit of bombshell news recently dropped on the endocrinology and hypertension communities: PA may be much more prevalent that previously suspected, occurring in roughly 20% of patients with hypertension, according to study results that also came out in 2020 (Ann Int Med. 2020 Jul 7;173[1]:10-20).
The upshot, according to Dr. Feldman and others, is that researchers will need to find reliable criteria besides imaging for identifying PA patients with an increased likelihood of having a lateralized source for their excess aldosterone production. That’s “the only hope,” said Dr. Feldman, “so we won’t have to do AVS on 20 million Americans.”
Unfortunately, the path toward a successful screen to winnow down candidates for AVS has been long and not especially fruitful, with efforts dating back at least 50 years, and with one of the most recent efforts at stratifying PA patients by certain laboratory measures getting dismissed as producing a benefit that “might not be substantial,” wrote Michael Stowasser, MBBS, in a published commentary (J Hypertension. 2020 Jul;38[7]:1259-61).
In contrast to Dr. Feldman, Dr. Stowasser was more optimistic about the prospects for avoiding an immediate crisis in AVS assessment of PA patients, mostly because so few patients with PA are now identified by clinicians. Given the poor record clinicians have historically rung up diagnosing PA, “it would seem unlikely that we are going to be flooded with AVS requests any time soon,” he wrote. There is also reason to hope that increased demand for AVS will help broaden availability, and innovative testing methods promise to speed up the procedure, said Dr. Stowasser, a professor of medicine at the University of Queensland in Brisbane, Australia and director of the Endocrine Hypertension Research Centre at Greenslopes and Princess Alexandra Hospitals in Brisbane, in an interview.
But regardless of whether AVS testing becomes more available or streamlined, recent events suggest there will be little way to avoid eventually having to run millions of these diagnostic procedures.
Patients with PA “who decide they will not want surgery do not need AVS. For all other patients with PA, you need AVS. The medical system will just have to respond,” Dr. Carey concluded.
Dr. Carey, Dr. Yang, Dr. Feldman, and Dr. Stowasser had no relevant disclosures.