Cardiology News

The chance that patients with severe aortic stenosis (AS) will receive aortic valve replacement (AVR) is worse than the flip of a coin, even a decade after the gamechanging transcatheter option became available, a new study suggests.

Of the study’s 6,150 patients with an indication or potential indication for AVR, 48% received the procedure at Massachusetts General Hospital and its partner institution Brigham and Women’s Hospital, both in Boston – both of which have active, high-volume transcatheter and surgical AVR (TAVR/SAVR) programs.

“Essentially, this is a best-case scenario. So, unfortunately, I think on the national level we are likely to see rates that are far worse than what we observed here,” senior author Sammy Elmariah, MD, PhD, Massachusetts General Hospital, told this news organization.

The volume of AVR increased more than 10-fold over the 18-year study period (2000 to 2017), driven by the exponential growth of TAVR, he noted. However, the graying of America led to an even greater increase in the number of patients with severe AS and an indication for AVR.

The study, led by Shawn X. Li, MD, MBA, of Mass General, was published in the March 8 issue of the Journal of the American College of Cardiology.

Previous research has provided equally compelling data on the undertreatment of AS, including a 2021 study using natural language processing (NLP) that found AVR use was just 35.6% within 1 year of diagnosis and varied wildly among managing cardiologists.

The present study used NLP tools to identify symptoms consistent with severe AS in the medical record coupled with echocardiographic data from 10,795 patients with severe AS (valve area <1 cm2). Patients were divided into four AS subtypes and then classified as having a class 1 indication (high-gradient AS with symptoms or reduced ejection fraction [EF]) or a potential class 2a indication (low-gradient AS with symptoms) for AVR.

Among patients with high-gradient AS and class 1 indication for AVR, 1 in 3 did not receive AVR over the study period, including 30% with a normal EF and 47% with a low EF.

In those with low-gradient AS, 67% with a normal EF and 62% with a low EF did not receive AVR. The low-gradient groups were significantly less likely to receive AVR both in the entire study period and in the more contemporary period from 2014 to 2017, despite the valvular heart disease guideline 2014 update indicating AVR was “reasonable” in patients with low-gradient AS – a 2a recommendation upgraded to class 1 in the most recent 2020 update.
 

Better survival

In patients with a class 1 or potential class 2a indication, AVR was associated with a significantly lower risk of mortality in all four AS subgroups:

• High gradient/normal EF: 3% vs. 15%; adjusted hazard ratio, 0.42
• High-gradient/low EF: 16% vs. 72%; aHR, 0.28
• Low-gradient/normal EF: 5% vs. 14%; aHR, 0.73
• Low-gradient/low EF: 11% vs. 34%; aHR, 0.48; P < .001 for all

“I think what we need to do is change the paradigm, such that patients with a valve area that is less than or equal to 1 [cm2] is severe aortic stenosis until proven otherwise, and that essentially establishes a premise by which we default to treat these patients unless we can prove that it is in fact moderate,” Dr. Elmariah said.

Unfortunately, the opposite is currently true today, he said, and the default is not to treat and put patients through surgery or an invasive TAVR procedure unless physicians can definitively prove that it is severe AS. But they’re not always correct and don’t always have the ability to truly differentiate moderate from severe disease.

“The question, therefore, is ‘What do we do with those patients?’” Dr. Elmariah asked. “I think if a patient has symptoms, then we are obligated to intervene, given the stark difference in mortality that one sees when these patients go undertreated.”
 

Sounding the alarm

Robert Bonow, MD, a professor of cardiology at Northwestern University in Chicago and a writing committee member for the 2014 guideline update, said the study is a “big wake-up call” and “the take-home message is that we are missing some patients who have treatable aortic stenosis.”

The sheer magnitude of the problem, however, can be difficult to fully ascertain from administrative data like this, he said. Notably, patients who did not receive AVR were significantly older, with 37% aged 81-90 years and 12% over age 90, and had a lower hematocrit and lower estimated glomerular filtration rate. But it’s not clear how many had cancer, end-stage renal disease, or severe lung disease, which could have factored into the decision to undergo AVR.

“What’s also an issue is that over 50% of patients had low gradient disease, which is very problematic and takes careful assessment in an individual patient,” said Dr. Bonow, who is also editor-in-chief of JAMA Cardiology. “That’s all being generated by a low valve area of less than 1 cm2 from echo reports, so that’s not necessarily a careful prospective echo assessment ... so some of the patients with low-gradient disease may not have true severe aortic stenosis.”

Dr. Elmariah agreed that echocardiogram reports are not always clear cut and pointed out that referral to a valve specialist was highly predictive of whether or not a patient underwent AVR, supporting the class 1 guideline recommendation.

He also noted that Mass General is launching the DETECT-AS trial to determine whether electronic physician notifications highlighting clinical practice guideline recommendations will improve AVR utilization over standard care in 940 patients with severe AS on echocardiogram, defined by a valve area less than 1 cm2.

Reached for comment, Catherine Otto, MD, director of the Heart Valve Clinic at the University of Washington, Seattle, and a fellow member of the 2014 guideline writing committee, said “this adds to the data [that] we’re undertreating severe aortic stenosis, and it continues to be surprising given the availability of transcatheter options.”

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

The chance that patients with severe aortic stenosis (AS) will receive aortic valve replacement (AVR) is worse than the flip of a coin, even a decade after the gamechanging transcatheter option became available, a new study suggests.

Of the study’s 6,150 patients with an indication or potential indication for AVR, 48% received the procedure at Massachusetts General Hospital and its partner institution Brigham and Women’s Hospital, both in Boston – both of which have active, high-volume transcatheter and surgical AVR (TAVR/SAVR) programs.

“Essentially, this is a best-case scenario. So, unfortunately, I think on the national level we are likely to see rates that are far worse than what we observed here,” senior author Sammy Elmariah, MD, PhD, Massachusetts General Hospital, told this news organization.

The volume of AVR increased more than 10-fold over the 18-year study period (2000 to 2017), driven by the exponential growth of TAVR, he noted. However, the graying of America led to an even greater increase in the number of patients with severe AS and an indication for AVR.

The study, led by Shawn X. Li, MD, MBA, of Mass General, was published in the March 8 issue of the Journal of the American College of Cardiology.

Previous research has provided equally compelling data on the undertreatment of AS, including a 2021 study using natural language processing (NLP) that found AVR use was just 35.6% within 1 year of diagnosis and varied wildly among managing cardiologists.

The present study used NLP tools to identify symptoms consistent with severe AS in the medical record coupled with echocardiographic data from 10,795 patients with severe AS (valve area <1 cm2). Patients were divided into four AS subtypes and then classified as having a class 1 indication (high-gradient AS with symptoms or reduced ejection fraction [EF]) or a potential class 2a indication (low-gradient AS with symptoms) for AVR.

Among patients with high-gradient AS and class 1 indication for AVR, 1 in 3 did not receive AVR over the study period, including 30% with a normal EF and 47% with a low EF.

In those with low-gradient AS, 67% with a normal EF and 62% with a low EF did not receive AVR. The low-gradient groups were significantly less likely to receive AVR both in the entire study period and in the more contemporary period from 2014 to 2017, despite the valvular heart disease guideline 2014 update indicating AVR was “reasonable” in patients with low-gradient AS – a 2a recommendation upgraded to class 1 in the most recent 2020 update.
 

Better survival

In patients with a class 1 or potential class 2a indication, AVR was associated with a significantly lower risk of mortality in all four AS subgroups:

• High gradient/normal EF: 3% vs. 15%; adjusted hazard ratio, 0.42
• High-gradient/low EF: 16% vs. 72%; aHR, 0.28
• Low-gradient/normal EF: 5% vs. 14%; aHR, 0.73
• Low-gradient/low EF: 11% vs. 34%; aHR, 0.48; P < .001 for all

“I think what we need to do is change the paradigm, such that patients with a valve area that is less than or equal to 1 [cm2] is severe aortic stenosis until proven otherwise, and that essentially establishes a premise by which we default to treat these patients unless we can prove that it is in fact moderate,” Dr. Elmariah said.

Unfortunately, the opposite is currently true today, he said, and the default is not to treat and put patients through surgery or an invasive TAVR procedure unless physicians can definitively prove that it is severe AS. But they’re not always correct and don’t always have the ability to truly differentiate moderate from severe disease.

“The question, therefore, is ‘What do we do with those patients?’” Dr. Elmariah asked. “I think if a patient has symptoms, then we are obligated to intervene, given the stark difference in mortality that one sees when these patients go undertreated.”
 

Sounding the alarm

Robert Bonow, MD, a professor of cardiology at Northwestern University in Chicago and a writing committee member for the 2014 guideline update, said the study is a “big wake-up call” and “the take-home message is that we are missing some patients who have treatable aortic stenosis.”

The sheer magnitude of the problem, however, can be difficult to fully ascertain from administrative data like this, he said. Notably, patients who did not receive AVR were significantly older, with 37% aged 81-90 years and 12% over age 90, and had a lower hematocrit and lower estimated glomerular filtration rate. But it’s not clear how many had cancer, end-stage renal disease, or severe lung disease, which could have factored into the decision to undergo AVR.

“What’s also an issue is that over 50% of patients had low gradient disease, which is very problematic and takes careful assessment in an individual patient,” said Dr. Bonow, who is also editor-in-chief of JAMA Cardiology. “That’s all being generated by a low valve area of less than 1 cm2 from echo reports, so that’s not necessarily a careful prospective echo assessment ... so some of the patients with low-gradient disease may not have true severe aortic stenosis.”

Dr. Elmariah agreed that echocardiogram reports are not always clear cut and pointed out that referral to a valve specialist was highly predictive of whether or not a patient underwent AVR, supporting the class 1 guideline recommendation.

He also noted that Mass General is launching the DETECT-AS trial to determine whether electronic physician notifications highlighting clinical practice guideline recommendations will improve AVR utilization over standard care in 940 patients with severe AS on echocardiogram, defined by a valve area less than 1 cm2.

Reached for comment, Catherine Otto, MD, director of the Heart Valve Clinic at the University of Washington, Seattle, and a fellow member of the 2014 guideline writing committee, said “this adds to the data [that] we’re undertreating severe aortic stenosis, and it continues to be surprising given the availability of transcatheter options.”

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

The chance that patients with severe aortic stenosis (AS) will receive aortic valve replacement (AVR) is worse than the flip of a coin, even a decade after the gamechanging transcatheter option became available, a new study suggests.

Of the study’s 6,150 patients with an indication or potential indication for AVR, 48% received the procedure at Massachusetts General Hospital and its partner institution Brigham and Women’s Hospital, both in Boston – both of which have active, high-volume transcatheter and surgical AVR (TAVR/SAVR) programs.

“Essentially, this is a best-case scenario. So, unfortunately, I think on the national level we are likely to see rates that are far worse than what we observed here,” senior author Sammy Elmariah, MD, PhD, Massachusetts General Hospital, told this news organization.

The volume of AVR increased more than 10-fold over the 18-year study period (2000 to 2017), driven by the exponential growth of TAVR, he noted. However, the graying of America led to an even greater increase in the number of patients with severe AS and an indication for AVR.

The study, led by Shawn X. Li, MD, MBA, of Mass General, was published in the March 8 issue of the Journal of the American College of Cardiology.

Previous research has provided equally compelling data on the undertreatment of AS, including a 2021 study using natural language processing (NLP) that found AVR use was just 35.6% within 1 year of diagnosis and varied wildly among managing cardiologists.

The present study used NLP tools to identify symptoms consistent with severe AS in the medical record coupled with echocardiographic data from 10,795 patients with severe AS (valve area <1 cm2). Patients were divided into four AS subtypes and then classified as having a class 1 indication (high-gradient AS with symptoms or reduced ejection fraction [EF]) or a potential class 2a indication (low-gradient AS with symptoms) for AVR.

Among patients with high-gradient AS and class 1 indication for AVR, 1 in 3 did not receive AVR over the study period, including 30% with a normal EF and 47% with a low EF.

In those with low-gradient AS, 67% with a normal EF and 62% with a low EF did not receive AVR. The low-gradient groups were significantly less likely to receive AVR both in the entire study period and in the more contemporary period from 2014 to 2017, despite the valvular heart disease guideline 2014 update indicating AVR was “reasonable” in patients with low-gradient AS – a 2a recommendation upgraded to class 1 in the most recent 2020 update.
 

Better survival

In patients with a class 1 or potential class 2a indication, AVR was associated with a significantly lower risk of mortality in all four AS subgroups:

• High gradient/normal EF: 3% vs. 15%; adjusted hazard ratio, 0.42
• High-gradient/low EF: 16% vs. 72%; aHR, 0.28
• Low-gradient/normal EF: 5% vs. 14%; aHR, 0.73
• Low-gradient/low EF: 11% vs. 34%; aHR, 0.48; P < .001 for all

“I think what we need to do is change the paradigm, such that patients with a valve area that is less than or equal to 1 [cm2] is severe aortic stenosis until proven otherwise, and that essentially establishes a premise by which we default to treat these patients unless we can prove that it is in fact moderate,” Dr. Elmariah said.

Unfortunately, the opposite is currently true today, he said, and the default is not to treat and put patients through surgery or an invasive TAVR procedure unless physicians can definitively prove that it is severe AS. But they’re not always correct and don’t always have the ability to truly differentiate moderate from severe disease.

“The question, therefore, is ‘What do we do with those patients?’” Dr. Elmariah asked. “I think if a patient has symptoms, then we are obligated to intervene, given the stark difference in mortality that one sees when these patients go undertreated.”
 

Sounding the alarm

Robert Bonow, MD, a professor of cardiology at Northwestern University in Chicago and a writing committee member for the 2014 guideline update, said the study is a “big wake-up call” and “the take-home message is that we are missing some patients who have treatable aortic stenosis.”

The sheer magnitude of the problem, however, can be difficult to fully ascertain from administrative data like this, he said. Notably, patients who did not receive AVR were significantly older, with 37% aged 81-90 years and 12% over age 90, and had a lower hematocrit and lower estimated glomerular filtration rate. But it’s not clear how many had cancer, end-stage renal disease, or severe lung disease, which could have factored into the decision to undergo AVR.

“What’s also an issue is that over 50% of patients had low gradient disease, which is very problematic and takes careful assessment in an individual patient,” said Dr. Bonow, who is also editor-in-chief of JAMA Cardiology. “That’s all being generated by a low valve area of less than 1 cm2 from echo reports, so that’s not necessarily a careful prospective echo assessment ... so some of the patients with low-gradient disease may not have true severe aortic stenosis.”

Dr. Elmariah agreed that echocardiogram reports are not always clear cut and pointed out that referral to a valve specialist was highly predictive of whether or not a patient underwent AVR, supporting the class 1 guideline recommendation.

He also noted that Mass General is launching the DETECT-AS trial to determine whether electronic physician notifications highlighting clinical practice guideline recommendations will improve AVR utilization over standard care in 940 patients with severe AS on echocardiogram, defined by a valve area less than 1 cm2.

Reached for comment, Catherine Otto, MD, director of the Heart Valve Clinic at the University of Washington, Seattle, and a fellow member of the 2014 guideline writing committee, said “this adds to the data [that] we’re undertreating severe aortic stenosis, and it continues to be surprising given the availability of transcatheter options.”

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

Increasingly active patterns of physical activity were linked with reduced rates of overall mortality and cardiovascular disease (CVD), but early rather than later in late life, in a 20-year follow-up cohort study.

In this population of people older than 65 years, researchers found that physical activity overall was associated with lower rates of incident CVD, particularly among men, and the association was strongest in people 70 to 75 years of age, rather than in older age groups.

They also looked at “trajectories,” or changes in activity over time, and found that a stable-high trajectory of activity was associated with a significantly lower risk for cardiovascular outcomes in men than in those with a stable-low trajectory. For women, more physical activity was consistently associated with lower CVD outcomes, although not statistically significantly so, except for overall mortality, which did reach significance.

Notably, the greatest reduction in cardiovascular risk was reported in people who did more than 20 minutes of physical exercise each day, and it was more pronounced in those 70 years of age.

Physical activity was also associated with a lower incidence of heart failure and coronary heart disease in older people, again especially early on in late life, reported Claudio Barbiellini Amidei, MD, University of Padua, Italy, and colleagues.

The data suggest that physical activity is more effective in preventing CVD onset when implemented early rather than later in life, noted Dr. Amidei in an email.

“The findings of our study are suggestive of a protective effect of physical activity in late-life on cardiovascular health. WHO recommendations for adults and older adults are to practice at least 20 minutes of moderate to vigorous physical activity per day. I believe this is a realistic target, and policy makers should raise awareness on the importance of achieving this goal at all ages, including in late-life,” Dr. Amidei said.

The study was published online Feb. 14 in Heart.

Previous research has demonstrated that the most benefit of high physical activity, compared with low, begins at about 60 years of age, and that is because younger people are at much lower risk, noted Carl “Chip” Lavie MD, FACC, medical director of cardiac rehabilitation and prevention, Ochsner Clinical School–The University of Queensland School of Medicine, New Orleans, who was not involved in the study.

“At quite old ages, for example over age 80, resistance exercise or weight training and balance training may be even more important than aerobic training,” he added.

Activity ‘trajectories’

The benefits of physical activity on cardiovascular risk are well established, the researchers note. Less clear is the role that trajectories of activity over time play, although research to date suggests a reduction in risk with increasing activity from mid-life to early old age, they write.

For the current analysis, the researchers assessed 3,099 Italian participants. Mean age was about 75 years, and baseline data were collected from 1995 to 1997.

Follow-up visits were conducted after 4 years and again after 7 years. Using hospital medical records and mortality data, the researchers were able to collect surveillance data through 2018. Hospital records, surveys, and clinical assessments helped them identify incident and prevalent cardiovascular diseases, such as stroke, coronary heart disease, and heart failure.

Participants’ physical activity patterns were classified as stable-high, low-increasing, high-decreasing, and stable-low. Exposure was evaluated at 70, 75, 80, and 85 years of age.

“In our analyses, we focused on moderate to vigorous physical activity, and these include a broad range of exercises, such as walking very briskly, playing tennis, [and] jogging, but comprise also other activities, such as gardening or doing household chores,” said Dr. Amidei.

Patterns of stable-low physical activity were linked to a significantly greater risk for cardiovascular outcomes in men than patterns of stable-high physical activity (hazard ratio, 0.48; 95% confidence interval, 0.27-0.86; P for trend = .002).

No significant relation was found between physical activity and stroke, the researchers note.

“The benefits of physical activity seem to lessen above the age of 75 years and seem more important in men,” noted Dr. Lavie. “This may be partly due to the higher risk of CVD in men. Women typically lag 13 to 15 years behind men for CVD but start catching up in older years.”

Limitations of the study include lack of information regarding physical activity during mid-life, the limited number of stroke events, the relatively few participants older than 85 years, and potential recall bias, the researchers note.

Another limitation was that the physical activity data were based on patient surveys collected 3 years apart and did not involve the use of an accelerometer, the researchers add.

“Future observational studies are required to confirm our findings and pathophysiological studies are warranted to examine the underlying biological mechanisms. Physical activity is likely to be beneficial at any age, but to summarize our findings, we could say that when it comes to being physically active, the sooner the better,” concluded Dr. Amidei.

Dr. Amidei reports no relevant financial relationships.

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

Increasingly active patterns of physical activity were linked with reduced rates of overall mortality and cardiovascular disease (CVD), but early rather than later in late life, in a 20-year follow-up cohort study.

In this population of people older than 65 years, researchers found that physical activity overall was associated with lower rates of incident CVD, particularly among men, and the association was strongest in people 70 to 75 years of age, rather than in older age groups.

They also looked at “trajectories,” or changes in activity over time, and found that a stable-high trajectory of activity was associated with a significantly lower risk for cardiovascular outcomes in men than in those with a stable-low trajectory. For women, more physical activity was consistently associated with lower CVD outcomes, although not statistically significantly so, except for overall mortality, which did reach significance.

Notably, the greatest reduction in cardiovascular risk was reported in people who did more than 20 minutes of physical exercise each day, and it was more pronounced in those 70 years of age.

Physical activity was also associated with a lower incidence of heart failure and coronary heart disease in older people, again especially early on in late life, reported Claudio Barbiellini Amidei, MD, University of Padua, Italy, and colleagues.

The data suggest that physical activity is more effective in preventing CVD onset when implemented early rather than later in life, noted Dr. Amidei in an email.

“The findings of our study are suggestive of a protective effect of physical activity in late-life on cardiovascular health. WHO recommendations for adults and older adults are to practice at least 20 minutes of moderate to vigorous physical activity per day. I believe this is a realistic target, and policy makers should raise awareness on the importance of achieving this goal at all ages, including in late-life,” Dr. Amidei said.

The study was published online Feb. 14 in Heart.

Previous research has demonstrated that the most benefit of high physical activity, compared with low, begins at about 60 years of age, and that is because younger people are at much lower risk, noted Carl “Chip” Lavie MD, FACC, medical director of cardiac rehabilitation and prevention, Ochsner Clinical School–The University of Queensland School of Medicine, New Orleans, who was not involved in the study.

“At quite old ages, for example over age 80, resistance exercise or weight training and balance training may be even more important than aerobic training,” he added.

Activity ‘trajectories’

The benefits of physical activity on cardiovascular risk are well established, the researchers note. Less clear is the role that trajectories of activity over time play, although research to date suggests a reduction in risk with increasing activity from mid-life to early old age, they write.

For the current analysis, the researchers assessed 3,099 Italian participants. Mean age was about 75 years, and baseline data were collected from 1995 to 1997.

Follow-up visits were conducted after 4 years and again after 7 years. Using hospital medical records and mortality data, the researchers were able to collect surveillance data through 2018. Hospital records, surveys, and clinical assessments helped them identify incident and prevalent cardiovascular diseases, such as stroke, coronary heart disease, and heart failure.

Participants’ physical activity patterns were classified as stable-high, low-increasing, high-decreasing, and stable-low. Exposure was evaluated at 70, 75, 80, and 85 years of age.

“In our analyses, we focused on moderate to vigorous physical activity, and these include a broad range of exercises, such as walking very briskly, playing tennis, [and] jogging, but comprise also other activities, such as gardening or doing household chores,” said Dr. Amidei.

Patterns of stable-low physical activity were linked to a significantly greater risk for cardiovascular outcomes in men than patterns of stable-high physical activity (hazard ratio, 0.48; 95% confidence interval, 0.27-0.86; P for trend = .002).

No significant relation was found between physical activity and stroke, the researchers note.

“The benefits of physical activity seem to lessen above the age of 75 years and seem more important in men,” noted Dr. Lavie. “This may be partly due to the higher risk of CVD in men. Women typically lag 13 to 15 years behind men for CVD but start catching up in older years.”

Limitations of the study include lack of information regarding physical activity during mid-life, the limited number of stroke events, the relatively few participants older than 85 years, and potential recall bias, the researchers note.

Another limitation was that the physical activity data were based on patient surveys collected 3 years apart and did not involve the use of an accelerometer, the researchers add.

“Future observational studies are required to confirm our findings and pathophysiological studies are warranted to examine the underlying biological mechanisms. Physical activity is likely to be beneficial at any age, but to summarize our findings, we could say that when it comes to being physically active, the sooner the better,” concluded Dr. Amidei.

Dr. Amidei reports no relevant financial relationships.

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

Increasingly active patterns of physical activity were linked with reduced rates of overall mortality and cardiovascular disease (CVD), but early rather than later in late life, in a 20-year follow-up cohort study.

In this population of people older than 65 years, researchers found that physical activity overall was associated with lower rates of incident CVD, particularly among men, and the association was strongest in people 70 to 75 years of age, rather than in older age groups.

They also looked at “trajectories,” or changes in activity over time, and found that a stable-high trajectory of activity was associated with a significantly lower risk for cardiovascular outcomes in men than in those with a stable-low trajectory. For women, more physical activity was consistently associated with lower CVD outcomes, although not statistically significantly so, except for overall mortality, which did reach significance.

Notably, the greatest reduction in cardiovascular risk was reported in people who did more than 20 minutes of physical exercise each day, and it was more pronounced in those 70 years of age.

Physical activity was also associated with a lower incidence of heart failure and coronary heart disease in older people, again especially early on in late life, reported Claudio Barbiellini Amidei, MD, University of Padua, Italy, and colleagues.

The data suggest that physical activity is more effective in preventing CVD onset when implemented early rather than later in life, noted Dr. Amidei in an email.

“The findings of our study are suggestive of a protective effect of physical activity in late-life on cardiovascular health. WHO recommendations for adults and older adults are to practice at least 20 minutes of moderate to vigorous physical activity per day. I believe this is a realistic target, and policy makers should raise awareness on the importance of achieving this goal at all ages, including in late-life,” Dr. Amidei said.

The study was published online Feb. 14 in Heart.

Previous research has demonstrated that the most benefit of high physical activity, compared with low, begins at about 60 years of age, and that is because younger people are at much lower risk, noted Carl “Chip” Lavie MD, FACC, medical director of cardiac rehabilitation and prevention, Ochsner Clinical School–The University of Queensland School of Medicine, New Orleans, who was not involved in the study.

“At quite old ages, for example over age 80, resistance exercise or weight training and balance training may be even more important than aerobic training,” he added.

Activity ‘trajectories’

The benefits of physical activity on cardiovascular risk are well established, the researchers note. Less clear is the role that trajectories of activity over time play, although research to date suggests a reduction in risk with increasing activity from mid-life to early old age, they write.

For the current analysis, the researchers assessed 3,099 Italian participants. Mean age was about 75 years, and baseline data were collected from 1995 to 1997.

Follow-up visits were conducted after 4 years and again after 7 years. Using hospital medical records and mortality data, the researchers were able to collect surveillance data through 2018. Hospital records, surveys, and clinical assessments helped them identify incident and prevalent cardiovascular diseases, such as stroke, coronary heart disease, and heart failure.

Participants’ physical activity patterns were classified as stable-high, low-increasing, high-decreasing, and stable-low. Exposure was evaluated at 70, 75, 80, and 85 years of age.

“In our analyses, we focused on moderate to vigorous physical activity, and these include a broad range of exercises, such as walking very briskly, playing tennis, [and] jogging, but comprise also other activities, such as gardening or doing household chores,” said Dr. Amidei.

Patterns of stable-low physical activity were linked to a significantly greater risk for cardiovascular outcomes in men than patterns of stable-high physical activity (hazard ratio, 0.48; 95% confidence interval, 0.27-0.86; P for trend = .002).

No significant relation was found between physical activity and stroke, the researchers note.

“The benefits of physical activity seem to lessen above the age of 75 years and seem more important in men,” noted Dr. Lavie. “This may be partly due to the higher risk of CVD in men. Women typically lag 13 to 15 years behind men for CVD but start catching up in older years.”

Limitations of the study include lack of information regarding physical activity during mid-life, the limited number of stroke events, the relatively few participants older than 85 years, and potential recall bias, the researchers note.

Another limitation was that the physical activity data were based on patient surveys collected 3 years apart and did not involve the use of an accelerometer, the researchers add.

“Future observational studies are required to confirm our findings and pathophysiological studies are warranted to examine the underlying biological mechanisms. Physical activity is likely to be beneficial at any age, but to summarize our findings, we could say that when it comes to being physically active, the sooner the better,” concluded Dr. Amidei.

Dr. Amidei reports no relevant financial relationships.

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

Earlier menopause appears to be associated with a higher risk of dementia, and earlier onset of dementia, compared with menopause at normal age or later, according to a large study.

“Being aware of this increased risk can help women practice strategies to prevent dementia and to work with their physicians to closely monitor their cognitive status as they age,” study investigator Wenting Hao, MD, with Shandong University, Jinan, China, says in a news release.

The findings were presented in an e-poster March 1 at the Epidemiology, Prevention, Lifestyle & Cardiometabolic Health (EPI|Lifestyle) 2022 conference sponsored by the American Heart Association.
 

UK Biobank data

Dr. Hao and colleagues examined health data for 153,291 women who were 60 years old on average when they became participants in the UK Biobank.

Age at menopause was categorized as premature (younger than age 40), early (40 to 44 years), reference (45 to 51), 52 to 55 years, and 55+ years.

Compared with women who entered menopause around age 50 years (reference), women who experienced premature menopause were 35% more likely to develop some type of dementia later in life (hazard ratio, 1.35; 95% confidence interval, 1.22 to 1.91).

Women with early menopause were also more likely to develop early-onset dementia, that is, before age 65 (HR, 1.31; 95% confidence interval, 1.07 to 1.72).

Women who entered menopause later (at age 52+) had dementia risk similar to women who entered menopause at the average age of 50 to 51 years.

The results were adjusted for relevant cofactors, including age at last exam, race, educational level, cigarette and alcohol use, body mass index, cardiovascular disease, diabetes, income, and leisure and physical activities.

Blame it on estrogen?

Reduced estrogen levels may be a factor in the possible connection between early menopause and dementia, Dr. Hao and her colleagues say.

Estradiol plays a key role in a range of neurological functions, so the reduction of endogenous estrogen at menopause may aggravate brain changes related to neurodegenerative disease and speed up progression of dementia, they explain.

“We know that the lack of estrogen over the long term enhances oxidative stress, which may increase brain aging and lead to cognitive impairment,” Dr. Hao adds.

Limitations of the study include reliance on self-reported information about age at menopause onset.

Also, the researchers did not evaluate dementia rates in women who had a naturally occurring early menopause separate from the women with surgery-induced menopause, which may affect the results.

Finally, the data used for this study included mostly White women living in the U.K. and may not generalize to other populations.
 

Supportive evidence, critical area of research

The U.K. study supports results of a previously reported Kaiser Permanente study, which showed women who entered menopause at age 45 or younger were at 28% greater dementia risk, compared with women who experienced menopause after age 45.

Reached for comment, Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, noted that nearly two-thirds of Americans with Alzheimer’s are women.

“We know Alzheimer’s and other dementias impact a greater number of women than men, but we don’t know why,” she told this news organization.

“Lifelong differences in women may affect their risk or affect what is contributing to their underlying biology of the disease, and we need more research to better understand what may be these contributing factors,” said Dr. Snyder.

“Reproductive history is one critical area being studied. The physical and hormonal changes that occur during menopause – as well as other hormonal changes throughout life – are considerable, and it’s important to understand what impact, if any, these changes may have on the brain,” Dr. Snyder added.

“The potential link between reproduction history and brain health is intriguing, but much more research in this area is needed to understand these links,” she said.

The study was funded by the Start-up Foundation for Scientific Research at Shandong University. Dr. Hao and Dr. Snyder have disclosed no relevant financial relationships.

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

Earlier menopause appears to be associated with a higher risk of dementia, and earlier onset of dementia, compared with menopause at normal age or later, according to a large study.

“Being aware of this increased risk can help women practice strategies to prevent dementia and to work with their physicians to closely monitor their cognitive status as they age,” study investigator Wenting Hao, MD, with Shandong University, Jinan, China, says in a news release.

The findings were presented in an e-poster March 1 at the Epidemiology, Prevention, Lifestyle & Cardiometabolic Health (EPI|Lifestyle) 2022 conference sponsored by the American Heart Association.
 

UK Biobank data

Dr. Hao and colleagues examined health data for 153,291 women who were 60 years old on average when they became participants in the UK Biobank.

Age at menopause was categorized as premature (younger than age 40), early (40 to 44 years), reference (45 to 51), 52 to 55 years, and 55+ years.

Compared with women who entered menopause around age 50 years (reference), women who experienced premature menopause were 35% more likely to develop some type of dementia later in life (hazard ratio, 1.35; 95% confidence interval, 1.22 to 1.91).

Women with early menopause were also more likely to develop early-onset dementia, that is, before age 65 (HR, 1.31; 95% confidence interval, 1.07 to 1.72).

Women who entered menopause later (at age 52+) had dementia risk similar to women who entered menopause at the average age of 50 to 51 years.

The results were adjusted for relevant cofactors, including age at last exam, race, educational level, cigarette and alcohol use, body mass index, cardiovascular disease, diabetes, income, and leisure and physical activities.

Blame it on estrogen?

Reduced estrogen levels may be a factor in the possible connection between early menopause and dementia, Dr. Hao and her colleagues say.

Estradiol plays a key role in a range of neurological functions, so the reduction of endogenous estrogen at menopause may aggravate brain changes related to neurodegenerative disease and speed up progression of dementia, they explain.

“We know that the lack of estrogen over the long term enhances oxidative stress, which may increase brain aging and lead to cognitive impairment,” Dr. Hao adds.

Limitations of the study include reliance on self-reported information about age at menopause onset.

Also, the researchers did not evaluate dementia rates in women who had a naturally occurring early menopause separate from the women with surgery-induced menopause, which may affect the results.

Finally, the data used for this study included mostly White women living in the U.K. and may not generalize to other populations.
 

Supportive evidence, critical area of research

The U.K. study supports results of a previously reported Kaiser Permanente study, which showed women who entered menopause at age 45 or younger were at 28% greater dementia risk, compared with women who experienced menopause after age 45.

Reached for comment, Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, noted that nearly two-thirds of Americans with Alzheimer’s are women.

“We know Alzheimer’s and other dementias impact a greater number of women than men, but we don’t know why,” she told this news organization.

“Lifelong differences in women may affect their risk or affect what is contributing to their underlying biology of the disease, and we need more research to better understand what may be these contributing factors,” said Dr. Snyder.

“Reproductive history is one critical area being studied. The physical and hormonal changes that occur during menopause – as well as other hormonal changes throughout life – are considerable, and it’s important to understand what impact, if any, these changes may have on the brain,” Dr. Snyder added.

“The potential link between reproduction history and brain health is intriguing, but much more research in this area is needed to understand these links,” she said.

The study was funded by the Start-up Foundation for Scientific Research at Shandong University. Dr. Hao and Dr. Snyder have disclosed no relevant financial relationships.

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

Earlier menopause appears to be associated with a higher risk of dementia, and earlier onset of dementia, compared with menopause at normal age or later, according to a large study.

“Being aware of this increased risk can help women practice strategies to prevent dementia and to work with their physicians to closely monitor their cognitive status as they age,” study investigator Wenting Hao, MD, with Shandong University, Jinan, China, says in a news release.

The findings were presented in an e-poster March 1 at the Epidemiology, Prevention, Lifestyle & Cardiometabolic Health (EPI|Lifestyle) 2022 conference sponsored by the American Heart Association.
 

UK Biobank data

Dr. Hao and colleagues examined health data for 153,291 women who were 60 years old on average when they became participants in the UK Biobank.

Age at menopause was categorized as premature (younger than age 40), early (40 to 44 years), reference (45 to 51), 52 to 55 years, and 55+ years.

Compared with women who entered menopause around age 50 years (reference), women who experienced premature menopause were 35% more likely to develop some type of dementia later in life (hazard ratio, 1.35; 95% confidence interval, 1.22 to 1.91).

Women with early menopause were also more likely to develop early-onset dementia, that is, before age 65 (HR, 1.31; 95% confidence interval, 1.07 to 1.72).

Women who entered menopause later (at age 52+) had dementia risk similar to women who entered menopause at the average age of 50 to 51 years.

The results were adjusted for relevant cofactors, including age at last exam, race, educational level, cigarette and alcohol use, body mass index, cardiovascular disease, diabetes, income, and leisure and physical activities.

Blame it on estrogen?

Reduced estrogen levels may be a factor in the possible connection between early menopause and dementia, Dr. Hao and her colleagues say.

Estradiol plays a key role in a range of neurological functions, so the reduction of endogenous estrogen at menopause may aggravate brain changes related to neurodegenerative disease and speed up progression of dementia, they explain.

“We know that the lack of estrogen over the long term enhances oxidative stress, which may increase brain aging and lead to cognitive impairment,” Dr. Hao adds.

Limitations of the study include reliance on self-reported information about age at menopause onset.

Also, the researchers did not evaluate dementia rates in women who had a naturally occurring early menopause separate from the women with surgery-induced menopause, which may affect the results.

Finally, the data used for this study included mostly White women living in the U.K. and may not generalize to other populations.
 

Supportive evidence, critical area of research

The U.K. study supports results of a previously reported Kaiser Permanente study, which showed women who entered menopause at age 45 or younger were at 28% greater dementia risk, compared with women who experienced menopause after age 45.

Reached for comment, Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, noted that nearly two-thirds of Americans with Alzheimer’s are women.

“We know Alzheimer’s and other dementias impact a greater number of women than men, but we don’t know why,” she told this news organization.

“Lifelong differences in women may affect their risk or affect what is contributing to their underlying biology of the disease, and we need more research to better understand what may be these contributing factors,” said Dr. Snyder.

“Reproductive history is one critical area being studied. The physical and hormonal changes that occur during menopause – as well as other hormonal changes throughout life – are considerable, and it’s important to understand what impact, if any, these changes may have on the brain,” Dr. Snyder added.

“The potential link between reproduction history and brain health is intriguing, but much more research in this area is needed to understand these links,” she said.

The study was funded by the Start-up Foundation for Scientific Research at Shandong University. Dr. Hao and Dr. Snyder have disclosed no relevant financial relationships.

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

Research suggests that physicians have suicidal thoughts at about twice the rate of the general population (7.2% vs. 4%). Now, as they bear the weight of a multiyear pandemic alongside the perpetual struggle to maintain some semblance of work-life balance, their resiliency has been stretched to the brink.

In 2022, the Medscape Physician Suicide Report surveyed more than 13,000 physicians in 29 specialties who were candid about their experiences with suicidal thoughts, how they support their besieged colleagues, and their go-to coping strategies.

Overall, 21% of physicians reported having feelings of depression. Of those, 24% had clinical depression and 64% had colloquial depression. Physicians who felt sad or blue decreased slightly, compared with the 2021 report, but the number of physicians experiencing severe depression rose 4%.

One in 10 physicians said they have thought about or attempted suicide. However, the number of physicians with suicidal thoughts dropped to 9%, down substantially from the 22% who reported similar feelings in 2020.

Still, there was a slight uptick in women physicians contemplating suicide, likely linked to their larger share of childcare and family responsibilities.

Washington University School of Medicine

“They have needed to pull double duty even more than usual, and that may have increased their sense of burnout and vulnerability to suicidal thoughts,” said Andrea Giedinghagen, MD, assistant professor in the department of psychiatry at Washington University in St. Louis, and coauthor of “Physician Suicide: A Call to Action
 

Fighting the stigma of seeking mental health help

Although the number of physicians attempting, but not completing suicide, has remained steady at 1% for several years, the recent passage of the Dr. Lorna Breen Health Care Provider Protection Act by Congress aims to drive that figure even lower. Dr. Breen, an ED physician at New York–Presbyterian Hospital, died by suicide in April 2020. Overwhelmed by the onslaught of COVID patients, Dr. Breen was reluctant to seek mental health services for fear of being ostracized.

“Many physicians don’t seek mental health care due to fear of negative consequences in the workplace, including retribution, exclusion, loss of license, or even their job,” Gary Price, MD, president of The Physicians Foundation, told this news organization. “This was the experience of Dr. Lorna Breen. She was convinced that if she talked to a professional, she would lose her medical license. Perhaps if Dr. Breen was equipped with the accurate information – there is no mental health reporting requirement in her state’s medical license application – it might have saved her life.”

This same stigma was reflected in the survey, with one physician saying: “I’m afraid that if I spoke to a therapist, I’d have to report receiving psychiatric treatment to credentialing or licensing boards.” Roughly 40% of survey respondents, regardless of age, chose not to disclose their suicidal thoughts to anyone, not even a family member or suicide hotline. And just a tiny portion of physicians (10% of men and 13% of women) said that a colleague had discussed their suicidal thoughts with them.

“There is a longstanding culture of silence around physician mental health in the medical community,” said Dr. Price. “The strategies within the Act are critical to fixing this culture and making it acceptable and normalized for physicians to seek mental health care,” and for it to “become a fundamental and ongoing element of being a practicing physician.”

As part of the legislation, the Department of Health & Human Services must award grants to hospitals, medical associations, and other entities to facilitate mental health programs for providers. They must also establish policy recommendations and conduct campaigns to improve providers’ mental and behavioral health, encourage providers to seek mental health support and assistance, remove barriers to such treatment, and identify best practices to prevent suicide and promote resiliency
 

Addressing barriers to mental health

The new bill is a step in the right direction, but Dr. Price said health organizations must do more to address the six key structural barriers that are “discouraging physicians from seeking [mental health] help,” such as the inclusion of “intrusive mental health questions on medical board, hospital credentialing, and malpractice insurance applications.”

In addition, employers should allow physicians to seek out-of-network mental health services, if necessary, and not cause further humiliation by requiring them to be treated by colleagues within their hospital system. A similar proposal has recently been introduced and is gaining traction in Utah, following the suicide of ED physician Scott Jolley, MD, in 2021 after he was admitted for psychiatric care where he worked.

Diminishing the stigma surrounding physicians’ mental health encourages a more open dialogue, so if a colleague reaches out – listen. “Start by thanking the colleague for sharing the information: ‘I’m sure that wasn’t easy but I appreciate that you respect me enough to share this. Let’s talk more,’ ” said Michael F. Myers, MD, professor of clinical psychiatry at State University of New York, Brooklyn . “Then ask what you can do to help, which cuts down on the sense of isolation that colleague may feel.”

According to the survey, many physicians have developed strategies to support their happiness and mental health. Although fewer than 10% said reducing work hours or transitioning to a part-time schedule was most effective, the majority of physicians relied on spending time with family and friends (68%) – a choice that has considerable benefits.

“Close and intimate relationships are the single most protective factor for our mental health,” said Peter Yellowlees, MBBS, MD, chief wellness officer for UC Davis Health and professor of psychiatry at the University of California, Davis. “Isolation and loneliness are very important stressors, and we know that about 25% of the population reports being lonely.”

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

Research suggests that physicians have suicidal thoughts at about twice the rate of the general population (7.2% vs. 4%). Now, as they bear the weight of a multiyear pandemic alongside the perpetual struggle to maintain some semblance of work-life balance, their resiliency has been stretched to the brink.

In 2022, the Medscape Physician Suicide Report surveyed more than 13,000 physicians in 29 specialties who were candid about their experiences with suicidal thoughts, how they support their besieged colleagues, and their go-to coping strategies.

Overall, 21% of physicians reported having feelings of depression. Of those, 24% had clinical depression and 64% had colloquial depression. Physicians who felt sad or blue decreased slightly, compared with the 2021 report, but the number of physicians experiencing severe depression rose 4%.

One in 10 physicians said they have thought about or attempted suicide. However, the number of physicians with suicidal thoughts dropped to 9%, down substantially from the 22% who reported similar feelings in 2020.

Still, there was a slight uptick in women physicians contemplating suicide, likely linked to their larger share of childcare and family responsibilities.

Washington University School of Medicine

“They have needed to pull double duty even more than usual, and that may have increased their sense of burnout and vulnerability to suicidal thoughts,” said Andrea Giedinghagen, MD, assistant professor in the department of psychiatry at Washington University in St. Louis, and coauthor of “Physician Suicide: A Call to Action
 

Fighting the stigma of seeking mental health help

Although the number of physicians attempting, but not completing suicide, has remained steady at 1% for several years, the recent passage of the Dr. Lorna Breen Health Care Provider Protection Act by Congress aims to drive that figure even lower. Dr. Breen, an ED physician at New York–Presbyterian Hospital, died by suicide in April 2020. Overwhelmed by the onslaught of COVID patients, Dr. Breen was reluctant to seek mental health services for fear of being ostracized.

“Many physicians don’t seek mental health care due to fear of negative consequences in the workplace, including retribution, exclusion, loss of license, or even their job,” Gary Price, MD, president of The Physicians Foundation, told this news organization. “This was the experience of Dr. Lorna Breen. She was convinced that if she talked to a professional, she would lose her medical license. Perhaps if Dr. Breen was equipped with the accurate information – there is no mental health reporting requirement in her state’s medical license application – it might have saved her life.”

This same stigma was reflected in the survey, with one physician saying: “I’m afraid that if I spoke to a therapist, I’d have to report receiving psychiatric treatment to credentialing or licensing boards.” Roughly 40% of survey respondents, regardless of age, chose not to disclose their suicidal thoughts to anyone, not even a family member or suicide hotline. And just a tiny portion of physicians (10% of men and 13% of women) said that a colleague had discussed their suicidal thoughts with them.

“There is a longstanding culture of silence around physician mental health in the medical community,” said Dr. Price. “The strategies within the Act are critical to fixing this culture and making it acceptable and normalized for physicians to seek mental health care,” and for it to “become a fundamental and ongoing element of being a practicing physician.”

As part of the legislation, the Department of Health & Human Services must award grants to hospitals, medical associations, and other entities to facilitate mental health programs for providers. They must also establish policy recommendations and conduct campaigns to improve providers’ mental and behavioral health, encourage providers to seek mental health support and assistance, remove barriers to such treatment, and identify best practices to prevent suicide and promote resiliency
 

Addressing barriers to mental health

The new bill is a step in the right direction, but Dr. Price said health organizations must do more to address the six key structural barriers that are “discouraging physicians from seeking [mental health] help,” such as the inclusion of “intrusive mental health questions on medical board, hospital credentialing, and malpractice insurance applications.”

In addition, employers should allow physicians to seek out-of-network mental health services, if necessary, and not cause further humiliation by requiring them to be treated by colleagues within their hospital system. A similar proposal has recently been introduced and is gaining traction in Utah, following the suicide of ED physician Scott Jolley, MD, in 2021 after he was admitted for psychiatric care where he worked.

Diminishing the stigma surrounding physicians’ mental health encourages a more open dialogue, so if a colleague reaches out – listen. “Start by thanking the colleague for sharing the information: ‘I’m sure that wasn’t easy but I appreciate that you respect me enough to share this. Let’s talk more,’ ” said Michael F. Myers, MD, professor of clinical psychiatry at State University of New York, Brooklyn . “Then ask what you can do to help, which cuts down on the sense of isolation that colleague may feel.”

According to the survey, many physicians have developed strategies to support their happiness and mental health. Although fewer than 10% said reducing work hours or transitioning to a part-time schedule was most effective, the majority of physicians relied on spending time with family and friends (68%) – a choice that has considerable benefits.

“Close and intimate relationships are the single most protective factor for our mental health,” said Peter Yellowlees, MBBS, MD, chief wellness officer for UC Davis Health and professor of psychiatry at the University of California, Davis. “Isolation and loneliness are very important stressors, and we know that about 25% of the population reports being lonely.”

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

Research suggests that physicians have suicidal thoughts at about twice the rate of the general population (7.2% vs. 4%). Now, as they bear the weight of a multiyear pandemic alongside the perpetual struggle to maintain some semblance of work-life balance, their resiliency has been stretched to the brink.

In 2022, the Medscape Physician Suicide Report surveyed more than 13,000 physicians in 29 specialties who were candid about their experiences with suicidal thoughts, how they support their besieged colleagues, and their go-to coping strategies.

Overall, 21% of physicians reported having feelings of depression. Of those, 24% had clinical depression and 64% had colloquial depression. Physicians who felt sad or blue decreased slightly, compared with the 2021 report, but the number of physicians experiencing severe depression rose 4%.

One in 10 physicians said they have thought about or attempted suicide. However, the number of physicians with suicidal thoughts dropped to 9%, down substantially from the 22% who reported similar feelings in 2020.

Still, there was a slight uptick in women physicians contemplating suicide, likely linked to their larger share of childcare and family responsibilities.

Washington University School of Medicine

“They have needed to pull double duty even more than usual, and that may have increased their sense of burnout and vulnerability to suicidal thoughts,” said Andrea Giedinghagen, MD, assistant professor in the department of psychiatry at Washington University in St. Louis, and coauthor of “Physician Suicide: A Call to Action
 

Fighting the stigma of seeking mental health help

Although the number of physicians attempting, but not completing suicide, has remained steady at 1% for several years, the recent passage of the Dr. Lorna Breen Health Care Provider Protection Act by Congress aims to drive that figure even lower. Dr. Breen, an ED physician at New York–Presbyterian Hospital, died by suicide in April 2020. Overwhelmed by the onslaught of COVID patients, Dr. Breen was reluctant to seek mental health services for fear of being ostracized.

“Many physicians don’t seek mental health care due to fear of negative consequences in the workplace, including retribution, exclusion, loss of license, or even their job,” Gary Price, MD, president of The Physicians Foundation, told this news organization. “This was the experience of Dr. Lorna Breen. She was convinced that if she talked to a professional, she would lose her medical license. Perhaps if Dr. Breen was equipped with the accurate information – there is no mental health reporting requirement in her state’s medical license application – it might have saved her life.”

This same stigma was reflected in the survey, with one physician saying: “I’m afraid that if I spoke to a therapist, I’d have to report receiving psychiatric treatment to credentialing or licensing boards.” Roughly 40% of survey respondents, regardless of age, chose not to disclose their suicidal thoughts to anyone, not even a family member or suicide hotline. And just a tiny portion of physicians (10% of men and 13% of women) said that a colleague had discussed their suicidal thoughts with them.

“There is a longstanding culture of silence around physician mental health in the medical community,” said Dr. Price. “The strategies within the Act are critical to fixing this culture and making it acceptable and normalized for physicians to seek mental health care,” and for it to “become a fundamental and ongoing element of being a practicing physician.”

As part of the legislation, the Department of Health & Human Services must award grants to hospitals, medical associations, and other entities to facilitate mental health programs for providers. They must also establish policy recommendations and conduct campaigns to improve providers’ mental and behavioral health, encourage providers to seek mental health support and assistance, remove barriers to such treatment, and identify best practices to prevent suicide and promote resiliency
 

Addressing barriers to mental health

The new bill is a step in the right direction, but Dr. Price said health organizations must do more to address the six key structural barriers that are “discouraging physicians from seeking [mental health] help,” such as the inclusion of “intrusive mental health questions on medical board, hospital credentialing, and malpractice insurance applications.”

In addition, employers should allow physicians to seek out-of-network mental health services, if necessary, and not cause further humiliation by requiring them to be treated by colleagues within their hospital system. A similar proposal has recently been introduced and is gaining traction in Utah, following the suicide of ED physician Scott Jolley, MD, in 2021 after he was admitted for psychiatric care where he worked.

Diminishing the stigma surrounding physicians’ mental health encourages a more open dialogue, so if a colleague reaches out – listen. “Start by thanking the colleague for sharing the information: ‘I’m sure that wasn’t easy but I appreciate that you respect me enough to share this. Let’s talk more,’ ” said Michael F. Myers, MD, professor of clinical psychiatry at State University of New York, Brooklyn . “Then ask what you can do to help, which cuts down on the sense of isolation that colleague may feel.”

According to the survey, many physicians have developed strategies to support their happiness and mental health. Although fewer than 10% said reducing work hours or transitioning to a part-time schedule was most effective, the majority of physicians relied on spending time with family and friends (68%) – a choice that has considerable benefits.

“Close and intimate relationships are the single most protective factor for our mental health,” said Peter Yellowlees, MBBS, MD, chief wellness officer for UC Davis Health and professor of psychiatry at the University of California, Davis. “Isolation and loneliness are very important stressors, and we know that about 25% of the population reports being lonely.”

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

Patients with familial hypercholesterolemia (FH) who start lipid-lowering treatment earlier in life may reduce their cardiovascular risk, compared with those who don’t begin treatment early, according to results of a recent meta-analysis.

They showed a difference in the carotid intima-media thickness (IMT) between patients with and without FH that increased with age, but there was also a difference in IMT seen among patients with FH who started treatment early, compared with untreated patients with FH, Kika van Bergen en Henegouwen, of the departments of pediatrics and epidemiology and data science at Amsterdam University Medical Center, and colleagues wrote in their report, published in the Journal of Clinical Lipidology.

“The fact that the difference in IMT increases with age between FH patients and unaffected controls, and is more pronounced in studies with untreated FH patients than in studies with treated patients, suggests that starting treatment already at a young age in patients with FH is preferred,” the researchers wrote. “However, despite treatment, IMT in treated FH patients is still thicker in comparison to subjects without FH.”

The researchers identified 42 studies with among patients with FH and healthy control groups across the MEDLINE, EMBASE and Trials.gov databases up to a cutoff date of April 2020, with 39 studies specifically examining carotid IMT, 2 studies evaluating carotid and femoral IMT, and 1 study evaluating femoral IMT alone. Overall, the researchers examined IMT measurements in 3,796 patients with FH and 2,363 control group participants.

Although data on age and gender for FH and control groups were not available in 6 studies, the mean age ranged from 9 to 57 years for patients with FH and from 8 to 61 years in the control group. Men comprised just under half of both the FH and control groups.

The mean between-group difference in carotid IMT in 34 studies was 0.11 mm (95% confidence interval, 0.06-0.15 mm; P < .001) for patients with FH, compared with the control group, while the mean difference in femoral IMT in three studies was 0.47 mm (95% CI, 0.19-0.74 mm; P < .001) between FH and control groups.

In 13 studies in which data on differences between partly treated and untreated FH were available, there was a significant between-group difference in carotid IMT with partly treated patients with FH, compared with the control group (0.05 mm; 95% CI, 0.03-0.08 mm; P < .001), but a larger mean between-group difference in carotid IMT among untreated patients with FH, compared with a control group (0.12 mm; 95% CI, 0.03-0.21 mm; P = .009).

The researchers also analyzed how age impacts carotid IMT, and they found patients with FH had a mean increase of 0.0018 mm (95% CI, –0.0007 to 0.0042 mm) over a control group in 34 studies. For patients with partly treated FH, compared with patients with untreated FH, the mean between-group increase per year was smaller (0.0023 mm; 95% CI, 0.0021-0.0025 mm), compared with the control group (0.0104 mm; 95% CI, 0.0100-0.0108 mm).

“This sign of residual risk might suggest that more robust cholesterol-lowering treatment and achieving treatment targets, or earlier treatment initiation, is needed to reduce IMT progression to non-FH conditions,” the researchers said. “Therefore, we must find and diagnose these patients, and treat them according to current guidelines.”

Limitations of the authors’ meta-analyses include heterogeneity among studies, differences in IMT measurement protocols, and inclusion of studies with an open-label design. Although randomized clinical trials would be preferable to compare treatment effect, “since statin therapy is indicated in FH patients to reduce [cardiovascular disease], it would be unethical to have a placebo group,” they said.

The authors reported no relevant financial disclosures.

Patients with familial hypercholesterolemia (FH) who start lipid-lowering treatment earlier in life may reduce their cardiovascular risk, compared with those who don’t begin treatment early, according to results of a recent meta-analysis.

They showed a difference in the carotid intima-media thickness (IMT) between patients with and without FH that increased with age, but there was also a difference in IMT seen among patients with FH who started treatment early, compared with untreated patients with FH, Kika van Bergen en Henegouwen, of the departments of pediatrics and epidemiology and data science at Amsterdam University Medical Center, and colleagues wrote in their report, published in the Journal of Clinical Lipidology.

“The fact that the difference in IMT increases with age between FH patients and unaffected controls, and is more pronounced in studies with untreated FH patients than in studies with treated patients, suggests that starting treatment already at a young age in patients with FH is preferred,” the researchers wrote. “However, despite treatment, IMT in treated FH patients is still thicker in comparison to subjects without FH.”

The researchers identified 42 studies with among patients with FH and healthy control groups across the MEDLINE, EMBASE and Trials.gov databases up to a cutoff date of April 2020, with 39 studies specifically examining carotid IMT, 2 studies evaluating carotid and femoral IMT, and 1 study evaluating femoral IMT alone. Overall, the researchers examined IMT measurements in 3,796 patients with FH and 2,363 control group participants.

Although data on age and gender for FH and control groups were not available in 6 studies, the mean age ranged from 9 to 57 years for patients with FH and from 8 to 61 years in the control group. Men comprised just under half of both the FH and control groups.

The mean between-group difference in carotid IMT in 34 studies was 0.11 mm (95% confidence interval, 0.06-0.15 mm; P < .001) for patients with FH, compared with the control group, while the mean difference in femoral IMT in three studies was 0.47 mm (95% CI, 0.19-0.74 mm; P < .001) between FH and control groups.

In 13 studies in which data on differences between partly treated and untreated FH were available, there was a significant between-group difference in carotid IMT with partly treated patients with FH, compared with the control group (0.05 mm; 95% CI, 0.03-0.08 mm; P < .001), but a larger mean between-group difference in carotid IMT among untreated patients with FH, compared with a control group (0.12 mm; 95% CI, 0.03-0.21 mm; P = .009).

The researchers also analyzed how age impacts carotid IMT, and they found patients with FH had a mean increase of 0.0018 mm (95% CI, –0.0007 to 0.0042 mm) over a control group in 34 studies. For patients with partly treated FH, compared with patients with untreated FH, the mean between-group increase per year was smaller (0.0023 mm; 95% CI, 0.0021-0.0025 mm), compared with the control group (0.0104 mm; 95% CI, 0.0100-0.0108 mm).

“This sign of residual risk might suggest that more robust cholesterol-lowering treatment and achieving treatment targets, or earlier treatment initiation, is needed to reduce IMT progression to non-FH conditions,” the researchers said. “Therefore, we must find and diagnose these patients, and treat them according to current guidelines.”

Limitations of the authors’ meta-analyses include heterogeneity among studies, differences in IMT measurement protocols, and inclusion of studies with an open-label design. Although randomized clinical trials would be preferable to compare treatment effect, “since statin therapy is indicated in FH patients to reduce [cardiovascular disease], it would be unethical to have a placebo group,” they said.

The authors reported no relevant financial disclosures.

Patients with familial hypercholesterolemia (FH) who start lipid-lowering treatment earlier in life may reduce their cardiovascular risk, compared with those who don’t begin treatment early, according to results of a recent meta-analysis.

They showed a difference in the carotid intima-media thickness (IMT) between patients with and without FH that increased with age, but there was also a difference in IMT seen among patients with FH who started treatment early, compared with untreated patients with FH, Kika van Bergen en Henegouwen, of the departments of pediatrics and epidemiology and data science at Amsterdam University Medical Center, and colleagues wrote in their report, published in the Journal of Clinical Lipidology.

“The fact that the difference in IMT increases with age between FH patients and unaffected controls, and is more pronounced in studies with untreated FH patients than in studies with treated patients, suggests that starting treatment already at a young age in patients with FH is preferred,” the researchers wrote. “However, despite treatment, IMT in treated FH patients is still thicker in comparison to subjects without FH.”

The researchers identified 42 studies with among patients with FH and healthy control groups across the MEDLINE, EMBASE and Trials.gov databases up to a cutoff date of April 2020, with 39 studies specifically examining carotid IMT, 2 studies evaluating carotid and femoral IMT, and 1 study evaluating femoral IMT alone. Overall, the researchers examined IMT measurements in 3,796 patients with FH and 2,363 control group participants.

Although data on age and gender for FH and control groups were not available in 6 studies, the mean age ranged from 9 to 57 years for patients with FH and from 8 to 61 years in the control group. Men comprised just under half of both the FH and control groups.

The mean between-group difference in carotid IMT in 34 studies was 0.11 mm (95% confidence interval, 0.06-0.15 mm; P < .001) for patients with FH, compared with the control group, while the mean difference in femoral IMT in three studies was 0.47 mm (95% CI, 0.19-0.74 mm; P < .001) between FH and control groups.

In 13 studies in which data on differences between partly treated and untreated FH were available, there was a significant between-group difference in carotid IMT with partly treated patients with FH, compared with the control group (0.05 mm; 95% CI, 0.03-0.08 mm; P < .001), but a larger mean between-group difference in carotid IMT among untreated patients with FH, compared with a control group (0.12 mm; 95% CI, 0.03-0.21 mm; P = .009).

The researchers also analyzed how age impacts carotid IMT, and they found patients with FH had a mean increase of 0.0018 mm (95% CI, –0.0007 to 0.0042 mm) over a control group in 34 studies. For patients with partly treated FH, compared with patients with untreated FH, the mean between-group increase per year was smaller (0.0023 mm; 95% CI, 0.0021-0.0025 mm), compared with the control group (0.0104 mm; 95% CI, 0.0100-0.0108 mm).

“This sign of residual risk might suggest that more robust cholesterol-lowering treatment and achieving treatment targets, or earlier treatment initiation, is needed to reduce IMT progression to non-FH conditions,” the researchers said. “Therefore, we must find and diagnose these patients, and treat them according to current guidelines.”

Limitations of the authors’ meta-analyses include heterogeneity among studies, differences in IMT measurement protocols, and inclusion of studies with an open-label design. Although randomized clinical trials would be preferable to compare treatment effect, “since statin therapy is indicated in FH patients to reduce [cardiovascular disease], it would be unethical to have a placebo group,” they said.

The authors reported no relevant financial disclosures.

The prevalence of metabolic syndrome varies according to how it is defined, but approximately 30% of psoriatic arthritis (PsA) patients met the criteria in a cohort study of 724 individuals, as did approximately 23%-63% of patients across multiple studies, investigators from Spain report.

Previous studies of people with PsA in particular suggest they are at an increased risk of cardiovascular disease and have a higher prevalence of metabolic syndrome, prompting recommendations on cardiovascular risk management for patients with PsA, wrote the authors, Ana Urruticoechea-Arana, MD, of the department of rheumatology, Hospital Can Misses, Ibiza, Spain, and colleagues.

However, assessing the prevalence of metabolic syndrome remains a challenge because the definition varies across studies, they noted.

For a more thorough assessment of the prevalence of metabolic syndrome in this population, the researchers conducted a study using two sources: a systematic literature review of 18 studies published up to March 2019, and data on patients with PsA enrolled in the CARMA (Spanish Cardiovascular in Rheumatology) project, a longitudinal cohort observational study of adults with inflammatory diseases in Spain. The findings were published March 1 in the Journal of Clinical Rheumatology.

The literature review included a total of a total of 2,452 patients with PsA, with a mean age between 42 and 59 years, and a mean disease duration ranging from 3 to 14 years.

The definitions of metabolic syndrome varied; the most common was the definition from the National Cholesterol Education Program (NECP ATP III). Other definitions used in the studies included those issued by the International Diabetes Federation, the World Health Organization, and the American Heart Association.

Across these studies, the rate of metabolic syndrome ranged from 23.5% to 62.9%. Prevalence was similar between men and women. One study that included patients with a PsA disease duration of only 3 years showed a prevalence of 38%, similar to the average prevalence overall. Another study showed a significantly higher prevalence of metabolic syndrome in patients with PsA and cutaneous psoriasis, compared with those without psoriasis (40.8% vs. 13.16%; P = .006).

The CARMA study included 724 patients with PsA; 45.4% were women and 21.8% were smokers. The mean age of the population in this study was 51 years, and the mean disease duration was 9 years. Overall, 222 patients (30.7%) met at least three criteria for metabolic syndrome, based on the NCEP ATP III definition. The most common abnormal findings for traditional cardiovascular risk factors in the CARMA cohort were high blood pressure (66.8%), hyperglycemia (42.6%), and hypertriglyceridemia (30.6%).

Despite the variation in prevalence of metabolic syndrome, depending on the definition used, the authors wrote, “It can be stated that the rate of [metabolic syndrome] in patients with PsA is in general very high, especially if we take into account the mean age of patients included in the studies.”

“These findings support the hypotheses that this increase in the inflammatory pathway in PsA may contribute a higher risk of cardiovascular events and [metabolic syndrome] in patients with PsA than patients with psoriasis alone, the risk being even higher in severe PsA,” and that insulin resistance, metabolic syndrome, and atherosclerotic events “may have a common inflammatory basis,” the researchers wrote in their discussion of the results.

The study findings were limited by several factors, most importantly the variation in definitions of metabolic syndrome in the literature review, which limits the generalizability of the results, the researchers said. Limitations of the CARMA study include the focus only on patients who were being cared for in hospitals, which might yield an overestimation of metabolic syndrome, they added.

However, the results support findings from previous studies and highlight the need for proper assessment of body weight and cardiovascular risk factors in patients with PsA at the onset of disease, they said.

“Furthermore, it is necessary to conduct more research to standardize (and modify as appropriate) the definition of [metabolic syndrome] and establish the best strategy for managing it in these patients,” they concluded.

The study was funded by an independent grant from UCB Pharma. One author disclosed receiving grants from Pfizer, Abbvie, Novartis, Roche, UCB, Sanofi, BMS, Lilly, MSD, and Janssen. Lead author Dr. Urruticoechea-Arana and the other authors had no disclosures.

The prevalence of metabolic syndrome varies according to how it is defined, but approximately 30% of psoriatic arthritis (PsA) patients met the criteria in a cohort study of 724 individuals, as did approximately 23%-63% of patients across multiple studies, investigators from Spain report.

Previous studies of people with PsA in particular suggest they are at an increased risk of cardiovascular disease and have a higher prevalence of metabolic syndrome, prompting recommendations on cardiovascular risk management for patients with PsA, wrote the authors, Ana Urruticoechea-Arana, MD, of the department of rheumatology, Hospital Can Misses, Ibiza, Spain, and colleagues.

However, assessing the prevalence of metabolic syndrome remains a challenge because the definition varies across studies, they noted.

For a more thorough assessment of the prevalence of metabolic syndrome in this population, the researchers conducted a study using two sources: a systematic literature review of 18 studies published up to March 2019, and data on patients with PsA enrolled in the CARMA (Spanish Cardiovascular in Rheumatology) project, a longitudinal cohort observational study of adults with inflammatory diseases in Spain. The findings were published March 1 in the Journal of Clinical Rheumatology.

The literature review included a total of a total of 2,452 patients with PsA, with a mean age between 42 and 59 years, and a mean disease duration ranging from 3 to 14 years.

The definitions of metabolic syndrome varied; the most common was the definition from the National Cholesterol Education Program (NECP ATP III). Other definitions used in the studies included those issued by the International Diabetes Federation, the World Health Organization, and the American Heart Association.

Across these studies, the rate of metabolic syndrome ranged from 23.5% to 62.9%. Prevalence was similar between men and women. One study that included patients with a PsA disease duration of only 3 years showed a prevalence of 38%, similar to the average prevalence overall. Another study showed a significantly higher prevalence of metabolic syndrome in patients with PsA and cutaneous psoriasis, compared with those without psoriasis (40.8% vs. 13.16%; P = .006).

The CARMA study included 724 patients with PsA; 45.4% were women and 21.8% were smokers. The mean age of the population in this study was 51 years, and the mean disease duration was 9 years. Overall, 222 patients (30.7%) met at least three criteria for metabolic syndrome, based on the NCEP ATP III definition. The most common abnormal findings for traditional cardiovascular risk factors in the CARMA cohort were high blood pressure (66.8%), hyperglycemia (42.6%), and hypertriglyceridemia (30.6%).

Despite the variation in prevalence of metabolic syndrome, depending on the definition used, the authors wrote, “It can be stated that the rate of [metabolic syndrome] in patients with PsA is in general very high, especially if we take into account the mean age of patients included in the studies.”

“These findings support the hypotheses that this increase in the inflammatory pathway in PsA may contribute a higher risk of cardiovascular events and [metabolic syndrome] in patients with PsA than patients with psoriasis alone, the risk being even higher in severe PsA,” and that insulin resistance, metabolic syndrome, and atherosclerotic events “may have a common inflammatory basis,” the researchers wrote in their discussion of the results.

The study findings were limited by several factors, most importantly the variation in definitions of metabolic syndrome in the literature review, which limits the generalizability of the results, the researchers said. Limitations of the CARMA study include the focus only on patients who were being cared for in hospitals, which might yield an overestimation of metabolic syndrome, they added.

However, the results support findings from previous studies and highlight the need for proper assessment of body weight and cardiovascular risk factors in patients with PsA at the onset of disease, they said.

“Furthermore, it is necessary to conduct more research to standardize (and modify as appropriate) the definition of [metabolic syndrome] and establish the best strategy for managing it in these patients,” they concluded.

The study was funded by an independent grant from UCB Pharma. One author disclosed receiving grants from Pfizer, Abbvie, Novartis, Roche, UCB, Sanofi, BMS, Lilly, MSD, and Janssen. Lead author Dr. Urruticoechea-Arana and the other authors had no disclosures.

The prevalence of metabolic syndrome varies according to how it is defined, but approximately 30% of psoriatic arthritis (PsA) patients met the criteria in a cohort study of 724 individuals, as did approximately 23%-63% of patients across multiple studies, investigators from Spain report.

Previous studies of people with PsA in particular suggest they are at an increased risk of cardiovascular disease and have a higher prevalence of metabolic syndrome, prompting recommendations on cardiovascular risk management for patients with PsA, wrote the authors, Ana Urruticoechea-Arana, MD, of the department of rheumatology, Hospital Can Misses, Ibiza, Spain, and colleagues.

However, assessing the prevalence of metabolic syndrome remains a challenge because the definition varies across studies, they noted.

For a more thorough assessment of the prevalence of metabolic syndrome in this population, the researchers conducted a study using two sources: a systematic literature review of 18 studies published up to March 2019, and data on patients with PsA enrolled in the CARMA (Spanish Cardiovascular in Rheumatology) project, a longitudinal cohort observational study of adults with inflammatory diseases in Spain. The findings were published March 1 in the Journal of Clinical Rheumatology.

The literature review included a total of a total of 2,452 patients with PsA, with a mean age between 42 and 59 years, and a mean disease duration ranging from 3 to 14 years.

The definitions of metabolic syndrome varied; the most common was the definition from the National Cholesterol Education Program (NECP ATP III). Other definitions used in the studies included those issued by the International Diabetes Federation, the World Health Organization, and the American Heart Association.

Across these studies, the rate of metabolic syndrome ranged from 23.5% to 62.9%. Prevalence was similar between men and women. One study that included patients with a PsA disease duration of only 3 years showed a prevalence of 38%, similar to the average prevalence overall. Another study showed a significantly higher prevalence of metabolic syndrome in patients with PsA and cutaneous psoriasis, compared with those without psoriasis (40.8% vs. 13.16%; P = .006).

The CARMA study included 724 patients with PsA; 45.4% were women and 21.8% were smokers. The mean age of the population in this study was 51 years, and the mean disease duration was 9 years. Overall, 222 patients (30.7%) met at least three criteria for metabolic syndrome, based on the NCEP ATP III definition. The most common abnormal findings for traditional cardiovascular risk factors in the CARMA cohort were high blood pressure (66.8%), hyperglycemia (42.6%), and hypertriglyceridemia (30.6%).

Despite the variation in prevalence of metabolic syndrome, depending on the definition used, the authors wrote, “It can be stated that the rate of [metabolic syndrome] in patients with PsA is in general very high, especially if we take into account the mean age of patients included in the studies.”

“These findings support the hypotheses that this increase in the inflammatory pathway in PsA may contribute a higher risk of cardiovascular events and [metabolic syndrome] in patients with PsA than patients with psoriasis alone, the risk being even higher in severe PsA,” and that insulin resistance, metabolic syndrome, and atherosclerotic events “may have a common inflammatory basis,” the researchers wrote in their discussion of the results.

The study findings were limited by several factors, most importantly the variation in definitions of metabolic syndrome in the literature review, which limits the generalizability of the results, the researchers said. Limitations of the CARMA study include the focus only on patients who were being cared for in hospitals, which might yield an overestimation of metabolic syndrome, they added.

However, the results support findings from previous studies and highlight the need for proper assessment of body weight and cardiovascular risk factors in patients with PsA at the onset of disease, they said.

“Furthermore, it is necessary to conduct more research to standardize (and modify as appropriate) the definition of [metabolic syndrome] and establish the best strategy for managing it in these patients,” they concluded.

The study was funded by an independent grant from UCB Pharma. One author disclosed receiving grants from Pfizer, Abbvie, Novartis, Roche, UCB, Sanofi, BMS, Lilly, MSD, and Janssen. Lead author Dr. Urruticoechea-Arana and the other authors had no disclosures.

The debate on whether the popular class of antihypertensive drugs, angiotensin receptor blockers (ARBs), may be associated with an increased risk for cancer has been reopened with the publication of a new meta-analysis.

The analysis found an increasing risk for cancer, and specifically lung cancer, with increasing cumulative exposure to these drugs.

The findings are reported in a study published online in PLOS ONE.

The author of this new meta-analysis is Ilke Sipahi, MD, a cardiologist from Acibadem University Medical School, Istanbul, who previously raised this issue in an initial meta-analysis published in 2010.

“The new meta-analysis is important because it is the first study to investigate whether there is a dose response in the association between ARBs and cancer,” Dr. Sipahi told this news organization.

“I found a clear signal of increased risk of cancer as exposure to ARBs increased, and the association started to become significant when the maximum dose was taken for 3 years,” he added.

Dr. Sipahi explained that in the first meta-analysis published in Lancet Oncology, he and his colleagues reported an increased cancer risk with ARBs based on observations from high-exposure trials – those that included higher doses of ARBs with a long duration of follow-up.

Following this publication, an investigation by the U.S. Food and Drug Administration refuted the risk, and a collaboration of ARB trial investigators also performed an analysis published in the Journal of Hypertension (2011. doi: 10.1097/HJH.0b013e328344a7de), which again did not show an increased risk for cancer with use of ARBs.

Dr. Sipahi claims that those analyses by the FDA and the ARB Trialists Collaboration, which were all trial-level meta-analyses, diluted the “high exposure” data (including higher doses taken for longer periods of time) with a large amount of other data on much lower exposures (lower doses and/or shorter time periods).

“The overall risk would then inevitably become nonsignificant. These analyses also did not look at different exposure levels,” he says.

“For cancer, the degree of exposure is obviously very important. The risk associated with smoking 2 or 3 cigarettes a day for a year is very different from that of smoking 2 packs a day for 40 years. The same principle applies to taking a medication,” Dr. Sipahi asserts.

From these latest data, he estimates that 120 patients needed to be treated with the maximal daily dose of an ARB for 4.7 years for one excess cancer diagnosis, and 464 patients needed to be treated for one excess lung cancer.

“Given that at least 200 million individuals are being treated with an ARB globally, approximately 1.7 million excess cancers (and 430,000 lung cancers) in 4.6 years could be potentially caused by this class of drugs,” he suggests.

For the current analysis, Dr. Sipahi used trial-level data taken from the paper by the ARB Trialists Collaboration and investigated the effect of exposure to ARBs – including both the dose taken and the length of treatment – on risk for cancer. He performed metaregression analyses that he says has not been done before.

“I mathematically quantitated the degree of exposure in each trial. And when the degree of exposure was correlated with risk of cancer, there was a significant association.”

The new meta-analysis includes 15 randomized controlled trials. The two coprimary outcomes were the relationship between cumulative exposure to ARBs and risk for all cancers combined and the relationship between cumulative exposure and risk for lung cancer.

In the trials, 74,021 patients were randomly assigned to an ARB, resulting in a total cumulative exposure of 172,389 person-years of exposure to daily high dose (or equivalent), and 61,197 patients were randomly assigned to control.

Results showed a highly significant correlation between the degree of cumulative exposure to ARBs and risk for all cancers combined (slope = 0.07; 95% confidence interval, 0.03-0.11; P < .001) and also lung cancer (slope = 0.16; 95% CI, 0.05-0.27; P = .003).

In trials where the cumulative exposure was greater than 3 years of exposure to daily high dose, there was a statistically significant increase in risk for all cancers combined (risk ratio, 1.11; 95% CI, 1.03-1.19; P = .006).

There was also a statistically significant increase in risk for lung cancers in trials where the cumulative exposure was greater than 2.5 years (RR, 1.21; 95% CI, 1.02-1.44; P = .03).

In trials with lower cumulative exposure to ARBs, there was no increased risk either for all cancers combined or lung cancer.

Dr. Sipahi reports that the cumulative exposure-risk relationship with ARBs was independent of background angiotensin-converting enzyme (ACE) inhibitor treatment or the type of control (placebo or nonplacebo control).

But he acknowledges that since this is a trial-level analysis, the effects of patient characteristics such as age and smoking status could not be examined because of lack of patient-level data.

Dr. Sipahi says he does not know the mechanism behind these findings, but he draws attention to the recent withdrawal of several thousand lots of ARB formulations because of the presence of potentially carcinogenic impurities that have been suggested to be a byproduct of ARB synthesis.

He also claims that unlike some other classes of antihypertensives, ARBs have not been shown to reduce the risk for MI, leading him to conclude that “other classes of antihypertensives with good safety and efficacy data (such as ACE-inhibitors, calcium-channel blockers or others) should become the preferred first-line agents in the treatment of hypertension.”

Dr. Sipahi wants the FDA to reinvestigate the issue of ARBs and cancer risk using individual patient data. “They already have the patient-level data from the trials. They should look at it more carefully and look at exposure levels and how they relate to cancer risk,” he said. “And the fact that there have been studies linking high ARB exposure levels to increased cancer risk should at least get a warning on the drug labels.”
 

A ‘clear increase’ in risk

Dr. Sipahi also points out that a link between ARBs and cancer has been found in another meta-analysis performed in 2013 by senior FDA analyst Thomas Marciniak, MD.

“Because he worked at the FDA, [Dr.] Marciniak had access to individual patent data. This is the best type of analysis and generally produces more accurate results than a trial-level meta-analysis,” Dr. Sipahi commented.

Dr. Marciniak’s analysis, which is available on the FDA website as part of another document, was not officially published elsewhere, and no further action has been taken on the issue.

Contacted by this news organization, Dr. Marciniak, who has now retired from the FDA, said he not only conducted a patient-level meta-analysis but also followed up adverse effects reported in the trials that could have been a symptom of cancer to establish further whether the patient was later diagnosed with cancer or not.

“I used every scrap of information sent in, including serious adverse event reports. I saw a clear increase in lung cancer risk with the ARBs,” Dr. Marciniak said. He did not, however, perform a dose-response relationship analysis.

Asked why his analysis and those from Dr. Sipahi reach different conclusions to those from the ARB Trialists Collaboration and the official FDA investigations, Dr. Marciniak said: “It may be that there were too many low-exposure trials that just washed out the difference. But trial data generally do not capture adverse events such as cancer, which takes a long time to develop, very well, and if you’re not really looking for it, you’re probably not going to find it.”

Dr. Marciniak said that Dr. Sipahi’s current findings are in line with his results. “Finding a dose response, to me, is extremely compelling, and I think the signal here is real,” he commented. “I think this new paper from Dr. Sipahi verifies what I found. I think the FDA should now release all individual patient data it has.”

Contacted for comment, an FDA spokesperson said, “Generally the FDA does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

They added: “The FDA has ongoing assessment, surveillance, compliance, and pharmaceutical quality efforts across every product area, and we will continue to work with drug manufacturers to ensure safe, effective, and high-quality drugs for the American public. When we identify new and previously unrecognized risks to safety and quality, we react swiftly to resolve the problem, as we have done in responding to the recent findings of nitrosamines in certain medicines.”
 

Analysis ‘should be taken seriously’

Commenting on this new study, Steve Nissen, MD, a key figure in analyzing such complex data and who has himself uncovered problems with high-profile drugs in the past, says the current analysis should be taken seriously. 

Dr. Nissen, who was Dr. Sipahi’s senior during his post-doc position at the Cleveland Clinic, wrote an editorial accompanying Dr. Sipahi’s first paper and calling for urgent regulatory review of the evidence.

He says the new findings add to previous evidence suggesting a possible risk for cancer with ARBs.

“[Dr.] Sipahi is a capable researcher, and this analysis needs to be taken seriously, but it needs to be verified. It is not possible to draw a strong conclusion on this analysis, as it is not based on individual patient data, but I don’t think it should be ignored,” Dr. Nissen stated.

“I will say again what I said 12 years ago – that the regulatory agencies need to carefully review all their data in a very detailed way. The FDA and EMA have access to the individual patient data and are both very capable of doing the required analyses.”
 

Limitations of trial-level analysis

Asked to evaluate the statistics in the current paper, Andrew Althouse, PhD, an assistant professor of medicine at the University of Pittsburgh, and a clinical trial statistician, explained that the best way to do a thorough analysis of the relationship between ARB exposure and risk for incident cancer would involve the use of patient-level data.

“As such data were not available to Dr. Sipahi, I believe he is doing as well as he can. But without full access to individual patient-level data from the respective trials, it is difficult to support any firm conclusions,” Dr. Althouse said in an interview.

He suggested that the meta-regression analyses used in the paper were unable to properly estimate the relationship between ARB exposure and risk for incident cancer. 

“Taken at face value, the current analysis suggests that [in] trials with longer follow-up duration (and therefore greater cumulative exposure to ARB for the treatment group), the risk of developing cancer for patients in the ARB group versus the non-ARB group was progressively higher. But this study doesn’t take into account the actual amount of follow-up time for individual patients or potential differences in the amount of follow-up time between the two groups in each trial,” he noted.

Dr. Althouse says this raises the possibility of “competing risks” or the idea that if ARBs reduce cardiovascular disease and cardiovascular death, then there would be more patients remaining in that arm who could go on to develop cancer. “So a crude count of the number of cancer cases may look as though patients receiving ARBs are ‘more likely’ to develop cancer, but this is a mirage.”

He added: “When there are some patients dying during the study, the only way to tell whether the intervention actually increased the risk of other health-related complications is to have an analysis that properly accounts for each patient’s time-at-risk of the outcome. Unfortunately, properly analyzing this requires the use of patient-level data.”
 

Cardiologists skeptical?

Cardiology experts asked for thoughts on the new meta-analysis were also cautious to read too much into the findings.

Franz Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “Perhaps one would simply ignore this rambling, cherrypicking-based condemnation of ARBs if it were not for the powerful negative connotation of the word cancer. Thus, the meta-analysis of Dr. Sipahi purporting that ARBs could be increasing the development of cancers in a cumulative way is of concern to both physicians and patients.”

But, raising a similar point to Dr. Althouse about competing risks, Dr. Messerli said: “We have to consider that as one gets older, the cardiovascular disease state and cancer state will compete with each other for the outcome of death. The better that therapies protect against cardiovascular death, the more they will increase life expectancy and thus the risk of cancer.”

He also added that “in head-to-head comparisons with ACE inhibitors, ARBs showed similar efficacy in terms of death, CV mortality, MI, stroke, and end-stage kidney disease, so can we agree that the attempt of Dr. Sipahi to disparage ARBs as a class is much ado about nothing?”

Dr. Nissen, however, said he views the idea of competing risk as “a bit of a stretch” in this case. “Although ARBs are effective antihypertensive drugs, I would say there is very little evidence that they would prolong survival versus other antihypertensives.”

Dr. Sipahi also claims that this argument is not relevant to the current analysis. “ARBs did not increase survival in any of the high-exposure trials that showed an excess in cancers. Therefore, competing outcomes, or ‘survival bias’ to be more specific, is not a possibility here,” he says.

George Bakris, MD, professor of medicine at the University of Chicago Medicine, noted that while the current study shows a slight increase in cancer incidence, especially lung cancer, among those taking ARBs for more than 3 years, it “totally ignores the overwhelming cardiovascular risk reduction seen in the trials.”

“Moreover,” he adds, “the author notes that the findings were independent of ACE-inhibitors, but he can’t rule out smoking and age as factors, two major risk factors for cancer and lung cancer, specifically. Thus, as typical of these types of analyses, the associations are probably true/true unrelated or, at best, partially related.”

Dr. Bakris referred to the potentially carcinogenic nitrosamine and azido compounds found in several ARB formulations that have resulted in recalls.

“At any stage of drug synthesis throughout each product’s lifetime, these impurities may evolve if an amine reacts with a nitrosating agent coexisting under appropriate conditions,” he said. “Drug regulatory authorities worldwide have established stringent guidelines on nitrosamine contamination for all drug products. The studies noted in the author’s analysis were done well before these guidelines were implemented. Hence, many of the issues raised by the authors using trials from 10-20 years ago are not of significant concern.”

Still, the cardiology experts all agreed on one thing – that patients should continue to take ARBs as prescribed.  

Noting that worldwide authorities are now addressing the issue of possible carcinogen contamination, Dr. Bakris stressed that patients “should not panic and should not stop their meds.”

Dr. Nissen added: “What we don’t want is for patents who are taking ARBs to stop taking these medications – hypertension is a deadly disorder, and these drugs have proven cardiovascular benefits.”

Dr. Sipahi received no specific funding for this work. He reports receiving lecture honoraria from Novartis, Boehringer Ingelheim, Sanofi, Sandoz, Bristol-Myers Squibb, Bayer, Pfizer, Ranbaxy, Servier, and ARIS and served on advisory boards for Novartis, Sanofi, Servier, Bristol-Myers Squibb, Pfizer, Bayer and I.E. Ulagay. The other commenters do not report any relevant disclosures.

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

The debate on whether the popular class of antihypertensive drugs, angiotensin receptor blockers (ARBs), may be associated with an increased risk for cancer has been reopened with the publication of a new meta-analysis.

The analysis found an increasing risk for cancer, and specifically lung cancer, with increasing cumulative exposure to these drugs.

The findings are reported in a study published online in PLOS ONE.

The author of this new meta-analysis is Ilke Sipahi, MD, a cardiologist from Acibadem University Medical School, Istanbul, who previously raised this issue in an initial meta-analysis published in 2010.

“The new meta-analysis is important because it is the first study to investigate whether there is a dose response in the association between ARBs and cancer,” Dr. Sipahi told this news organization.

“I found a clear signal of increased risk of cancer as exposure to ARBs increased, and the association started to become significant when the maximum dose was taken for 3 years,” he added.

Dr. Sipahi explained that in the first meta-analysis published in Lancet Oncology, he and his colleagues reported an increased cancer risk with ARBs based on observations from high-exposure trials – those that included higher doses of ARBs with a long duration of follow-up.

Following this publication, an investigation by the U.S. Food and Drug Administration refuted the risk, and a collaboration of ARB trial investigators also performed an analysis published in the Journal of Hypertension (2011. doi: 10.1097/HJH.0b013e328344a7de), which again did not show an increased risk for cancer with use of ARBs.

Dr. Sipahi claims that those analyses by the FDA and the ARB Trialists Collaboration, which were all trial-level meta-analyses, diluted the “high exposure” data (including higher doses taken for longer periods of time) with a large amount of other data on much lower exposures (lower doses and/or shorter time periods).

“The overall risk would then inevitably become nonsignificant. These analyses also did not look at different exposure levels,” he says.

“For cancer, the degree of exposure is obviously very important. The risk associated with smoking 2 or 3 cigarettes a day for a year is very different from that of smoking 2 packs a day for 40 years. The same principle applies to taking a medication,” Dr. Sipahi asserts.

From these latest data, he estimates that 120 patients needed to be treated with the maximal daily dose of an ARB for 4.7 years for one excess cancer diagnosis, and 464 patients needed to be treated for one excess lung cancer.

“Given that at least 200 million individuals are being treated with an ARB globally, approximately 1.7 million excess cancers (and 430,000 lung cancers) in 4.6 years could be potentially caused by this class of drugs,” he suggests.

For the current analysis, Dr. Sipahi used trial-level data taken from the paper by the ARB Trialists Collaboration and investigated the effect of exposure to ARBs – including both the dose taken and the length of treatment – on risk for cancer. He performed metaregression analyses that he says has not been done before.

“I mathematically quantitated the degree of exposure in each trial. And when the degree of exposure was correlated with risk of cancer, there was a significant association.”

The new meta-analysis includes 15 randomized controlled trials. The two coprimary outcomes were the relationship between cumulative exposure to ARBs and risk for all cancers combined and the relationship between cumulative exposure and risk for lung cancer.

In the trials, 74,021 patients were randomly assigned to an ARB, resulting in a total cumulative exposure of 172,389 person-years of exposure to daily high dose (or equivalent), and 61,197 patients were randomly assigned to control.

Results showed a highly significant correlation between the degree of cumulative exposure to ARBs and risk for all cancers combined (slope = 0.07; 95% confidence interval, 0.03-0.11; P < .001) and also lung cancer (slope = 0.16; 95% CI, 0.05-0.27; P = .003).

In trials where the cumulative exposure was greater than 3 years of exposure to daily high dose, there was a statistically significant increase in risk for all cancers combined (risk ratio, 1.11; 95% CI, 1.03-1.19; P = .006).

There was also a statistically significant increase in risk for lung cancers in trials where the cumulative exposure was greater than 2.5 years (RR, 1.21; 95% CI, 1.02-1.44; P = .03).

In trials with lower cumulative exposure to ARBs, there was no increased risk either for all cancers combined or lung cancer.

Dr. Sipahi reports that the cumulative exposure-risk relationship with ARBs was independent of background angiotensin-converting enzyme (ACE) inhibitor treatment or the type of control (placebo or nonplacebo control).

But he acknowledges that since this is a trial-level analysis, the effects of patient characteristics such as age and smoking status could not be examined because of lack of patient-level data.

Dr. Sipahi says he does not know the mechanism behind these findings, but he draws attention to the recent withdrawal of several thousand lots of ARB formulations because of the presence of potentially carcinogenic impurities that have been suggested to be a byproduct of ARB synthesis.

He also claims that unlike some other classes of antihypertensives, ARBs have not been shown to reduce the risk for MI, leading him to conclude that “other classes of antihypertensives with good safety and efficacy data (such as ACE-inhibitors, calcium-channel blockers or others) should become the preferred first-line agents in the treatment of hypertension.”

Dr. Sipahi wants the FDA to reinvestigate the issue of ARBs and cancer risk using individual patient data. “They already have the patient-level data from the trials. They should look at it more carefully and look at exposure levels and how they relate to cancer risk,” he said. “And the fact that there have been studies linking high ARB exposure levels to increased cancer risk should at least get a warning on the drug labels.”
 

A ‘clear increase’ in risk

Dr. Sipahi also points out that a link between ARBs and cancer has been found in another meta-analysis performed in 2013 by senior FDA analyst Thomas Marciniak, MD.

“Because he worked at the FDA, [Dr.] Marciniak had access to individual patent data. This is the best type of analysis and generally produces more accurate results than a trial-level meta-analysis,” Dr. Sipahi commented.

Dr. Marciniak’s analysis, which is available on the FDA website as part of another document, was not officially published elsewhere, and no further action has been taken on the issue.

Contacted by this news organization, Dr. Marciniak, who has now retired from the FDA, said he not only conducted a patient-level meta-analysis but also followed up adverse effects reported in the trials that could have been a symptom of cancer to establish further whether the patient was later diagnosed with cancer or not.

“I used every scrap of information sent in, including serious adverse event reports. I saw a clear increase in lung cancer risk with the ARBs,” Dr. Marciniak said. He did not, however, perform a dose-response relationship analysis.

Asked why his analysis and those from Dr. Sipahi reach different conclusions to those from the ARB Trialists Collaboration and the official FDA investigations, Dr. Marciniak said: “It may be that there were too many low-exposure trials that just washed out the difference. But trial data generally do not capture adverse events such as cancer, which takes a long time to develop, very well, and if you’re not really looking for it, you’re probably not going to find it.”

Dr. Marciniak said that Dr. Sipahi’s current findings are in line with his results. “Finding a dose response, to me, is extremely compelling, and I think the signal here is real,” he commented. “I think this new paper from Dr. Sipahi verifies what I found. I think the FDA should now release all individual patient data it has.”

Contacted for comment, an FDA spokesperson said, “Generally the FDA does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

They added: “The FDA has ongoing assessment, surveillance, compliance, and pharmaceutical quality efforts across every product area, and we will continue to work with drug manufacturers to ensure safe, effective, and high-quality drugs for the American public. When we identify new and previously unrecognized risks to safety and quality, we react swiftly to resolve the problem, as we have done in responding to the recent findings of nitrosamines in certain medicines.”
 

Analysis ‘should be taken seriously’

Commenting on this new study, Steve Nissen, MD, a key figure in analyzing such complex data and who has himself uncovered problems with high-profile drugs in the past, says the current analysis should be taken seriously. 

Dr. Nissen, who was Dr. Sipahi’s senior during his post-doc position at the Cleveland Clinic, wrote an editorial accompanying Dr. Sipahi’s first paper and calling for urgent regulatory review of the evidence.

He says the new findings add to previous evidence suggesting a possible risk for cancer with ARBs.

“[Dr.] Sipahi is a capable researcher, and this analysis needs to be taken seriously, but it needs to be verified. It is not possible to draw a strong conclusion on this analysis, as it is not based on individual patient data, but I don’t think it should be ignored,” Dr. Nissen stated.

“I will say again what I said 12 years ago – that the regulatory agencies need to carefully review all their data in a very detailed way. The FDA and EMA have access to the individual patient data and are both very capable of doing the required analyses.”
 

Limitations of trial-level analysis

Asked to evaluate the statistics in the current paper, Andrew Althouse, PhD, an assistant professor of medicine at the University of Pittsburgh, and a clinical trial statistician, explained that the best way to do a thorough analysis of the relationship between ARB exposure and risk for incident cancer would involve the use of patient-level data.

“As such data were not available to Dr. Sipahi, I believe he is doing as well as he can. But without full access to individual patient-level data from the respective trials, it is difficult to support any firm conclusions,” Dr. Althouse said in an interview.

He suggested that the meta-regression analyses used in the paper were unable to properly estimate the relationship between ARB exposure and risk for incident cancer. 

“Taken at face value, the current analysis suggests that [in] trials with longer follow-up duration (and therefore greater cumulative exposure to ARB for the treatment group), the risk of developing cancer for patients in the ARB group versus the non-ARB group was progressively higher. But this study doesn’t take into account the actual amount of follow-up time for individual patients or potential differences in the amount of follow-up time between the two groups in each trial,” he noted.

Dr. Althouse says this raises the possibility of “competing risks” or the idea that if ARBs reduce cardiovascular disease and cardiovascular death, then there would be more patients remaining in that arm who could go on to develop cancer. “So a crude count of the number of cancer cases may look as though patients receiving ARBs are ‘more likely’ to develop cancer, but this is a mirage.”

He added: “When there are some patients dying during the study, the only way to tell whether the intervention actually increased the risk of other health-related complications is to have an analysis that properly accounts for each patient’s time-at-risk of the outcome. Unfortunately, properly analyzing this requires the use of patient-level data.”
 

Cardiologists skeptical?

Cardiology experts asked for thoughts on the new meta-analysis were also cautious to read too much into the findings.

Franz Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “Perhaps one would simply ignore this rambling, cherrypicking-based condemnation of ARBs if it were not for the powerful negative connotation of the word cancer. Thus, the meta-analysis of Dr. Sipahi purporting that ARBs could be increasing the development of cancers in a cumulative way is of concern to both physicians and patients.”

But, raising a similar point to Dr. Althouse about competing risks, Dr. Messerli said: “We have to consider that as one gets older, the cardiovascular disease state and cancer state will compete with each other for the outcome of death. The better that therapies protect against cardiovascular death, the more they will increase life expectancy and thus the risk of cancer.”

He also added that “in head-to-head comparisons with ACE inhibitors, ARBs showed similar efficacy in terms of death, CV mortality, MI, stroke, and end-stage kidney disease, so can we agree that the attempt of Dr. Sipahi to disparage ARBs as a class is much ado about nothing?”

Dr. Nissen, however, said he views the idea of competing risk as “a bit of a stretch” in this case. “Although ARBs are effective antihypertensive drugs, I would say there is very little evidence that they would prolong survival versus other antihypertensives.”

Dr. Sipahi also claims that this argument is not relevant to the current analysis. “ARBs did not increase survival in any of the high-exposure trials that showed an excess in cancers. Therefore, competing outcomes, or ‘survival bias’ to be more specific, is not a possibility here,” he says.

George Bakris, MD, professor of medicine at the University of Chicago Medicine, noted that while the current study shows a slight increase in cancer incidence, especially lung cancer, among those taking ARBs for more than 3 years, it “totally ignores the overwhelming cardiovascular risk reduction seen in the trials.”

“Moreover,” he adds, “the author notes that the findings were independent of ACE-inhibitors, but he can’t rule out smoking and age as factors, two major risk factors for cancer and lung cancer, specifically. Thus, as typical of these types of analyses, the associations are probably true/true unrelated or, at best, partially related.”

Dr. Bakris referred to the potentially carcinogenic nitrosamine and azido compounds found in several ARB formulations that have resulted in recalls.

“At any stage of drug synthesis throughout each product’s lifetime, these impurities may evolve if an amine reacts with a nitrosating agent coexisting under appropriate conditions,” he said. “Drug regulatory authorities worldwide have established stringent guidelines on nitrosamine contamination for all drug products. The studies noted in the author’s analysis were done well before these guidelines were implemented. Hence, many of the issues raised by the authors using trials from 10-20 years ago are not of significant concern.”

Still, the cardiology experts all agreed on one thing – that patients should continue to take ARBs as prescribed.  

Noting that worldwide authorities are now addressing the issue of possible carcinogen contamination, Dr. Bakris stressed that patients “should not panic and should not stop their meds.”

Dr. Nissen added: “What we don’t want is for patents who are taking ARBs to stop taking these medications – hypertension is a deadly disorder, and these drugs have proven cardiovascular benefits.”

Dr. Sipahi received no specific funding for this work. He reports receiving lecture honoraria from Novartis, Boehringer Ingelheim, Sanofi, Sandoz, Bristol-Myers Squibb, Bayer, Pfizer, Ranbaxy, Servier, and ARIS and served on advisory boards for Novartis, Sanofi, Servier, Bristol-Myers Squibb, Pfizer, Bayer and I.E. Ulagay. The other commenters do not report any relevant disclosures.

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

The debate on whether the popular class of antihypertensive drugs, angiotensin receptor blockers (ARBs), may be associated with an increased risk for cancer has been reopened with the publication of a new meta-analysis.

The analysis found an increasing risk for cancer, and specifically lung cancer, with increasing cumulative exposure to these drugs.

The findings are reported in a study published online in PLOS ONE.

The author of this new meta-analysis is Ilke Sipahi, MD, a cardiologist from Acibadem University Medical School, Istanbul, who previously raised this issue in an initial meta-analysis published in 2010.

“The new meta-analysis is important because it is the first study to investigate whether there is a dose response in the association between ARBs and cancer,” Dr. Sipahi told this news organization.

“I found a clear signal of increased risk of cancer as exposure to ARBs increased, and the association started to become significant when the maximum dose was taken for 3 years,” he added.

Dr. Sipahi explained that in the first meta-analysis published in Lancet Oncology, he and his colleagues reported an increased cancer risk with ARBs based on observations from high-exposure trials – those that included higher doses of ARBs with a long duration of follow-up.

Following this publication, an investigation by the U.S. Food and Drug Administration refuted the risk, and a collaboration of ARB trial investigators also performed an analysis published in the Journal of Hypertension (2011. doi: 10.1097/HJH.0b013e328344a7de), which again did not show an increased risk for cancer with use of ARBs.

Dr. Sipahi claims that those analyses by the FDA and the ARB Trialists Collaboration, which were all trial-level meta-analyses, diluted the “high exposure” data (including higher doses taken for longer periods of time) with a large amount of other data on much lower exposures (lower doses and/or shorter time periods).

“The overall risk would then inevitably become nonsignificant. These analyses also did not look at different exposure levels,” he says.

“For cancer, the degree of exposure is obviously very important. The risk associated with smoking 2 or 3 cigarettes a day for a year is very different from that of smoking 2 packs a day for 40 years. The same principle applies to taking a medication,” Dr. Sipahi asserts.

From these latest data, he estimates that 120 patients needed to be treated with the maximal daily dose of an ARB for 4.7 years for one excess cancer diagnosis, and 464 patients needed to be treated for one excess lung cancer.

“Given that at least 200 million individuals are being treated with an ARB globally, approximately 1.7 million excess cancers (and 430,000 lung cancers) in 4.6 years could be potentially caused by this class of drugs,” he suggests.

For the current analysis, Dr. Sipahi used trial-level data taken from the paper by the ARB Trialists Collaboration and investigated the effect of exposure to ARBs – including both the dose taken and the length of treatment – on risk for cancer. He performed metaregression analyses that he says has not been done before.

“I mathematically quantitated the degree of exposure in each trial. And when the degree of exposure was correlated with risk of cancer, there was a significant association.”

The new meta-analysis includes 15 randomized controlled trials. The two coprimary outcomes were the relationship between cumulative exposure to ARBs and risk for all cancers combined and the relationship between cumulative exposure and risk for lung cancer.

In the trials, 74,021 patients were randomly assigned to an ARB, resulting in a total cumulative exposure of 172,389 person-years of exposure to daily high dose (or equivalent), and 61,197 patients were randomly assigned to control.

Results showed a highly significant correlation between the degree of cumulative exposure to ARBs and risk for all cancers combined (slope = 0.07; 95% confidence interval, 0.03-0.11; P < .001) and also lung cancer (slope = 0.16; 95% CI, 0.05-0.27; P = .003).

In trials where the cumulative exposure was greater than 3 years of exposure to daily high dose, there was a statistically significant increase in risk for all cancers combined (risk ratio, 1.11; 95% CI, 1.03-1.19; P = .006).

There was also a statistically significant increase in risk for lung cancers in trials where the cumulative exposure was greater than 2.5 years (RR, 1.21; 95% CI, 1.02-1.44; P = .03).

In trials with lower cumulative exposure to ARBs, there was no increased risk either for all cancers combined or lung cancer.

Dr. Sipahi reports that the cumulative exposure-risk relationship with ARBs was independent of background angiotensin-converting enzyme (ACE) inhibitor treatment or the type of control (placebo or nonplacebo control).

But he acknowledges that since this is a trial-level analysis, the effects of patient characteristics such as age and smoking status could not be examined because of lack of patient-level data.

Dr. Sipahi says he does not know the mechanism behind these findings, but he draws attention to the recent withdrawal of several thousand lots of ARB formulations because of the presence of potentially carcinogenic impurities that have been suggested to be a byproduct of ARB synthesis.

He also claims that unlike some other classes of antihypertensives, ARBs have not been shown to reduce the risk for MI, leading him to conclude that “other classes of antihypertensives with good safety and efficacy data (such as ACE-inhibitors, calcium-channel blockers or others) should become the preferred first-line agents in the treatment of hypertension.”

Dr. Sipahi wants the FDA to reinvestigate the issue of ARBs and cancer risk using individual patient data. “They already have the patient-level data from the trials. They should look at it more carefully and look at exposure levels and how they relate to cancer risk,” he said. “And the fact that there have been studies linking high ARB exposure levels to increased cancer risk should at least get a warning on the drug labels.”
 

A ‘clear increase’ in risk

Dr. Sipahi also points out that a link between ARBs and cancer has been found in another meta-analysis performed in 2013 by senior FDA analyst Thomas Marciniak, MD.

“Because he worked at the FDA, [Dr.] Marciniak had access to individual patent data. This is the best type of analysis and generally produces more accurate results than a trial-level meta-analysis,” Dr. Sipahi commented.

Dr. Marciniak’s analysis, which is available on the FDA website as part of another document, was not officially published elsewhere, and no further action has been taken on the issue.

Contacted by this news organization, Dr. Marciniak, who has now retired from the FDA, said he not only conducted a patient-level meta-analysis but also followed up adverse effects reported in the trials that could have been a symptom of cancer to establish further whether the patient was later diagnosed with cancer or not.

“I used every scrap of information sent in, including serious adverse event reports. I saw a clear increase in lung cancer risk with the ARBs,” Dr. Marciniak said. He did not, however, perform a dose-response relationship analysis.

Asked why his analysis and those from Dr. Sipahi reach different conclusions to those from the ARB Trialists Collaboration and the official FDA investigations, Dr. Marciniak said: “It may be that there were too many low-exposure trials that just washed out the difference. But trial data generally do not capture adverse events such as cancer, which takes a long time to develop, very well, and if you’re not really looking for it, you’re probably not going to find it.”

Dr. Marciniak said that Dr. Sipahi’s current findings are in line with his results. “Finding a dose response, to me, is extremely compelling, and I think the signal here is real,” he commented. “I think this new paper from Dr. Sipahi verifies what I found. I think the FDA should now release all individual patient data it has.”

Contacted for comment, an FDA spokesperson said, “Generally the FDA does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

They added: “The FDA has ongoing assessment, surveillance, compliance, and pharmaceutical quality efforts across every product area, and we will continue to work with drug manufacturers to ensure safe, effective, and high-quality drugs for the American public. When we identify new and previously unrecognized risks to safety and quality, we react swiftly to resolve the problem, as we have done in responding to the recent findings of nitrosamines in certain medicines.”
 

Analysis ‘should be taken seriously’

Commenting on this new study, Steve Nissen, MD, a key figure in analyzing such complex data and who has himself uncovered problems with high-profile drugs in the past, says the current analysis should be taken seriously. 

Dr. Nissen, who was Dr. Sipahi’s senior during his post-doc position at the Cleveland Clinic, wrote an editorial accompanying Dr. Sipahi’s first paper and calling for urgent regulatory review of the evidence.

He says the new findings add to previous evidence suggesting a possible risk for cancer with ARBs.

“[Dr.] Sipahi is a capable researcher, and this analysis needs to be taken seriously, but it needs to be verified. It is not possible to draw a strong conclusion on this analysis, as it is not based on individual patient data, but I don’t think it should be ignored,” Dr. Nissen stated.

“I will say again what I said 12 years ago – that the regulatory agencies need to carefully review all their data in a very detailed way. The FDA and EMA have access to the individual patient data and are both very capable of doing the required analyses.”
 

Limitations of trial-level analysis

Asked to evaluate the statistics in the current paper, Andrew Althouse, PhD, an assistant professor of medicine at the University of Pittsburgh, and a clinical trial statistician, explained that the best way to do a thorough analysis of the relationship between ARB exposure and risk for incident cancer would involve the use of patient-level data.

“As such data were not available to Dr. Sipahi, I believe he is doing as well as he can. But without full access to individual patient-level data from the respective trials, it is difficult to support any firm conclusions,” Dr. Althouse said in an interview.

He suggested that the meta-regression analyses used in the paper were unable to properly estimate the relationship between ARB exposure and risk for incident cancer. 

“Taken at face value, the current analysis suggests that [in] trials with longer follow-up duration (and therefore greater cumulative exposure to ARB for the treatment group), the risk of developing cancer for patients in the ARB group versus the non-ARB group was progressively higher. But this study doesn’t take into account the actual amount of follow-up time for individual patients or potential differences in the amount of follow-up time between the two groups in each trial,” he noted.

Dr. Althouse says this raises the possibility of “competing risks” or the idea that if ARBs reduce cardiovascular disease and cardiovascular death, then there would be more patients remaining in that arm who could go on to develop cancer. “So a crude count of the number of cancer cases may look as though patients receiving ARBs are ‘more likely’ to develop cancer, but this is a mirage.”

He added: “When there are some patients dying during the study, the only way to tell whether the intervention actually increased the risk of other health-related complications is to have an analysis that properly accounts for each patient’s time-at-risk of the outcome. Unfortunately, properly analyzing this requires the use of patient-level data.”
 

Cardiologists skeptical?

Cardiology experts asked for thoughts on the new meta-analysis were also cautious to read too much into the findings.

Franz Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “Perhaps one would simply ignore this rambling, cherrypicking-based condemnation of ARBs if it were not for the powerful negative connotation of the word cancer. Thus, the meta-analysis of Dr. Sipahi purporting that ARBs could be increasing the development of cancers in a cumulative way is of concern to both physicians and patients.”

But, raising a similar point to Dr. Althouse about competing risks, Dr. Messerli said: “We have to consider that as one gets older, the cardiovascular disease state and cancer state will compete with each other for the outcome of death. The better that therapies protect against cardiovascular death, the more they will increase life expectancy and thus the risk of cancer.”

He also added that “in head-to-head comparisons with ACE inhibitors, ARBs showed similar efficacy in terms of death, CV mortality, MI, stroke, and end-stage kidney disease, so can we agree that the attempt of Dr. Sipahi to disparage ARBs as a class is much ado about nothing?”

Dr. Nissen, however, said he views the idea of competing risk as “a bit of a stretch” in this case. “Although ARBs are effective antihypertensive drugs, I would say there is very little evidence that they would prolong survival versus other antihypertensives.”

Dr. Sipahi also claims that this argument is not relevant to the current analysis. “ARBs did not increase survival in any of the high-exposure trials that showed an excess in cancers. Therefore, competing outcomes, or ‘survival bias’ to be more specific, is not a possibility here,” he says.

George Bakris, MD, professor of medicine at the University of Chicago Medicine, noted that while the current study shows a slight increase in cancer incidence, especially lung cancer, among those taking ARBs for more than 3 years, it “totally ignores the overwhelming cardiovascular risk reduction seen in the trials.”

“Moreover,” he adds, “the author notes that the findings were independent of ACE-inhibitors, but he can’t rule out smoking and age as factors, two major risk factors for cancer and lung cancer, specifically. Thus, as typical of these types of analyses, the associations are probably true/true unrelated or, at best, partially related.”

Dr. Bakris referred to the potentially carcinogenic nitrosamine and azido compounds found in several ARB formulations that have resulted in recalls.

“At any stage of drug synthesis throughout each product’s lifetime, these impurities may evolve if an amine reacts with a nitrosating agent coexisting under appropriate conditions,” he said. “Drug regulatory authorities worldwide have established stringent guidelines on nitrosamine contamination for all drug products. The studies noted in the author’s analysis were done well before these guidelines were implemented. Hence, many of the issues raised by the authors using trials from 10-20 years ago are not of significant concern.”

Still, the cardiology experts all agreed on one thing – that patients should continue to take ARBs as prescribed.  

Noting that worldwide authorities are now addressing the issue of possible carcinogen contamination, Dr. Bakris stressed that patients “should not panic and should not stop their meds.”

Dr. Nissen added: “What we don’t want is for patents who are taking ARBs to stop taking these medications – hypertension is a deadly disorder, and these drugs have proven cardiovascular benefits.”

Dr. Sipahi received no specific funding for this work. He reports receiving lecture honoraria from Novartis, Boehringer Ingelheim, Sanofi, Sandoz, Bristol-Myers Squibb, Bayer, Pfizer, Ranbaxy, Servier, and ARIS and served on advisory boards for Novartis, Sanofi, Servier, Bristol-Myers Squibb, Pfizer, Bayer and I.E. Ulagay. The other commenters do not report any relevant disclosures.

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

New signals of a potential additive benefit from the nonsteroidal mineralocorticoid antagonist finerenone (Kerendia) and a sodium-glucose transporter 2 inhibitor in patients with type 2 diabetes and chronic kidney disease (CKD) emerged in a follow-up report from the FIDELITY analysis, which combined data from more than 13,000 patients who received finerenone in either of the two pivotal trials with the agent.

The analysis showed that the 877 patients enrolled in either the FIDELIO DKD or FIGARO DKD trials taking an SGLT2 inhibitor at baseline had a 37% relative reduction in their urinary albumin-to-creatinine ratio (UACR), compared with placebo-treated patients after a median of 3 years on treatment.

Among the remaining 12,149 patients who did not receive an SGLT2 inhibitor, finerenone cut the average UACR by 32%, compared with placebo, said Peter Rossing, DMSc, MD, who presented the findings on Feb. 27 at the World Congress of Nephrology 2022 in Kuala Lumpur, Malaysia.

Primary endpoint results for FIDELIO-DKD and FIGARO-DKD also suggest similar additive effects of finerenone plus an SGLT2 inhibitor.

Results of the composite renal endpoint in each study – progression to kidney failure, renal death, or at least a 57% decline in estimated glomerular filtration rate (eGFR) from baseline – showed a 58% relative risk reduction in patients who received agents from both drug classes and a 20% relative risk reduction in those who only received finerenone, a between-group difference that was not significant.

For the composite cardiovascular event endpoint – cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure – the rate fell by 37%, compared with placebo, in patients who also received an SGLT2 inhibitor, and by 13%, compared with placebo, in those who received finerenone but no SGLT2 inhibitor, also a difference that was not significant.

‘A lot of interest in finerenone’ in U.S.

“The benefits of finerenone on cardiovascular and kidney outcomes were consistent, irrespective of SGLT2 inhibitor use at baseline,” concluded Dr. Rossing, professor and head of research at the Steno Diabetes Center in Copenhagen.

The new findings are a “suggestion that the two classes might be additive [in their effects], but more data are needed,” Dr. Rossing said during his presentation.

But he cautioned that in both pivotal trials randomization did not consider SGLT2 inhibitor use. All patients in the two trials were already receiving a renin-angiotensin system (RAS) inhibitor as background treatment, either an ACE inhibitor or angiotensin-receptor blocker.

The consequence of treatment with finerenone combined with an SGLT2 inhibitor is of growing importance because “an SGLT2 inhibitor is now recommended in most guidelines” for the type of patients enrolled in the two finerenone trials, explained Dr. Rossing.

He also noted that the first guideline to recommend routine use of finerenone in indicated patients appeared recently in the annual update to Standards of Medical Care in Diabetes – 2022 published by the American Diabetes Association.

The 2022 Standards states: “In patients with CKD who are at increased risk for cardiovascular events or CKD progression or are unable to use an SGLT2 inhibitor, a nonsteroidal mineralocorticoid receptor antagonist (finerenone) is recommended to reduce CKD progression and cardiovascular events.”

Results from FIDELIO-DKD, reported in the New England Journal of Medicine in 2020, and the main study, FIGARO-DKD, published in the same journal in 2021, led the Food and Drug Administration to approve finerenone in July 2021 to slow the progression of renal disease in patients with type 2 diabetes and CKD.

“My impression is that in the United States there is a lot of interest in finerenone,” Dr. Rossing said during the discussion following his presentation.

Finerenone has also been recently approved in the European Union.
 

‘Consistent’ benefits irrespective of SGLT2 inhibitors

“The cardiovascular and kidney benefits of finerenone were consistent irrespective of SGLT2 inhibitor use. This is definitely interesting and warrants a randomized controlled trial” to examine the relationship in a more rigorous way, commented Tejas Desai, MD, a nephrologist with the Department of Veterans Affairs, Charlotte, N.C.

That study, CONFIDENCE, is on its way, Dr. Rossing said during his talk. The randomized phase 2 trial has a planned enrollment of 800 patients with type 2 diabetes and CKD and three treatment groups: finerenone plus placebo, the SGLT2 inhibitor empagliflozin (Jardiance) plus placebo, or finerenone plus empagliflozin. The study will launch later in 2022 and has a planned completion date of late 2023.

“SGLT2 inhibitors, compared with finerenone, is where all of this is headed. We need a large trial that adjudicates the best medication to use with a RAS inhibitor,” Dr. Desai said in an interview.

The new analyses from the combined FIDELITY study expand on a previous report presented at the 2021 annual congress of the European Society of Cardiology and published in the European Heart Journal.
 

‘Impressive’ effect on cardiovascular events

The main findings from FIDELITY presented in those earlier reports, in 13,026 patients, showed there was a significant 14% relative reduction in the composite cardiovascular endpoint with finerenone, compared with placebo, during a median 3 years of follow-up.

The same report documented, in the total combined cohort, a significant 23% relative reduction in the composite renal endpoint in those taking finerenone compared with placebo.

“Reducing the risk of cardiovascular endpoints by a relative 14% is impressive,” and the time course showed a “relatively quick onset of action,” Dr. Desai noted.

He also characterized the enrolled patients, which included many with stage 3 or 4 CKD, as “not the sickest population of patients with CKD,” but rather “relatively healthier patients with CKD.”

Dr. Desai also downplayed the importance of the observed reduction in UACR associated with finerenone in FIDELITY.

“UACR is a surrogate marker. Results from many studies have shown improvements in UACR only to not show protection against falls in eGFR rate,” Dr. Desai said.

He was also reassured by the low incidence of hyperkalemia that led to discontinuation, which occurred in 1.7% of patients taking finerenone and in 0.6% of those taking placebo.

The types of patients enrolled in FIDELIO-DKD and FIGARO-DKD, who did not have eGFR rates below 25 mL/min per 1.73 m², are not particularly susceptible to this adverse effect, he said, noting, “I’m not overly concerned with hyperkalemia in this CKD population.

“I’m more concerned about [hyperkalemia in] patients with CKD and an eGFR of less than 25 mL/min per 1.73 m², but this was less than 1% of the enrolled population,” Dr. Desai observed.

FIDELIO-DKD, FIGARO-DKD, and FIDELITY were sponsored by Bayer, which markets finerenone (Kerendia). Dr. Rossing reported being a consultant for Bayer and other drug companies, and receiving research funding from AstraZeneca and Novo Nordisk. Dr. Desai reported no relevant financial relationships.

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

New signals of a potential additive benefit from the nonsteroidal mineralocorticoid antagonist finerenone (Kerendia) and a sodium-glucose transporter 2 inhibitor in patients with type 2 diabetes and chronic kidney disease (CKD) emerged in a follow-up report from the FIDELITY analysis, which combined data from more than 13,000 patients who received finerenone in either of the two pivotal trials with the agent.

The analysis showed that the 877 patients enrolled in either the FIDELIO DKD or FIGARO DKD trials taking an SGLT2 inhibitor at baseline had a 37% relative reduction in their urinary albumin-to-creatinine ratio (UACR), compared with placebo-treated patients after a median of 3 years on treatment.

Among the remaining 12,149 patients who did not receive an SGLT2 inhibitor, finerenone cut the average UACR by 32%, compared with placebo, said Peter Rossing, DMSc, MD, who presented the findings on Feb. 27 at the World Congress of Nephrology 2022 in Kuala Lumpur, Malaysia.

Primary endpoint results for FIDELIO-DKD and FIGARO-DKD also suggest similar additive effects of finerenone plus an SGLT2 inhibitor.

Results of the composite renal endpoint in each study – progression to kidney failure, renal death, or at least a 57% decline in estimated glomerular filtration rate (eGFR) from baseline – showed a 58% relative risk reduction in patients who received agents from both drug classes and a 20% relative risk reduction in those who only received finerenone, a between-group difference that was not significant.

For the composite cardiovascular event endpoint – cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure – the rate fell by 37%, compared with placebo, in patients who also received an SGLT2 inhibitor, and by 13%, compared with placebo, in those who received finerenone but no SGLT2 inhibitor, also a difference that was not significant.

‘A lot of interest in finerenone’ in U.S.

“The benefits of finerenone on cardiovascular and kidney outcomes were consistent, irrespective of SGLT2 inhibitor use at baseline,” concluded Dr. Rossing, professor and head of research at the Steno Diabetes Center in Copenhagen.

The new findings are a “suggestion that the two classes might be additive [in their effects], but more data are needed,” Dr. Rossing said during his presentation.

But he cautioned that in both pivotal trials randomization did not consider SGLT2 inhibitor use. All patients in the two trials were already receiving a renin-angiotensin system (RAS) inhibitor as background treatment, either an ACE inhibitor or angiotensin-receptor blocker.

The consequence of treatment with finerenone combined with an SGLT2 inhibitor is of growing importance because “an SGLT2 inhibitor is now recommended in most guidelines” for the type of patients enrolled in the two finerenone trials, explained Dr. Rossing.

He also noted that the first guideline to recommend routine use of finerenone in indicated patients appeared recently in the annual update to Standards of Medical Care in Diabetes – 2022 published by the American Diabetes Association.

The 2022 Standards states: “In patients with CKD who are at increased risk for cardiovascular events or CKD progression or are unable to use an SGLT2 inhibitor, a nonsteroidal mineralocorticoid receptor antagonist (finerenone) is recommended to reduce CKD progression and cardiovascular events.”

Results from FIDELIO-DKD, reported in the New England Journal of Medicine in 2020, and the main study, FIGARO-DKD, published in the same journal in 2021, led the Food and Drug Administration to approve finerenone in July 2021 to slow the progression of renal disease in patients with type 2 diabetes and CKD.

“My impression is that in the United States there is a lot of interest in finerenone,” Dr. Rossing said during the discussion following his presentation.

Finerenone has also been recently approved in the European Union.
 

‘Consistent’ benefits irrespective of SGLT2 inhibitors

“The cardiovascular and kidney benefits of finerenone were consistent irrespective of SGLT2 inhibitor use. This is definitely interesting and warrants a randomized controlled trial” to examine the relationship in a more rigorous way, commented Tejas Desai, MD, a nephrologist with the Department of Veterans Affairs, Charlotte, N.C.

That study, CONFIDENCE, is on its way, Dr. Rossing said during his talk. The randomized phase 2 trial has a planned enrollment of 800 patients with type 2 diabetes and CKD and three treatment groups: finerenone plus placebo, the SGLT2 inhibitor empagliflozin (Jardiance) plus placebo, or finerenone plus empagliflozin. The study will launch later in 2022 and has a planned completion date of late 2023.

“SGLT2 inhibitors, compared with finerenone, is where all of this is headed. We need a large trial that adjudicates the best medication to use with a RAS inhibitor,” Dr. Desai said in an interview.

The new analyses from the combined FIDELITY study expand on a previous report presented at the 2021 annual congress of the European Society of Cardiology and published in the European Heart Journal.
 

‘Impressive’ effect on cardiovascular events

The main findings from FIDELITY presented in those earlier reports, in 13,026 patients, showed there was a significant 14% relative reduction in the composite cardiovascular endpoint with finerenone, compared with placebo, during a median 3 years of follow-up.

The same report documented, in the total combined cohort, a significant 23% relative reduction in the composite renal endpoint in those taking finerenone compared with placebo.

“Reducing the risk of cardiovascular endpoints by a relative 14% is impressive,” and the time course showed a “relatively quick onset of action,” Dr. Desai noted.

He also characterized the enrolled patients, which included many with stage 3 or 4 CKD, as “not the sickest population of patients with CKD,” but rather “relatively healthier patients with CKD.”

Dr. Desai also downplayed the importance of the observed reduction in UACR associated with finerenone in FIDELITY.

“UACR is a surrogate marker. Results from many studies have shown improvements in UACR only to not show protection against falls in eGFR rate,” Dr. Desai said.

He was also reassured by the low incidence of hyperkalemia that led to discontinuation, which occurred in 1.7% of patients taking finerenone and in 0.6% of those taking placebo.

The types of patients enrolled in FIDELIO-DKD and FIGARO-DKD, who did not have eGFR rates below 25 mL/min per 1.73 m², are not particularly susceptible to this adverse effect, he said, noting, “I’m not overly concerned with hyperkalemia in this CKD population.

“I’m more concerned about [hyperkalemia in] patients with CKD and an eGFR of less than 25 mL/min per 1.73 m², but this was less than 1% of the enrolled population,” Dr. Desai observed.

FIDELIO-DKD, FIGARO-DKD, and FIDELITY were sponsored by Bayer, which markets finerenone (Kerendia). Dr. Rossing reported being a consultant for Bayer and other drug companies, and receiving research funding from AstraZeneca and Novo Nordisk. Dr. Desai reported no relevant financial relationships.

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

New signals of a potential additive benefit from the nonsteroidal mineralocorticoid antagonist finerenone (Kerendia) and a sodium-glucose transporter 2 inhibitor in patients with type 2 diabetes and chronic kidney disease (CKD) emerged in a follow-up report from the FIDELITY analysis, which combined data from more than 13,000 patients who received finerenone in either of the two pivotal trials with the agent.

The analysis showed that the 877 patients enrolled in either the FIDELIO DKD or FIGARO DKD trials taking an SGLT2 inhibitor at baseline had a 37% relative reduction in their urinary albumin-to-creatinine ratio (UACR), compared with placebo-treated patients after a median of 3 years on treatment.

Among the remaining 12,149 patients who did not receive an SGLT2 inhibitor, finerenone cut the average UACR by 32%, compared with placebo, said Peter Rossing, DMSc, MD, who presented the findings on Feb. 27 at the World Congress of Nephrology 2022 in Kuala Lumpur, Malaysia.

Primary endpoint results for FIDELIO-DKD and FIGARO-DKD also suggest similar additive effects of finerenone plus an SGLT2 inhibitor.

Results of the composite renal endpoint in each study – progression to kidney failure, renal death, or at least a 57% decline in estimated glomerular filtration rate (eGFR) from baseline – showed a 58% relative risk reduction in patients who received agents from both drug classes and a 20% relative risk reduction in those who only received finerenone, a between-group difference that was not significant.

For the composite cardiovascular event endpoint – cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure – the rate fell by 37%, compared with placebo, in patients who also received an SGLT2 inhibitor, and by 13%, compared with placebo, in those who received finerenone but no SGLT2 inhibitor, also a difference that was not significant.

‘A lot of interest in finerenone’ in U.S.

“The benefits of finerenone on cardiovascular and kidney outcomes were consistent, irrespective of SGLT2 inhibitor use at baseline,” concluded Dr. Rossing, professor and head of research at the Steno Diabetes Center in Copenhagen.

The new findings are a “suggestion that the two classes might be additive [in their effects], but more data are needed,” Dr. Rossing said during his presentation.

But he cautioned that in both pivotal trials randomization did not consider SGLT2 inhibitor use. All patients in the two trials were already receiving a renin-angiotensin system (RAS) inhibitor as background treatment, either an ACE inhibitor or angiotensin-receptor blocker.

The consequence of treatment with finerenone combined with an SGLT2 inhibitor is of growing importance because “an SGLT2 inhibitor is now recommended in most guidelines” for the type of patients enrolled in the two finerenone trials, explained Dr. Rossing.

He also noted that the first guideline to recommend routine use of finerenone in indicated patients appeared recently in the annual update to Standards of Medical Care in Diabetes – 2022 published by the American Diabetes Association.

The 2022 Standards states: “In patients with CKD who are at increased risk for cardiovascular events or CKD progression or are unable to use an SGLT2 inhibitor, a nonsteroidal mineralocorticoid receptor antagonist (finerenone) is recommended to reduce CKD progression and cardiovascular events.”

Results from FIDELIO-DKD, reported in the New England Journal of Medicine in 2020, and the main study, FIGARO-DKD, published in the same journal in 2021, led the Food and Drug Administration to approve finerenone in July 2021 to slow the progression of renal disease in patients with type 2 diabetes and CKD.

“My impression is that in the United States there is a lot of interest in finerenone,” Dr. Rossing said during the discussion following his presentation.

Finerenone has also been recently approved in the European Union.
 

‘Consistent’ benefits irrespective of SGLT2 inhibitors

“The cardiovascular and kidney benefits of finerenone were consistent irrespective of SGLT2 inhibitor use. This is definitely interesting and warrants a randomized controlled trial” to examine the relationship in a more rigorous way, commented Tejas Desai, MD, a nephrologist with the Department of Veterans Affairs, Charlotte, N.C.

That study, CONFIDENCE, is on its way, Dr. Rossing said during his talk. The randomized phase 2 trial has a planned enrollment of 800 patients with type 2 diabetes and CKD and three treatment groups: finerenone plus placebo, the SGLT2 inhibitor empagliflozin (Jardiance) plus placebo, or finerenone plus empagliflozin. The study will launch later in 2022 and has a planned completion date of late 2023.

“SGLT2 inhibitors, compared with finerenone, is where all of this is headed. We need a large trial that adjudicates the best medication to use with a RAS inhibitor,” Dr. Desai said in an interview.

The new analyses from the combined FIDELITY study expand on a previous report presented at the 2021 annual congress of the European Society of Cardiology and published in the European Heart Journal.
 

‘Impressive’ effect on cardiovascular events

The main findings from FIDELITY presented in those earlier reports, in 13,026 patients, showed there was a significant 14% relative reduction in the composite cardiovascular endpoint with finerenone, compared with placebo, during a median 3 years of follow-up.

The same report documented, in the total combined cohort, a significant 23% relative reduction in the composite renal endpoint in those taking finerenone compared with placebo.

“Reducing the risk of cardiovascular endpoints by a relative 14% is impressive,” and the time course showed a “relatively quick onset of action,” Dr. Desai noted.

He also characterized the enrolled patients, which included many with stage 3 or 4 CKD, as “not the sickest population of patients with CKD,” but rather “relatively healthier patients with CKD.”

Dr. Desai also downplayed the importance of the observed reduction in UACR associated with finerenone in FIDELITY.

“UACR is a surrogate marker. Results from many studies have shown improvements in UACR only to not show protection against falls in eGFR rate,” Dr. Desai said.

He was also reassured by the low incidence of hyperkalemia that led to discontinuation, which occurred in 1.7% of patients taking finerenone and in 0.6% of those taking placebo.

The types of patients enrolled in FIDELIO-DKD and FIGARO-DKD, who did not have eGFR rates below 25 mL/min per 1.73 m², are not particularly susceptible to this adverse effect, he said, noting, “I’m not overly concerned with hyperkalemia in this CKD population.

“I’m more concerned about [hyperkalemia in] patients with CKD and an eGFR of less than 25 mL/min per 1.73 m², but this was less than 1% of the enrolled population,” Dr. Desai observed.

FIDELIO-DKD, FIGARO-DKD, and FIDELITY were sponsored by Bayer, which markets finerenone (Kerendia). Dr. Rossing reported being a consultant for Bayer and other drug companies, and receiving research funding from AstraZeneca and Novo Nordisk. Dr. Desai reported no relevant financial relationships.

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

When Annie Uhing, MD, is stressed about work, she can call her mom. She and her mom are close, yes, but her mom is also a physician and understands the ups and downs of medical education and the unique challenges of being a woman in medicine.

“My mom and I were talking about this the other day – I don’t think we know any other mother-daughter pairs of doctors,” said Dr. Uhing.

Courtesy Dr. Charlene Gaebler-Uhing

In the United States, the number of female physicians has risen steadily since the mid- and late-20th century. As of 2019, women made up more than half of medical school classes across the country and 36.3% of the physician workforce.

Still, most female physicians are concentrated in a handful of specialties (such as pediatrics and obstetrics and gynecology) while the percentages of women in other areas remains extremely low (urology and orthopedic surgery). Many female physicians share anecdotal stories about not being taken seriously, like when a patient mistook them for a nurse, or preferred the advice of a male colleague to their own.

To celebrate International Women’s Day, this news organization talked to two families of female doctors about their experiences in medicine and how they inspire and support one another inside and outside the hospital.
 

Deborah, Charlene, and Annie

When Deborah Gaebler-Spira, MD, started medical school at the University of Illinois in 1975, women made up just 15% of her class. “For me, the idea that as a woman you could have a vocation that could be quite meaningful and self-directed – that was very important,” said Dr. Gaebler-Spira, now a pediatric rehabilitation physician at the Shirley Ryan Ability Lab and professor at Northwestern University in Chicago.

She blocked out a lot of discouragement along the way. In undergrad, the dean of the college warned Dr. Gaebler-Spira she’d never make it as a doctor. In medical school interviews, administrators could be hostile. “There was this feeling that you were taking a place of someone who really deserved it,” she said. When selecting a residency, Dr. Gaebler-Spira decided against a career in obstetrics because of the overt misogyny in the field at the time.

Instead, she went into pediatrics and physical medicine and rehabilitation, eventually working to become an expert in cerebral palsy. Along the way, Dr. Gaebler-Spira made lifelong friends with other female physicians and found strong female mentors, including Billie Adams, MD, and Helen Emery, MD.

When her sister, Charlene Gaebler-Uhing, MD, also decided to go into medicine, Dr. Gaebler-Spira said she “thought it was a sign of sanity as she was always much more competitive than I was! And if I could do it, no question she was able!”

Dr. Gaebler-Uhing, now an adolescent medicine specialist at Children’s Wisconsin in Milwaukee, followed her older sister’s footsteps to medical school in 1983, after first considering a career in social work.

While there were now more women going into medicine – her medical school class was about 25% women – problems persisted. During clinical rotations in residency, Dr. Gaebler-Uhing was often the only woman on a team and made the conscious decision to go professionally by her nickname, Charlie. “If a woman’s name was on the consult, her opinion and insights did not get the same value or respect as a male physician’s,” she said. “The only way they knew I was a woman was if they really knew me.”

The Gaebler sisters leaned on each other professionally and personally throughout their careers. When both sisters practiced in Chicago, they referred patients to one another. And Dr. Gaebler-Uhing said her older sister was a great role model for how to balance the dual roles of physician and parent, as few of the older female doctors who trained her were married or had a child.

Now Dr. Gaebler-Uhing’s daughter, Annie Uhing, MD, is entering medicine herself. She is currently pediatric resident at the University of Wisconsin American Family Hospital. She plans to do a chief year and then a pediatric endocrinology fellowship.

Growing up, Dr. Uhing wasn’t always sure she wanted to work as much as her parents, who are both doctors. But her mom provided a great example few of her friends had at home: “If you want to work, you should work and do what you want to do and it’s not wrong to want to have a really high-powered job as a woman,” said Dr. Uhing.

 

Kathryn, Susan, and Rita

The three sisters Kathryn Hudson, MD, Susan Schmidt, MD, and Rita Butler, MD, were inspired to go into medicine by their mother, Rita Watson, MD, who was one of the first female interventional cardiologists in the United States.

“I think we had a front row seat to what being a doctor was like,” said Dr. Hudson, a hematologist and oncologist and director of survivorship at Texas Oncology in Austin. Both parents were MDs – their dad was a pharmaceutical researcher at Merck – and they would excitedly discuss patient cases and drug development at the dinner table, said Dr. Butler, an interventional cardiology fellow at the Lankenau Heart Institute in Wynnewood, Pa.

All three sisters have vivid memories of ‘Take Your Daughter to Work Day’ at their mom’s hospital. “I remember going to Take Your Daughter to Work Day with her and watching her in action and thinking, oh my gosh, my mom is so cool and I want to be like her,” said Dr. Schmidt, a pediatric critical care specialist at St. Christopher’s Hospital for Children in Philadelphia. “I’ve always felt special that my mom was doing something really cool and really saving lives,” said Dr. Schmidt.

Their fourth sibling, John, isn’t a physician and “I honestly wonder if it’s because he never went to Take Your Daughter to Work Day!” said Dr. Butler.

Having a mother who had both a high-powered medical career and a family helped the three women know they could do the same. “It is a difficult journey, don’t get me wrong, but I never questioned that I could do it because my mom did it first,” said Dr. Hudson.

As adults, the sisters confide in one another as they navigate modern motherhood and careers, switching between discussing medical cases and parenting advice.

As hard as their mom worked while they were growing up, she didn’t have the pressure of living up to the “super mom” ideal we have now, said Dr. Butler. “Everyone wants women to work like they don’t have kids and everyone wants women to parent like they don’t have a job,” she said. Having two sisters who can provide reassurance and advice in that area goes a long way, she said.

“I think sharing that experience of navigating motherhood, a medical career, and marriage, and adult life with sisters who are going through all the same things is really special and I feel really fortunate for that,” said Dr. Schmidt.

*This story was updated on 3/8/2022.

When Annie Uhing, MD, is stressed about work, she can call her mom. She and her mom are close, yes, but her mom is also a physician and understands the ups and downs of medical education and the unique challenges of being a woman in medicine.

“My mom and I were talking about this the other day – I don’t think we know any other mother-daughter pairs of doctors,” said Dr. Uhing.

Courtesy Dr. Charlene Gaebler-Uhing

In the United States, the number of female physicians has risen steadily since the mid- and late-20th century. As of 2019, women made up more than half of medical school classes across the country and 36.3% of the physician workforce.

Still, most female physicians are concentrated in a handful of specialties (such as pediatrics and obstetrics and gynecology) while the percentages of women in other areas remains extremely low (urology and orthopedic surgery). Many female physicians share anecdotal stories about not being taken seriously, like when a patient mistook them for a nurse, or preferred the advice of a male colleague to their own.

To celebrate International Women’s Day, this news organization talked to two families of female doctors about their experiences in medicine and how they inspire and support one another inside and outside the hospital.
 

Deborah, Charlene, and Annie

When Deborah Gaebler-Spira, MD, started medical school at the University of Illinois in 1975, women made up just 15% of her class. “For me, the idea that as a woman you could have a vocation that could be quite meaningful and self-directed – that was very important,” said Dr. Gaebler-Spira, now a pediatric rehabilitation physician at the Shirley Ryan Ability Lab and professor at Northwestern University in Chicago.

She blocked out a lot of discouragement along the way. In undergrad, the dean of the college warned Dr. Gaebler-Spira she’d never make it as a doctor. In medical school interviews, administrators could be hostile. “There was this feeling that you were taking a place of someone who really deserved it,” she said. When selecting a residency, Dr. Gaebler-Spira decided against a career in obstetrics because of the overt misogyny in the field at the time.

Instead, she went into pediatrics and physical medicine and rehabilitation, eventually working to become an expert in cerebral palsy. Along the way, Dr. Gaebler-Spira made lifelong friends with other female physicians and found strong female mentors, including Billie Adams, MD, and Helen Emery, MD.

When her sister, Charlene Gaebler-Uhing, MD, also decided to go into medicine, Dr. Gaebler-Spira said she “thought it was a sign of sanity as she was always much more competitive than I was! And if I could do it, no question she was able!”

Dr. Gaebler-Uhing, now an adolescent medicine specialist at Children’s Wisconsin in Milwaukee, followed her older sister’s footsteps to medical school in 1983, after first considering a career in social work.

While there were now more women going into medicine – her medical school class was about 25% women – problems persisted. During clinical rotations in residency, Dr. Gaebler-Uhing was often the only woman on a team and made the conscious decision to go professionally by her nickname, Charlie. “If a woman’s name was on the consult, her opinion and insights did not get the same value or respect as a male physician’s,” she said. “The only way they knew I was a woman was if they really knew me.”

The Gaebler sisters leaned on each other professionally and personally throughout their careers. When both sisters practiced in Chicago, they referred patients to one another. And Dr. Gaebler-Uhing said her older sister was a great role model for how to balance the dual roles of physician and parent, as few of the older female doctors who trained her were married or had a child.

Now Dr. Gaebler-Uhing’s daughter, Annie Uhing, MD, is entering medicine herself. She is currently pediatric resident at the University of Wisconsin American Family Hospital. She plans to do a chief year and then a pediatric endocrinology fellowship.

Growing up, Dr. Uhing wasn’t always sure she wanted to work as much as her parents, who are both doctors. But her mom provided a great example few of her friends had at home: “If you want to work, you should work and do what you want to do and it’s not wrong to want to have a really high-powered job as a woman,” said Dr. Uhing.

 

Kathryn, Susan, and Rita

The three sisters Kathryn Hudson, MD, Susan Schmidt, MD, and Rita Butler, MD, were inspired to go into medicine by their mother, Rita Watson, MD, who was one of the first female interventional cardiologists in the United States.

“I think we had a front row seat to what being a doctor was like,” said Dr. Hudson, a hematologist and oncologist and director of survivorship at Texas Oncology in Austin. Both parents were MDs – their dad was a pharmaceutical researcher at Merck – and they would excitedly discuss patient cases and drug development at the dinner table, said Dr. Butler, an interventional cardiology fellow at the Lankenau Heart Institute in Wynnewood, Pa.

All three sisters have vivid memories of ‘Take Your Daughter to Work Day’ at their mom’s hospital. “I remember going to Take Your Daughter to Work Day with her and watching her in action and thinking, oh my gosh, my mom is so cool and I want to be like her,” said Dr. Schmidt, a pediatric critical care specialist at St. Christopher’s Hospital for Children in Philadelphia. “I’ve always felt special that my mom was doing something really cool and really saving lives,” said Dr. Schmidt.

Their fourth sibling, John, isn’t a physician and “I honestly wonder if it’s because he never went to Take Your Daughter to Work Day!” said Dr. Butler.

Having a mother who had both a high-powered medical career and a family helped the three women know they could do the same. “It is a difficult journey, don’t get me wrong, but I never questioned that I could do it because my mom did it first,” said Dr. Hudson.

As adults, the sisters confide in one another as they navigate modern motherhood and careers, switching between discussing medical cases and parenting advice.

As hard as their mom worked while they were growing up, she didn’t have the pressure of living up to the “super mom” ideal we have now, said Dr. Butler. “Everyone wants women to work like they don’t have kids and everyone wants women to parent like they don’t have a job,” she said. Having two sisters who can provide reassurance and advice in that area goes a long way, she said.

“I think sharing that experience of navigating motherhood, a medical career, and marriage, and adult life with sisters who are going through all the same things is really special and I feel really fortunate for that,” said Dr. Schmidt.

*This story was updated on 3/8/2022.

When Annie Uhing, MD, is stressed about work, she can call her mom. She and her mom are close, yes, but her mom is also a physician and understands the ups and downs of medical education and the unique challenges of being a woman in medicine.

“My mom and I were talking about this the other day – I don’t think we know any other mother-daughter pairs of doctors,” said Dr. Uhing.

Courtesy Dr. Charlene Gaebler-Uhing

In the United States, the number of female physicians has risen steadily since the mid- and late-20th century. As of 2019, women made up more than half of medical school classes across the country and 36.3% of the physician workforce.

Still, most female physicians are concentrated in a handful of specialties (such as pediatrics and obstetrics and gynecology) while the percentages of women in other areas remains extremely low (urology and orthopedic surgery). Many female physicians share anecdotal stories about not being taken seriously, like when a patient mistook them for a nurse, or preferred the advice of a male colleague to their own.

To celebrate International Women’s Day, this news organization talked to two families of female doctors about their experiences in medicine and how they inspire and support one another inside and outside the hospital.
 

Deborah, Charlene, and Annie

When Deborah Gaebler-Spira, MD, started medical school at the University of Illinois in 1975, women made up just 15% of her class. “For me, the idea that as a woman you could have a vocation that could be quite meaningful and self-directed – that was very important,” said Dr. Gaebler-Spira, now a pediatric rehabilitation physician at the Shirley Ryan Ability Lab and professor at Northwestern University in Chicago.

She blocked out a lot of discouragement along the way. In undergrad, the dean of the college warned Dr. Gaebler-Spira she’d never make it as a doctor. In medical school interviews, administrators could be hostile. “There was this feeling that you were taking a place of someone who really deserved it,” she said. When selecting a residency, Dr. Gaebler-Spira decided against a career in obstetrics because of the overt misogyny in the field at the time.

Instead, she went into pediatrics and physical medicine and rehabilitation, eventually working to become an expert in cerebral palsy. Along the way, Dr. Gaebler-Spira made lifelong friends with other female physicians and found strong female mentors, including Billie Adams, MD, and Helen Emery, MD.

When her sister, Charlene Gaebler-Uhing, MD, also decided to go into medicine, Dr. Gaebler-Spira said she “thought it was a sign of sanity as she was always much more competitive than I was! And if I could do it, no question she was able!”

Dr. Gaebler-Uhing, now an adolescent medicine specialist at Children’s Wisconsin in Milwaukee, followed her older sister’s footsteps to medical school in 1983, after first considering a career in social work.

While there were now more women going into medicine – her medical school class was about 25% women – problems persisted. During clinical rotations in residency, Dr. Gaebler-Uhing was often the only woman on a team and made the conscious decision to go professionally by her nickname, Charlie. “If a woman’s name was on the consult, her opinion and insights did not get the same value or respect as a male physician’s,” she said. “The only way they knew I was a woman was if they really knew me.”

The Gaebler sisters leaned on each other professionally and personally throughout their careers. When both sisters practiced in Chicago, they referred patients to one another. And Dr. Gaebler-Uhing said her older sister was a great role model for how to balance the dual roles of physician and parent, as few of the older female doctors who trained her were married or had a child.

Now Dr. Gaebler-Uhing’s daughter, Annie Uhing, MD, is entering medicine herself. She is currently pediatric resident at the University of Wisconsin American Family Hospital. She plans to do a chief year and then a pediatric endocrinology fellowship.

Growing up, Dr. Uhing wasn’t always sure she wanted to work as much as her parents, who are both doctors. But her mom provided a great example few of her friends had at home: “If you want to work, you should work and do what you want to do and it’s not wrong to want to have a really high-powered job as a woman,” said Dr. Uhing.

 

Kathryn, Susan, and Rita

The three sisters Kathryn Hudson, MD, Susan Schmidt, MD, and Rita Butler, MD, were inspired to go into medicine by their mother, Rita Watson, MD, who was one of the first female interventional cardiologists in the United States.

“I think we had a front row seat to what being a doctor was like,” said Dr. Hudson, a hematologist and oncologist and director of survivorship at Texas Oncology in Austin. Both parents were MDs – their dad was a pharmaceutical researcher at Merck – and they would excitedly discuss patient cases and drug development at the dinner table, said Dr. Butler, an interventional cardiology fellow at the Lankenau Heart Institute in Wynnewood, Pa.

All three sisters have vivid memories of ‘Take Your Daughter to Work Day’ at their mom’s hospital. “I remember going to Take Your Daughter to Work Day with her and watching her in action and thinking, oh my gosh, my mom is so cool and I want to be like her,” said Dr. Schmidt, a pediatric critical care specialist at St. Christopher’s Hospital for Children in Philadelphia. “I’ve always felt special that my mom was doing something really cool and really saving lives,” said Dr. Schmidt.

Their fourth sibling, John, isn’t a physician and “I honestly wonder if it’s because he never went to Take Your Daughter to Work Day!” said Dr. Butler.

Having a mother who had both a high-powered medical career and a family helped the three women know they could do the same. “It is a difficult journey, don’t get me wrong, but I never questioned that I could do it because my mom did it first,” said Dr. Hudson.

As adults, the sisters confide in one another as they navigate modern motherhood and careers, switching between discussing medical cases and parenting advice.

As hard as their mom worked while they were growing up, she didn’t have the pressure of living up to the “super mom” ideal we have now, said Dr. Butler. “Everyone wants women to work like they don’t have kids and everyone wants women to parent like they don’t have a job,” she said. Having two sisters who can provide reassurance and advice in that area goes a long way, she said.

“I think sharing that experience of navigating motherhood, a medical career, and marriage, and adult life with sisters who are going through all the same things is really special and I feel really fortunate for that,” said Dr. Schmidt.

*This story was updated on 3/8/2022.

Long or irregular menstrual cycles in relatively young women are linked an increased risk of both prevalent and incident nonalcoholic fatty liver disease (NAFLD), according to a cross-sectional study that included data on more than 70,000 women.

“Our results indicate that menstrual irregularity, which is easier to diagnose and usually presented earlier than PCOS [polycystic ovary syndrome] highlights the possibility of identifying premenopausal women at risk of developing NAFLD,” reported a team of authors primarily from Sungkyunkwan University, Seoul, South Korea.

The study evaluated women aged younger than 40 years who were participating in the Kangbuk Samsung Health Study, which involves a comprehensive biennial health examination at health centers in South Korea. Of the 135,090 women enrolled over a 6-year period who had at least one follow-up examination, 72,092 were available for analysis after excluding for a sizable list of confounding factors such as liver disease and infections; exposure to steatogenic medications, such as corticosteroids; hysterectomy; and pregnancy.
 

NAFLD prevalence climbs with longer menses

Of these women, 36.378 (27.7%) had menstrual cycles of 26-30 days and were identified as the index group. The prevalence of NAFLD in this group was 5.8%. For those with a menstrual cycle of 31-39 days, the prevalence rate climbed to 7.2%. For those with a menstrual cycle of at least 40 days or too irregular to estimate, the prevalence was 9.7%. The prevalence was 7.1% for those with a menstrual cycle less than 21 days.

The results of this study were published in the Journal of Clinical Endocrinology & Metabolism.

In those without NAFLD at baseline who were then followed for a mean of 4.4 years, there were 4,524 incident cases of NAFLD. Incidence density was calculated per 103 patient-years. In the index group, the rate was 18.4. It climbed to 20.2 for those with a menstrual cycle of 31-39 days and then to 22.9 for those with a menstrual cycle of at least 40 days. For those with a cycle of fewer than 21 days, the rate was 26.8.

After adjusting for age, body mass index, insulin resistance, and other confounders, the hazard ratio for incident NAFLD for those with long or irregular menstrual cycles compared with the incident group corresponded with a 22% increased risk (HR, 1.22; 95% confidence interval, 1.14-1.31). When calculated in a time-dependent analysis, the risk of NAFLD was increased by almost 50% (HR, 1.49; 95% CI, 1.38-1.60).


 

Risk persists with PCOS exclusion

PCOS has previously been associated with increased risk of NAFLD, but the association between long or irregular menstrual cycles and NAFLD persisted after women with PCOS were excluded.

The mechanism that links menstrual irregularity with NAFLD is unclear, but the investigators said that estrogen exposure is implicated. In addition to a previously reported associated between low estradiol levels and antiestrogens such as tamoxifen with increased risk of NAFLD, they cited studies associating estrogen replacement therapy with a reduced risk of NAFLD. The role of estrogen in suppressing inflammation, oxidative stress, and insulin resistance are all activities that might link more regular menses with a reduced risk of NAFLD, the authors contended.

Women older than 40 years were excluded from this analysis to reduce the possibility of perimenopausal changes as a confounding factor.

Of study limitations acknowledged by the investigators, the presence of NAFLD was diagnosed on ultrasonography rather than histology. Information on sex hormone or prolactin levels was not captured in relation to NAFLD incidence, and the lack of exposure to estrogen replacement therapy and oral contraceptives was based on self-reports from the participants.

Still, the large study size and the consistency of results after adjustment for multiple risk factors argue that long and irregular menstrual cycles do identify women at risk for NAFLD. One implication is that irregular menses can be a marker for NAFLD risk.

“Our findings do not prove a causal relationship, but they show that long or irregular menstrual cycles were significantly associated with an increased risk of developing NAFLD,” said Seungho Ryu, MD, PhD, a professor at the Sungkyunkwan University. Senior author of this study, Dr. Ryu emphasized in an interview that the association “was not explained by obesity or any other risk factor for NAFLD.”
 

Lifestyle changes may lower risk

The message is that “young women with long or irregular menstrual cycles may benefit from lifestyle changes to reduce the risk of NAFLD,” Dr. Ryu stated.

The Study of Women’s Health Across the Nation, which was started in 1994, has not evaluated NAFLD, but it did show a relationship between longer menstrual cycles and more cardiometabolic risk factors, according to Nanette Santoro MD, professor and chair, department of obstetrics & gynecology, University of Colorado at Denver, Aurora.

This suggests that others are “thinking along the same lines,” but in discussing this study with this news organization, she characterized some of the design elements as well as some of the findings in this study as “peculiar.”

In addition to a “very, very narrow definition of regular cycles,” she questioned the consistent hazard ratio for NAFLD for those with long cycles relative to other types of irregular menses. Presuming that the group with longer cycles would have included at least some patients with undiagnosed PCOS, she was would have expected that the risk would have been highest in this group. While conceding that differences in body composition of Korean women is a potential explanation for this apparent discrepancy, “I would like to see confirmed in other samples of women with more detailed metabolic assessments to understand who is at risk,” she said.

Not least problematic for the strength of the conclusions, the hazard ratio for NAFLD among women with long or irregular menstrual cycles was “pretty low.” She described this as a level at which the risk “is very susceptible to confounding and unlikely to influence clinical practice.”

Anuja Dokras, MD, PHD, a professor of obstetrics and gynecology and director of the PCOS Center at the University of Pennsylvania, Philadelphia, also questioned whether undiagnosed PCOS might have skewed the data.

“There is increasing data on the association between PCOS and NAFLD. Irregular menses is a key criterion for PCOS, and PCOS is the commonest reason for anovulation,” she said. Dr. Dokras therefore considered it possible that patients with unrecognized PCOS were included in the study, weakening the claim that risk of NAFLD and long menstrual cycles remains significant after controlling for PCOS.

Dr. Ryu and coinvestigators, Dr. Santoro, and Dr. Dokras reported no potential conflicts of interest.

Long or irregular menstrual cycles in relatively young women are linked an increased risk of both prevalent and incident nonalcoholic fatty liver disease (NAFLD), according to a cross-sectional study that included data on more than 70,000 women.

“Our results indicate that menstrual irregularity, which is easier to diagnose and usually presented earlier than PCOS [polycystic ovary syndrome] highlights the possibility of identifying premenopausal women at risk of developing NAFLD,” reported a team of authors primarily from Sungkyunkwan University, Seoul, South Korea.

The study evaluated women aged younger than 40 years who were participating in the Kangbuk Samsung Health Study, which involves a comprehensive biennial health examination at health centers in South Korea. Of the 135,090 women enrolled over a 6-year period who had at least one follow-up examination, 72,092 were available for analysis after excluding for a sizable list of confounding factors such as liver disease and infections; exposure to steatogenic medications, such as corticosteroids; hysterectomy; and pregnancy.
 

NAFLD prevalence climbs with longer menses

Of these women, 36.378 (27.7%) had menstrual cycles of 26-30 days and were identified as the index group. The prevalence of NAFLD in this group was 5.8%. For those with a menstrual cycle of 31-39 days, the prevalence rate climbed to 7.2%. For those with a menstrual cycle of at least 40 days or too irregular to estimate, the prevalence was 9.7%. The prevalence was 7.1% for those with a menstrual cycle less than 21 days.

The results of this study were published in the Journal of Clinical Endocrinology & Metabolism.

In those without NAFLD at baseline who were then followed for a mean of 4.4 years, there were 4,524 incident cases of NAFLD. Incidence density was calculated per 103 patient-years. In the index group, the rate was 18.4. It climbed to 20.2 for those with a menstrual cycle of 31-39 days and then to 22.9 for those with a menstrual cycle of at least 40 days. For those with a cycle of fewer than 21 days, the rate was 26.8.

After adjusting for age, body mass index, insulin resistance, and other confounders, the hazard ratio for incident NAFLD for those with long or irregular menstrual cycles compared with the incident group corresponded with a 22% increased risk (HR, 1.22; 95% confidence interval, 1.14-1.31). When calculated in a time-dependent analysis, the risk of NAFLD was increased by almost 50% (HR, 1.49; 95% CI, 1.38-1.60).


 

Risk persists with PCOS exclusion

PCOS has previously been associated with increased risk of NAFLD, but the association between long or irregular menstrual cycles and NAFLD persisted after women with PCOS were excluded.

The mechanism that links menstrual irregularity with NAFLD is unclear, but the investigators said that estrogen exposure is implicated. In addition to a previously reported associated between low estradiol levels and antiestrogens such as tamoxifen with increased risk of NAFLD, they cited studies associating estrogen replacement therapy with a reduced risk of NAFLD. The role of estrogen in suppressing inflammation, oxidative stress, and insulin resistance are all activities that might link more regular menses with a reduced risk of NAFLD, the authors contended.

Women older than 40 years were excluded from this analysis to reduce the possibility of perimenopausal changes as a confounding factor.

Of study limitations acknowledged by the investigators, the presence of NAFLD was diagnosed on ultrasonography rather than histology. Information on sex hormone or prolactin levels was not captured in relation to NAFLD incidence, and the lack of exposure to estrogen replacement therapy and oral contraceptives was based on self-reports from the participants.

Still, the large study size and the consistency of results after adjustment for multiple risk factors argue that long and irregular menstrual cycles do identify women at risk for NAFLD. One implication is that irregular menses can be a marker for NAFLD risk.

“Our findings do not prove a causal relationship, but they show that long or irregular menstrual cycles were significantly associated with an increased risk of developing NAFLD,” said Seungho Ryu, MD, PhD, a professor at the Sungkyunkwan University. Senior author of this study, Dr. Ryu emphasized in an interview that the association “was not explained by obesity or any other risk factor for NAFLD.”
 

Lifestyle changes may lower risk

The message is that “young women with long or irregular menstrual cycles may benefit from lifestyle changes to reduce the risk of NAFLD,” Dr. Ryu stated.

The Study of Women’s Health Across the Nation, which was started in 1994, has not evaluated NAFLD, but it did show a relationship between longer menstrual cycles and more cardiometabolic risk factors, according to Nanette Santoro MD, professor and chair, department of obstetrics & gynecology, University of Colorado at Denver, Aurora.

This suggests that others are “thinking along the same lines,” but in discussing this study with this news organization, she characterized some of the design elements as well as some of the findings in this study as “peculiar.”

In addition to a “very, very narrow definition of regular cycles,” she questioned the consistent hazard ratio for NAFLD for those with long cycles relative to other types of irregular menses. Presuming that the group with longer cycles would have included at least some patients with undiagnosed PCOS, she was would have expected that the risk would have been highest in this group. While conceding that differences in body composition of Korean women is a potential explanation for this apparent discrepancy, “I would like to see confirmed in other samples of women with more detailed metabolic assessments to understand who is at risk,” she said.

Not least problematic for the strength of the conclusions, the hazard ratio for NAFLD among women with long or irregular menstrual cycles was “pretty low.” She described this as a level at which the risk “is very susceptible to confounding and unlikely to influence clinical practice.”

Anuja Dokras, MD, PHD, a professor of obstetrics and gynecology and director of the PCOS Center at the University of Pennsylvania, Philadelphia, also questioned whether undiagnosed PCOS might have skewed the data.

“There is increasing data on the association between PCOS and NAFLD. Irregular menses is a key criterion for PCOS, and PCOS is the commonest reason for anovulation,” she said. Dr. Dokras therefore considered it possible that patients with unrecognized PCOS were included in the study, weakening the claim that risk of NAFLD and long menstrual cycles remains significant after controlling for PCOS.

Dr. Ryu and coinvestigators, Dr. Santoro, and Dr. Dokras reported no potential conflicts of interest.

Long or irregular menstrual cycles in relatively young women are linked an increased risk of both prevalent and incident nonalcoholic fatty liver disease (NAFLD), according to a cross-sectional study that included data on more than 70,000 women.

“Our results indicate that menstrual irregularity, which is easier to diagnose and usually presented earlier than PCOS [polycystic ovary syndrome] highlights the possibility of identifying premenopausal women at risk of developing NAFLD,” reported a team of authors primarily from Sungkyunkwan University, Seoul, South Korea.

The study evaluated women aged younger than 40 years who were participating in the Kangbuk Samsung Health Study, which involves a comprehensive biennial health examination at health centers in South Korea. Of the 135,090 women enrolled over a 6-year period who had at least one follow-up examination, 72,092 were available for analysis after excluding for a sizable list of confounding factors such as liver disease and infections; exposure to steatogenic medications, such as corticosteroids; hysterectomy; and pregnancy.
 

NAFLD prevalence climbs with longer menses

Of these women, 36.378 (27.7%) had menstrual cycles of 26-30 days and were identified as the index group. The prevalence of NAFLD in this group was 5.8%. For those with a menstrual cycle of 31-39 days, the prevalence rate climbed to 7.2%. For those with a menstrual cycle of at least 40 days or too irregular to estimate, the prevalence was 9.7%. The prevalence was 7.1% for those with a menstrual cycle less than 21 days.

The results of this study were published in the Journal of Clinical Endocrinology & Metabolism.

In those without NAFLD at baseline who were then followed for a mean of 4.4 years, there were 4,524 incident cases of NAFLD. Incidence density was calculated per 103 patient-years. In the index group, the rate was 18.4. It climbed to 20.2 for those with a menstrual cycle of 31-39 days and then to 22.9 for those with a menstrual cycle of at least 40 days. For those with a cycle of fewer than 21 days, the rate was 26.8.

After adjusting for age, body mass index, insulin resistance, and other confounders, the hazard ratio for incident NAFLD for those with long or irregular menstrual cycles compared with the incident group corresponded with a 22% increased risk (HR, 1.22; 95% confidence interval, 1.14-1.31). When calculated in a time-dependent analysis, the risk of NAFLD was increased by almost 50% (HR, 1.49; 95% CI, 1.38-1.60).


 

Risk persists with PCOS exclusion

PCOS has previously been associated with increased risk of NAFLD, but the association between long or irregular menstrual cycles and NAFLD persisted after women with PCOS were excluded.

The mechanism that links menstrual irregularity with NAFLD is unclear, but the investigators said that estrogen exposure is implicated. In addition to a previously reported associated between low estradiol levels and antiestrogens such as tamoxifen with increased risk of NAFLD, they cited studies associating estrogen replacement therapy with a reduced risk of NAFLD. The role of estrogen in suppressing inflammation, oxidative stress, and insulin resistance are all activities that might link more regular menses with a reduced risk of NAFLD, the authors contended.

Women older than 40 years were excluded from this analysis to reduce the possibility of perimenopausal changes as a confounding factor.

Of study limitations acknowledged by the investigators, the presence of NAFLD was diagnosed on ultrasonography rather than histology. Information on sex hormone or prolactin levels was not captured in relation to NAFLD incidence, and the lack of exposure to estrogen replacement therapy and oral contraceptives was based on self-reports from the participants.

Still, the large study size and the consistency of results after adjustment for multiple risk factors argue that long and irregular menstrual cycles do identify women at risk for NAFLD. One implication is that irregular menses can be a marker for NAFLD risk.

“Our findings do not prove a causal relationship, but they show that long or irregular menstrual cycles were significantly associated with an increased risk of developing NAFLD,” said Seungho Ryu, MD, PhD, a professor at the Sungkyunkwan University. Senior author of this study, Dr. Ryu emphasized in an interview that the association “was not explained by obesity or any other risk factor for NAFLD.”
 

Lifestyle changes may lower risk

The message is that “young women with long or irregular menstrual cycles may benefit from lifestyle changes to reduce the risk of NAFLD,” Dr. Ryu stated.

The Study of Women’s Health Across the Nation, which was started in 1994, has not evaluated NAFLD, but it did show a relationship between longer menstrual cycles and more cardiometabolic risk factors, according to Nanette Santoro MD, professor and chair, department of obstetrics & gynecology, University of Colorado at Denver, Aurora.

This suggests that others are “thinking along the same lines,” but in discussing this study with this news organization, she characterized some of the design elements as well as some of the findings in this study as “peculiar.”

In addition to a “very, very narrow definition of regular cycles,” she questioned the consistent hazard ratio for NAFLD for those with long cycles relative to other types of irregular menses. Presuming that the group with longer cycles would have included at least some patients with undiagnosed PCOS, she was would have expected that the risk would have been highest in this group. While conceding that differences in body composition of Korean women is a potential explanation for this apparent discrepancy, “I would like to see confirmed in other samples of women with more detailed metabolic assessments to understand who is at risk,” she said.

Not least problematic for the strength of the conclusions, the hazard ratio for NAFLD among women with long or irregular menstrual cycles was “pretty low.” She described this as a level at which the risk “is very susceptible to confounding and unlikely to influence clinical practice.”

Anuja Dokras, MD, PHD, a professor of obstetrics and gynecology and director of the PCOS Center at the University of Pennsylvania, Philadelphia, also questioned whether undiagnosed PCOS might have skewed the data.

“There is increasing data on the association between PCOS and NAFLD. Irregular menses is a key criterion for PCOS, and PCOS is the commonest reason for anovulation,” she said. Dr. Dokras therefore considered it possible that patients with unrecognized PCOS were included in the study, weakening the claim that risk of NAFLD and long menstrual cycles remains significant after controlling for PCOS.

Dr. Ryu and coinvestigators, Dr. Santoro, and Dr. Dokras reported no potential conflicts of interest.