Lipid Disorders

Two observational studies link better cardiovascular health (CVH) in childhood and midlife to reduced CV mortality and subclinical atherosclerosis in later life. Though many studies have examined CVH and CV mortality in later life, the two studies, published in JAMA Cardiology, examine longitudinal CVH and could inform lifestyle modification.

Together, the studies lend support to the American Heart Association 2010 Strategic Initiative, which put an emphasis on health promotion in children rather than CV disease prevention, Erica Spatz, MD, of Yale University, New Haven, Conn., wrote in an accompanying editorial.

Dr. Spatz pointed out that CV disease prevention can be a tough sell, especially in younger patients for whom the threat of heart disease is distant. These studies and others like them could capture evolving risk factors through patients’ lives, and connect them to current lifestyle and experiences. Such data could overcome barriers to behavioral change and lead to more personalized interventions, she wrote.
 

Framingham Offspring Study

One study, led by Vanessa Xanthakis, PhD, of Boston University, examined the relationship between the length of time during midlife spent in ideal CVH and various CV disease and mortality outcomes at the final examination.

The prospective study included 1,445 participants (mean age 60 years, 52% women) from a Framingham Heart Study Offspring investigation based in Massachusetts. The subjects had completed seven examinations. The current study ranged from 1991 to 2015, and encompassed the fifth, sixth, and seventh examinations. Researchers calculated CVH scores based on resting blood pressure, height, weight, total cholesterol level, fasting blood glucose level, smoking status, diet, and physical activity.

At the seventh examination, 39% of participants had poor CVH scores and 54% had intermediate scores. For each 5-year period of intermediate or ideal CVH (compared with poor) measured in previous examinations, during the follow-up period after the seventh examination, there was an associated reduction in risk for adverse outcomes including incident hypertension (hazard ratio, 0.67; 95% confidence interval, 056-0.80), diabetes (HR, 0.73; 95% CI, 0.57-0.93), chronic kidney disease (HR, 0.75; 95% CI, 0.63-0.89), CV disease (HR, 0.73; 95% CI, 0.63-0.85), and all-cause mortality (HR, 0.86; 95% CI, 0.76-0.97).

“Our results indicated that living longer in adulthood with better CVH may be potentially beneficial regardless of age because we did not observe statistically significant effect modification by age of the associations between duration in a given CVH score category and any outcome. Overall, our findings support the importance of promoting healthy behaviors throughout the life course,” the authors wrote.

The study was limited by several factors. Diet and physical activity were self-reported, and about half of participants were excluded after missing an examination, which could introduce bias.
 

International cohort study

The second study analyzed data from 9,388 individuals in five prospective cohorts in the United States and Finland. During 1973-2015, it tracked participants from childhood through middle age (age 8-55 years), linking CVH measures to subclinical atherosclerosis as measured by carotid intima-media thickness (cIMT) in middle age. Led by Norrina Allen, PhD, of the Northwestern University, Chicago, the researchers measured body mass index, total cholesterol level, blood pressure, glucose level, diet, physical activity, and smoking status during a minimum of three examinations. Based on those data, they classified participants as having ideal, intermediate, or poor CVH.

The researchers grouped the participants into five CVH trajectories: High-late decline, which started with high CVH scores at age 8 and maintained them through early adulthood (16%); high-moderate decline (high early scores, moderate decline; 26%); high-early decline (high early scores, early-life decline; 32%); intermediate-late decline (intermediate initial scores, late decline; 16%); and intermediate-early decline (10%). CVH stratification began early: At age 8, 25% of individuals had intermediate CVH scores.

After adjustment for demographics and baseline smoking, diet, and physical activity, the high-late decline CVH group had the smallest mean cIMT value (0.64 mm; 95 % CI, 0.63-0.65 mm), while the intermediate-early decline group, which had the poorest CVH, had the largest (0.72 mm; 95% CI, 0.69-0.76 mm; P less than .001). The relationship was the same even after adjustment for baseline or proximal CVH scores, showing that the trajectory of CVH scores was driving the measure of subclinical atherosclerosis.

“Although it remains important to provide treatment to individuals with elevated risk factor levels, the most effective way to reduce the burden of future CV disease may be to prevent the development of those CV disease risk factors, an approach termed primordial prevention. There is a large body of literature showing effective interventions that may help individuals maintain ideal CV health. Our findings suggest that these interventions are critical and should be implemented early in life to prevent the loss of CVH and future CV [disease] development,” the authors wrote.

The study’s limitations include the fact that analyzed cohorts were drawn from studies with varying protocols and CVH measurement methods. It is also limited by its observational nature.

The two studies were funded by a range of nonindustry sources.

SOURCES: Allen N et al. JAMA Cardiol. 2020 Mar 11. doi: 10.1001/jamacardio.2020.0140; Corlin N et al. JAMA Cardiol. 2020 Mar 11. doi: 10.1001/jamacardio.2020.0109.

Two observational studies link better cardiovascular health (CVH) in childhood and midlife to reduced CV mortality and subclinical atherosclerosis in later life. Though many studies have examined CVH and CV mortality in later life, the two studies, published in JAMA Cardiology, examine longitudinal CVH and could inform lifestyle modification.

Together, the studies lend support to the American Heart Association 2010 Strategic Initiative, which put an emphasis on health promotion in children rather than CV disease prevention, Erica Spatz, MD, of Yale University, New Haven, Conn., wrote in an accompanying editorial.

Dr. Spatz pointed out that CV disease prevention can be a tough sell, especially in younger patients for whom the threat of heart disease is distant. These studies and others like them could capture evolving risk factors through patients’ lives, and connect them to current lifestyle and experiences. Such data could overcome barriers to behavioral change and lead to more personalized interventions, she wrote.
 

Framingham Offspring Study

One study, led by Vanessa Xanthakis, PhD, of Boston University, examined the relationship between the length of time during midlife spent in ideal CVH and various CV disease and mortality outcomes at the final examination.

The prospective study included 1,445 participants (mean age 60 years, 52% women) from a Framingham Heart Study Offspring investigation based in Massachusetts. The subjects had completed seven examinations. The current study ranged from 1991 to 2015, and encompassed the fifth, sixth, and seventh examinations. Researchers calculated CVH scores based on resting blood pressure, height, weight, total cholesterol level, fasting blood glucose level, smoking status, diet, and physical activity.

At the seventh examination, 39% of participants had poor CVH scores and 54% had intermediate scores. For each 5-year period of intermediate or ideal CVH (compared with poor) measured in previous examinations, during the follow-up period after the seventh examination, there was an associated reduction in risk for adverse outcomes including incident hypertension (hazard ratio, 0.67; 95% confidence interval, 056-0.80), diabetes (HR, 0.73; 95% CI, 0.57-0.93), chronic kidney disease (HR, 0.75; 95% CI, 0.63-0.89), CV disease (HR, 0.73; 95% CI, 0.63-0.85), and all-cause mortality (HR, 0.86; 95% CI, 0.76-0.97).

“Our results indicated that living longer in adulthood with better CVH may be potentially beneficial regardless of age because we did not observe statistically significant effect modification by age of the associations between duration in a given CVH score category and any outcome. Overall, our findings support the importance of promoting healthy behaviors throughout the life course,” the authors wrote.

The study was limited by several factors. Diet and physical activity were self-reported, and about half of participants were excluded after missing an examination, which could introduce bias.
 

International cohort study

The second study analyzed data from 9,388 individuals in five prospective cohorts in the United States and Finland. During 1973-2015, it tracked participants from childhood through middle age (age 8-55 years), linking CVH measures to subclinical atherosclerosis as measured by carotid intima-media thickness (cIMT) in middle age. Led by Norrina Allen, PhD, of the Northwestern University, Chicago, the researchers measured body mass index, total cholesterol level, blood pressure, glucose level, diet, physical activity, and smoking status during a minimum of three examinations. Based on those data, they classified participants as having ideal, intermediate, or poor CVH.

The researchers grouped the participants into five CVH trajectories: High-late decline, which started with high CVH scores at age 8 and maintained them through early adulthood (16%); high-moderate decline (high early scores, moderate decline; 26%); high-early decline (high early scores, early-life decline; 32%); intermediate-late decline (intermediate initial scores, late decline; 16%); and intermediate-early decline (10%). CVH stratification began early: At age 8, 25% of individuals had intermediate CVH scores.

After adjustment for demographics and baseline smoking, diet, and physical activity, the high-late decline CVH group had the smallest mean cIMT value (0.64 mm; 95 % CI, 0.63-0.65 mm), while the intermediate-early decline group, which had the poorest CVH, had the largest (0.72 mm; 95% CI, 0.69-0.76 mm; P less than .001). The relationship was the same even after adjustment for baseline or proximal CVH scores, showing that the trajectory of CVH scores was driving the measure of subclinical atherosclerosis.

“Although it remains important to provide treatment to individuals with elevated risk factor levels, the most effective way to reduce the burden of future CV disease may be to prevent the development of those CV disease risk factors, an approach termed primordial prevention. There is a large body of literature showing effective interventions that may help individuals maintain ideal CV health. Our findings suggest that these interventions are critical and should be implemented early in life to prevent the loss of CVH and future CV [disease] development,” the authors wrote.

The study’s limitations include the fact that analyzed cohorts were drawn from studies with varying protocols and CVH measurement methods. It is also limited by its observational nature.

The two studies were funded by a range of nonindustry sources.

SOURCES: Allen N et al. JAMA Cardiol. 2020 Mar 11. doi: 10.1001/jamacardio.2020.0140; Corlin N et al. JAMA Cardiol. 2020 Mar 11. doi: 10.1001/jamacardio.2020.0109.

Two observational studies link better cardiovascular health (CVH) in childhood and midlife to reduced CV mortality and subclinical atherosclerosis in later life. Though many studies have examined CVH and CV mortality in later life, the two studies, published in JAMA Cardiology, examine longitudinal CVH and could inform lifestyle modification.

Together, the studies lend support to the American Heart Association 2010 Strategic Initiative, which put an emphasis on health promotion in children rather than CV disease prevention, Erica Spatz, MD, of Yale University, New Haven, Conn., wrote in an accompanying editorial.

Dr. Spatz pointed out that CV disease prevention can be a tough sell, especially in younger patients for whom the threat of heart disease is distant. These studies and others like them could capture evolving risk factors through patients’ lives, and connect them to current lifestyle and experiences. Such data could overcome barriers to behavioral change and lead to more personalized interventions, she wrote.
 

Framingham Offspring Study

One study, led by Vanessa Xanthakis, PhD, of Boston University, examined the relationship between the length of time during midlife spent in ideal CVH and various CV disease and mortality outcomes at the final examination.

The prospective study included 1,445 participants (mean age 60 years, 52% women) from a Framingham Heart Study Offspring investigation based in Massachusetts. The subjects had completed seven examinations. The current study ranged from 1991 to 2015, and encompassed the fifth, sixth, and seventh examinations. Researchers calculated CVH scores based on resting blood pressure, height, weight, total cholesterol level, fasting blood glucose level, smoking status, diet, and physical activity.

At the seventh examination, 39% of participants had poor CVH scores and 54% had intermediate scores. For each 5-year period of intermediate or ideal CVH (compared with poor) measured in previous examinations, during the follow-up period after the seventh examination, there was an associated reduction in risk for adverse outcomes including incident hypertension (hazard ratio, 0.67; 95% confidence interval, 056-0.80), diabetes (HR, 0.73; 95% CI, 0.57-0.93), chronic kidney disease (HR, 0.75; 95% CI, 0.63-0.89), CV disease (HR, 0.73; 95% CI, 0.63-0.85), and all-cause mortality (HR, 0.86; 95% CI, 0.76-0.97).

“Our results indicated that living longer in adulthood with better CVH may be potentially beneficial regardless of age because we did not observe statistically significant effect modification by age of the associations between duration in a given CVH score category and any outcome. Overall, our findings support the importance of promoting healthy behaviors throughout the life course,” the authors wrote.

The study was limited by several factors. Diet and physical activity were self-reported, and about half of participants were excluded after missing an examination, which could introduce bias.
 

International cohort study

The second study analyzed data from 9,388 individuals in five prospective cohorts in the United States and Finland. During 1973-2015, it tracked participants from childhood through middle age (age 8-55 years), linking CVH measures to subclinical atherosclerosis as measured by carotid intima-media thickness (cIMT) in middle age. Led by Norrina Allen, PhD, of the Northwestern University, Chicago, the researchers measured body mass index, total cholesterol level, blood pressure, glucose level, diet, physical activity, and smoking status during a minimum of three examinations. Based on those data, they classified participants as having ideal, intermediate, or poor CVH.

The researchers grouped the participants into five CVH trajectories: High-late decline, which started with high CVH scores at age 8 and maintained them through early adulthood (16%); high-moderate decline (high early scores, moderate decline; 26%); high-early decline (high early scores, early-life decline; 32%); intermediate-late decline (intermediate initial scores, late decline; 16%); and intermediate-early decline (10%). CVH stratification began early: At age 8, 25% of individuals had intermediate CVH scores.

After adjustment for demographics and baseline smoking, diet, and physical activity, the high-late decline CVH group had the smallest mean cIMT value (0.64 mm; 95 % CI, 0.63-0.65 mm), while the intermediate-early decline group, which had the poorest CVH, had the largest (0.72 mm; 95% CI, 0.69-0.76 mm; P less than .001). The relationship was the same even after adjustment for baseline or proximal CVH scores, showing that the trajectory of CVH scores was driving the measure of subclinical atherosclerosis.

“Although it remains important to provide treatment to individuals with elevated risk factor levels, the most effective way to reduce the burden of future CV disease may be to prevent the development of those CV disease risk factors, an approach termed primordial prevention. There is a large body of literature showing effective interventions that may help individuals maintain ideal CV health. Our findings suggest that these interventions are critical and should be implemented early in life to prevent the loss of CVH and future CV [disease] development,” the authors wrote.

The study’s limitations include the fact that analyzed cohorts were drawn from studies with varying protocols and CVH measurement methods. It is also limited by its observational nature.

The two studies were funded by a range of nonindustry sources.

SOURCES: Allen N et al. JAMA Cardiol. 2020 Mar 11. doi: 10.1001/jamacardio.2020.0140; Corlin N et al. JAMA Cardiol. 2020 Mar 11. doi: 10.1001/jamacardio.2020.0109.

PHOENIX – Consumption of red meat, particularly the processed form, is linked to a higher risk of developing coronary heart disease in men, results from a large prospective analysis demonstrated.

“The findings of this study are in line with randomized trials showing that the consumption of red meat, as compared with plant-based protein sources, increases LDL cholesterol levels, and with previous studies on red meat and risk of coronary heart disease,” lead study author Laila Al-Shaar, MPH, PhD, said in an interview in advance of the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting.

According to Dr. Al-Shaar, a postdoctoral research fellow in the department of nutrition at the T.H. Chan School of Public Health at Harvard University, Boston, most of the existing studies on red meat and heart disease have examined the impact of increasing consumption of red meat while decreasing consumption of all other foods. For the current study, she and her colleagues used a substitution analysis approach to understand how replacing red meat (total, processed, or unprocessed) with another protein-rich food was associated with the risk of heart disease. “This would potentially provide more specific guidance for healthier alternatives for those planning to cut down their red meat intake,” she said.

She and her colleagues prospectively followed 43,259 men in the Health Professionals Follow-up Study (1986-2012) who had no known history of cancer or cardiovascular disease. Diet was assessed by a standardized and validated food frequency questionnaire that was updated every 4 years. Dr. Al-Shaar and her colleagues used multivariate Cox models to estimate hazard ratios and 95% confidence intervals of CHD risk across categories of red meat consumption. They performed substitution analyses by comparing coefficients in models including alternative foods as continuous variables.

Over roughly 933,000 person-years of follow-up, the researchers documented 4,148 incident CHD cases. Of these, 1,680 were fatal. After multivariate adjustment for dietary and nondietary risk factors, both total and processed red meat intake were associated with a modestly higher risk of CHD (hazard ratio for a one serving/day increment, 1.08; 95% confidence interval, 1.01-1.14 for total red meat; and HR, 1.13; 95% CI, 1.03-1.22 for processed red meat). Substitutions of one serving per day of other foods (including nuts, legumes, soy, whole grains, and low- and high-fat dairy) for one serving per day of total red meat were associated with a 10%-47% lower CHD risk.

Stronger inverse associations were observed between some of these substitutions for red meat and risk of fatal CHD. Substituting nuts lowered the risk of fatal heart disease by 17%, while replacing red meat with whole grains was linked to a 48% reduction in that outcome. Those associations were more pronounced when replacing processed red meat.

“Processed meats and meats in general have been thought to be potentially not favorable in terms of cardiovascular disease and cardiovascular disease risk,” Robert H. Eckel, MD, professor emeritus of medicine at the University of Colorado Anschutz Medical Campus, Aurora, said in an interview. “Now we have increasing data that not only is there a negative cardiovascular disease impact of animal protein, but we see this on all-cause mortality, including cancer.”

Dr. Al-Shaar said that the findings “support current recommendations to limit consumption of red meat and suggest that high-quality plant-based proteins such as nuts, legumes, and soy are good alternatives for individuals planning to have better food choices and healthier eating patterns.”

She acknowledged certain limitations of the study, including its observational design and the fact that it was limited to non-Hispanic white health professionals, “thus limiting the generalizability of its findings to the whole population.”

Dr. Eckel, who is a past president of the American Heart Association, underscored the importance of one’s overall diet in mitigating the risk of developing coronary heart disease. “It’s not simply substituting animal protein with plant protein,” he said. “Fruits and vegetables and whole grains, lean protein from fish – a Mediterranean-style diet – is what the AHA recommends.”

Dr. Al-Shaar reported having no financial disclosures. The study was supported by a T32 training grant from the National Institutes of Health and by other grants from the NIH. The meeting was sponsored by the AHA.

[email protected]

SOURCE: Al-Shaar L et al. Epi/Lifestyle 2020, Abstract P512.

PHOENIX – Consumption of red meat, particularly the processed form, is linked to a higher risk of developing coronary heart disease in men, results from a large prospective analysis demonstrated.

“The findings of this study are in line with randomized trials showing that the consumption of red meat, as compared with plant-based protein sources, increases LDL cholesterol levels, and with previous studies on red meat and risk of coronary heart disease,” lead study author Laila Al-Shaar, MPH, PhD, said in an interview in advance of the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting.

According to Dr. Al-Shaar, a postdoctoral research fellow in the department of nutrition at the T.H. Chan School of Public Health at Harvard University, Boston, most of the existing studies on red meat and heart disease have examined the impact of increasing consumption of red meat while decreasing consumption of all other foods. For the current study, she and her colleagues used a substitution analysis approach to understand how replacing red meat (total, processed, or unprocessed) with another protein-rich food was associated with the risk of heart disease. “This would potentially provide more specific guidance for healthier alternatives for those planning to cut down their red meat intake,” she said.

She and her colleagues prospectively followed 43,259 men in the Health Professionals Follow-up Study (1986-2012) who had no known history of cancer or cardiovascular disease. Diet was assessed by a standardized and validated food frequency questionnaire that was updated every 4 years. Dr. Al-Shaar and her colleagues used multivariate Cox models to estimate hazard ratios and 95% confidence intervals of CHD risk across categories of red meat consumption. They performed substitution analyses by comparing coefficients in models including alternative foods as continuous variables.

Over roughly 933,000 person-years of follow-up, the researchers documented 4,148 incident CHD cases. Of these, 1,680 were fatal. After multivariate adjustment for dietary and nondietary risk factors, both total and processed red meat intake were associated with a modestly higher risk of CHD (hazard ratio for a one serving/day increment, 1.08; 95% confidence interval, 1.01-1.14 for total red meat; and HR, 1.13; 95% CI, 1.03-1.22 for processed red meat). Substitutions of one serving per day of other foods (including nuts, legumes, soy, whole grains, and low- and high-fat dairy) for one serving per day of total red meat were associated with a 10%-47% lower CHD risk.

Stronger inverse associations were observed between some of these substitutions for red meat and risk of fatal CHD. Substituting nuts lowered the risk of fatal heart disease by 17%, while replacing red meat with whole grains was linked to a 48% reduction in that outcome. Those associations were more pronounced when replacing processed red meat.

“Processed meats and meats in general have been thought to be potentially not favorable in terms of cardiovascular disease and cardiovascular disease risk,” Robert H. Eckel, MD, professor emeritus of medicine at the University of Colorado Anschutz Medical Campus, Aurora, said in an interview. “Now we have increasing data that not only is there a negative cardiovascular disease impact of animal protein, but we see this on all-cause mortality, including cancer.”

Dr. Al-Shaar said that the findings “support current recommendations to limit consumption of red meat and suggest that high-quality plant-based proteins such as nuts, legumes, and soy are good alternatives for individuals planning to have better food choices and healthier eating patterns.”

She acknowledged certain limitations of the study, including its observational design and the fact that it was limited to non-Hispanic white health professionals, “thus limiting the generalizability of its findings to the whole population.”

Dr. Eckel, who is a past president of the American Heart Association, underscored the importance of one’s overall diet in mitigating the risk of developing coronary heart disease. “It’s not simply substituting animal protein with plant protein,” he said. “Fruits and vegetables and whole grains, lean protein from fish – a Mediterranean-style diet – is what the AHA recommends.”

Dr. Al-Shaar reported having no financial disclosures. The study was supported by a T32 training grant from the National Institutes of Health and by other grants from the NIH. The meeting was sponsored by the AHA.

[email protected]

SOURCE: Al-Shaar L et al. Epi/Lifestyle 2020, Abstract P512.

PHOENIX – Consumption of red meat, particularly the processed form, is linked to a higher risk of developing coronary heart disease in men, results from a large prospective analysis demonstrated.

“The findings of this study are in line with randomized trials showing that the consumption of red meat, as compared with plant-based protein sources, increases LDL cholesterol levels, and with previous studies on red meat and risk of coronary heart disease,” lead study author Laila Al-Shaar, MPH, PhD, said in an interview in advance of the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting.

According to Dr. Al-Shaar, a postdoctoral research fellow in the department of nutrition at the T.H. Chan School of Public Health at Harvard University, Boston, most of the existing studies on red meat and heart disease have examined the impact of increasing consumption of red meat while decreasing consumption of all other foods. For the current study, she and her colleagues used a substitution analysis approach to understand how replacing red meat (total, processed, or unprocessed) with another protein-rich food was associated with the risk of heart disease. “This would potentially provide more specific guidance for healthier alternatives for those planning to cut down their red meat intake,” she said.

She and her colleagues prospectively followed 43,259 men in the Health Professionals Follow-up Study (1986-2012) who had no known history of cancer or cardiovascular disease. Diet was assessed by a standardized and validated food frequency questionnaire that was updated every 4 years. Dr. Al-Shaar and her colleagues used multivariate Cox models to estimate hazard ratios and 95% confidence intervals of CHD risk across categories of red meat consumption. They performed substitution analyses by comparing coefficients in models including alternative foods as continuous variables.

Over roughly 933,000 person-years of follow-up, the researchers documented 4,148 incident CHD cases. Of these, 1,680 were fatal. After multivariate adjustment for dietary and nondietary risk factors, both total and processed red meat intake were associated with a modestly higher risk of CHD (hazard ratio for a one serving/day increment, 1.08; 95% confidence interval, 1.01-1.14 for total red meat; and HR, 1.13; 95% CI, 1.03-1.22 for processed red meat). Substitutions of one serving per day of other foods (including nuts, legumes, soy, whole grains, and low- and high-fat dairy) for one serving per day of total red meat were associated with a 10%-47% lower CHD risk.

Stronger inverse associations were observed between some of these substitutions for red meat and risk of fatal CHD. Substituting nuts lowered the risk of fatal heart disease by 17%, while replacing red meat with whole grains was linked to a 48% reduction in that outcome. Those associations were more pronounced when replacing processed red meat.

“Processed meats and meats in general have been thought to be potentially not favorable in terms of cardiovascular disease and cardiovascular disease risk,” Robert H. Eckel, MD, professor emeritus of medicine at the University of Colorado Anschutz Medical Campus, Aurora, said in an interview. “Now we have increasing data that not only is there a negative cardiovascular disease impact of animal protein, but we see this on all-cause mortality, including cancer.”

Dr. Al-Shaar said that the findings “support current recommendations to limit consumption of red meat and suggest that high-quality plant-based proteins such as nuts, legumes, and soy are good alternatives for individuals planning to have better food choices and healthier eating patterns.”

She acknowledged certain limitations of the study, including its observational design and the fact that it was limited to non-Hispanic white health professionals, “thus limiting the generalizability of its findings to the whole population.”

Dr. Eckel, who is a past president of the American Heart Association, underscored the importance of one’s overall diet in mitigating the risk of developing coronary heart disease. “It’s not simply substituting animal protein with plant protein,” he said. “Fruits and vegetables and whole grains, lean protein from fish – a Mediterranean-style diet – is what the AHA recommends.”

Dr. Al-Shaar reported having no financial disclosures. The study was supported by a T32 training grant from the National Institutes of Health and by other grants from the NIH. The meeting was sponsored by the AHA.

[email protected]

SOURCE: Al-Shaar L et al. Epi/Lifestyle 2020, Abstract P512.

PHOENIX – Statin use for the secondary prevention of cardiovascular disease increased modestly between 2008 and 2017 in the United States, but more than 40% of patients with established atherosclerotic cardiovascular disease are still not on a statin.

Doug Brunk/MDedge News

In addition, even after release of the 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (Circulation. 2014;129:S1-45) that markedly increased the pool of eligible patients, disparities exist in the proportion of women versus men, and blacks and Hispanics versus whites with atherosclerotic cardiovascular disease (ASCVD) who are currently receiving a statin.

“Despite repeated calls for the use of statins for secondary prevention of CVD in multiple guidelines, gender and racial inequalities in the use of statins persist,” Joseph A. Salami, MD, MPH, said at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting, sponsored by the American Heart Association. “Cardiovascular disease remains the leading cause of death in the U.S. In 2017, it was responsible for 647,457 deaths. We have an opportunity to improve CVD-related outcomes and cost by intensifying efforts to use statins for the secondary prevention of CVD and closing gender and racial gaps. Action is needed.”

Dr. Salami, a biostatistician with the Baptist Health South Florida Center for Advanced Analytics in Coral Gables, based his remarks on an analysis of data contained in the 2008-2017 Medical Expenditure Panel Survey (MEPS), a national representative survey sponsored by the Agency for Healthcare Research and Quality. “Between 2013 and 2018 there were six different guidelines released encouraging statin use among ASCVD patients,” he said. “Besides the good number needed to treat, statin use on secondary prevention of CVD is cost effective.”

Given the proven efficacy of statin use in the prevention of CVD, he and his associates set out to examine trends in the proportion of adults with ASCVD using statins and to assess for gender and racial differences in their use. The researchers used ICD-9 and ICD-10 codes to define ASCVD among the MEPS study population, as well as self-reported history of coronary artery disease, peripheral artery disease, and stroke. After excluding adults aged younger than 40 years and those without ASCVD, this left a population of 15,911 patients. Of these, 44% were female, their mean age was 62 years, and 72% were Caucasian.

Overall, statin use increased from 50% in 2008 to 58.7% in 2017, with an average annual percentage change of 0.95% between 2010 and 2017 (P = .01). However, the annual percentage change in statin use was 0.25% among men versus 0.14% among women (P = .022). “Each year during the study period, more than 3 million women with ASCVD were not prescribed a statin, which translated into about 36 million adult-years,” Dr. Salami said. “In 2017, 16% of these women were African Americans and 15% were Hispanic.”

Logistic regression analysis revealed that in 2017, females with ASCVD were less likely to be prescribed a statin, compared with males (odds ratio, 0.52; P less than .001). In addition, compared with whites, blacks were less likely to be prescribed a statin (OR, 0.69; P = .012), as were Hispanics (OR, 0.62; P = .003). “In a multivariate logistic regression controlling for age, health insurance status, and comorbidities, the gender disparity remained statistically significant, but the racial disparity did not,” Dr. Salami said.

In an interview, one of the meeting session’s moderators, Sherry-Ann Brown, MD, PhD, characterized the study’s findings as sobering. “This should be an eye-opener for all of us in medicine, whether we are physicians, pharmacists, nurses, or researchers,” said Dr. Brown, who is a cardiologist and physician scientist at the Mayo Clinic in Rochester, Minn. “We’re all in this together, and we all have a role to play in addressing social determinants of health. I think we need to recognize the fact that we’re not treating blacks, Hispanics, and women to the degree that we should be, compared to whites and men. I think we need to do better, and we need to figure out how to reach that population, and how to improve.”

Dr. Salami acknowledged certain limitations of the study, including the fact that MEPS was carried out in a noninstitutionalized adult population and that the definition of ASCVD was based partly on self-report. “Therefore, an underestimation of number adults with ASCVD is likely,” he said. “We also couldn’t determine adherence to medication nor long-term use of statins among adults with ASCVD.”

He concluded his presentation by noting that, over the 10-year study period, there were about 71.2 million ASCVD adult-years without a statin prescription. “That is a staggering number,” Dr. Salami said.

He reported having no financial disclosures.

[email protected]

SOURCE: Salami A et al. Epi/Lifestyle 2020, Abstract 4.

PHOENIX – Statin use for the secondary prevention of cardiovascular disease increased modestly between 2008 and 2017 in the United States, but more than 40% of patients with established atherosclerotic cardiovascular disease are still not on a statin.

Doug Brunk/MDedge News

In addition, even after release of the 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (Circulation. 2014;129:S1-45) that markedly increased the pool of eligible patients, disparities exist in the proportion of women versus men, and blacks and Hispanics versus whites with atherosclerotic cardiovascular disease (ASCVD) who are currently receiving a statin.

“Despite repeated calls for the use of statins for secondary prevention of CVD in multiple guidelines, gender and racial inequalities in the use of statins persist,” Joseph A. Salami, MD, MPH, said at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting, sponsored by the American Heart Association. “Cardiovascular disease remains the leading cause of death in the U.S. In 2017, it was responsible for 647,457 deaths. We have an opportunity to improve CVD-related outcomes and cost by intensifying efforts to use statins for the secondary prevention of CVD and closing gender and racial gaps. Action is needed.”

Dr. Salami, a biostatistician with the Baptist Health South Florida Center for Advanced Analytics in Coral Gables, based his remarks on an analysis of data contained in the 2008-2017 Medical Expenditure Panel Survey (MEPS), a national representative survey sponsored by the Agency for Healthcare Research and Quality. “Between 2013 and 2018 there were six different guidelines released encouraging statin use among ASCVD patients,” he said. “Besides the good number needed to treat, statin use on secondary prevention of CVD is cost effective.”

Given the proven efficacy of statin use in the prevention of CVD, he and his associates set out to examine trends in the proportion of adults with ASCVD using statins and to assess for gender and racial differences in their use. The researchers used ICD-9 and ICD-10 codes to define ASCVD among the MEPS study population, as well as self-reported history of coronary artery disease, peripheral artery disease, and stroke. After excluding adults aged younger than 40 years and those without ASCVD, this left a population of 15,911 patients. Of these, 44% were female, their mean age was 62 years, and 72% were Caucasian.

Overall, statin use increased from 50% in 2008 to 58.7% in 2017, with an average annual percentage change of 0.95% between 2010 and 2017 (P = .01). However, the annual percentage change in statin use was 0.25% among men versus 0.14% among women (P = .022). “Each year during the study period, more than 3 million women with ASCVD were not prescribed a statin, which translated into about 36 million adult-years,” Dr. Salami said. “In 2017, 16% of these women were African Americans and 15% were Hispanic.”

Logistic regression analysis revealed that in 2017, females with ASCVD were less likely to be prescribed a statin, compared with males (odds ratio, 0.52; P less than .001). In addition, compared with whites, blacks were less likely to be prescribed a statin (OR, 0.69; P = .012), as were Hispanics (OR, 0.62; P = .003). “In a multivariate logistic regression controlling for age, health insurance status, and comorbidities, the gender disparity remained statistically significant, but the racial disparity did not,” Dr. Salami said.

In an interview, one of the meeting session’s moderators, Sherry-Ann Brown, MD, PhD, characterized the study’s findings as sobering. “This should be an eye-opener for all of us in medicine, whether we are physicians, pharmacists, nurses, or researchers,” said Dr. Brown, who is a cardiologist and physician scientist at the Mayo Clinic in Rochester, Minn. “We’re all in this together, and we all have a role to play in addressing social determinants of health. I think we need to recognize the fact that we’re not treating blacks, Hispanics, and women to the degree that we should be, compared to whites and men. I think we need to do better, and we need to figure out how to reach that population, and how to improve.”

Dr. Salami acknowledged certain limitations of the study, including the fact that MEPS was carried out in a noninstitutionalized adult population and that the definition of ASCVD was based partly on self-report. “Therefore, an underestimation of number adults with ASCVD is likely,” he said. “We also couldn’t determine adherence to medication nor long-term use of statins among adults with ASCVD.”

He concluded his presentation by noting that, over the 10-year study period, there were about 71.2 million ASCVD adult-years without a statin prescription. “That is a staggering number,” Dr. Salami said.

He reported having no financial disclosures.

[email protected]

SOURCE: Salami A et al. Epi/Lifestyle 2020, Abstract 4.

PHOENIX – Statin use for the secondary prevention of cardiovascular disease increased modestly between 2008 and 2017 in the United States, but more than 40% of patients with established atherosclerotic cardiovascular disease are still not on a statin.

Doug Brunk/MDedge News

In addition, even after release of the 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (Circulation. 2014;129:S1-45) that markedly increased the pool of eligible patients, disparities exist in the proportion of women versus men, and blacks and Hispanics versus whites with atherosclerotic cardiovascular disease (ASCVD) who are currently receiving a statin.

“Despite repeated calls for the use of statins for secondary prevention of CVD in multiple guidelines, gender and racial inequalities in the use of statins persist,” Joseph A. Salami, MD, MPH, said at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting, sponsored by the American Heart Association. “Cardiovascular disease remains the leading cause of death in the U.S. In 2017, it was responsible for 647,457 deaths. We have an opportunity to improve CVD-related outcomes and cost by intensifying efforts to use statins for the secondary prevention of CVD and closing gender and racial gaps. Action is needed.”

Dr. Salami, a biostatistician with the Baptist Health South Florida Center for Advanced Analytics in Coral Gables, based his remarks on an analysis of data contained in the 2008-2017 Medical Expenditure Panel Survey (MEPS), a national representative survey sponsored by the Agency for Healthcare Research and Quality. “Between 2013 and 2018 there were six different guidelines released encouraging statin use among ASCVD patients,” he said. “Besides the good number needed to treat, statin use on secondary prevention of CVD is cost effective.”

Given the proven efficacy of statin use in the prevention of CVD, he and his associates set out to examine trends in the proportion of adults with ASCVD using statins and to assess for gender and racial differences in their use. The researchers used ICD-9 and ICD-10 codes to define ASCVD among the MEPS study population, as well as self-reported history of coronary artery disease, peripheral artery disease, and stroke. After excluding adults aged younger than 40 years and those without ASCVD, this left a population of 15,911 patients. Of these, 44% were female, their mean age was 62 years, and 72% were Caucasian.

Overall, statin use increased from 50% in 2008 to 58.7% in 2017, with an average annual percentage change of 0.95% between 2010 and 2017 (P = .01). However, the annual percentage change in statin use was 0.25% among men versus 0.14% among women (P = .022). “Each year during the study period, more than 3 million women with ASCVD were not prescribed a statin, which translated into about 36 million adult-years,” Dr. Salami said. “In 2017, 16% of these women were African Americans and 15% were Hispanic.”

Logistic regression analysis revealed that in 2017, females with ASCVD were less likely to be prescribed a statin, compared with males (odds ratio, 0.52; P less than .001). In addition, compared with whites, blacks were less likely to be prescribed a statin (OR, 0.69; P = .012), as were Hispanics (OR, 0.62; P = .003). “In a multivariate logistic regression controlling for age, health insurance status, and comorbidities, the gender disparity remained statistically significant, but the racial disparity did not,” Dr. Salami said.

In an interview, one of the meeting session’s moderators, Sherry-Ann Brown, MD, PhD, characterized the study’s findings as sobering. “This should be an eye-opener for all of us in medicine, whether we are physicians, pharmacists, nurses, or researchers,” said Dr. Brown, who is a cardiologist and physician scientist at the Mayo Clinic in Rochester, Minn. “We’re all in this together, and we all have a role to play in addressing social determinants of health. I think we need to recognize the fact that we’re not treating blacks, Hispanics, and women to the degree that we should be, compared to whites and men. I think we need to do better, and we need to figure out how to reach that population, and how to improve.”

Dr. Salami acknowledged certain limitations of the study, including the fact that MEPS was carried out in a noninstitutionalized adult population and that the definition of ASCVD was based partly on self-report. “Therefore, an underestimation of number adults with ASCVD is likely,” he said. “We also couldn’t determine adherence to medication nor long-term use of statins among adults with ASCVD.”

He concluded his presentation by noting that, over the 10-year study period, there were about 71.2 million ASCVD adult-years without a statin prescription. “That is a staggering number,” Dr. Salami said.

He reported having no financial disclosures.

[email protected]

SOURCE: Salami A et al. Epi/Lifestyle 2020, Abstract 4.

For patients with nonalcoholic steatohepatitis (NASH) with cirrhosis and portal hypertension, belapectin therapy was safe but did not significantly improve fibrosis or hepatic venous pressure gradient, compared with placebo, according to the results of a multicenter phase 2b study.

After 52 weeks of infusions, the change in hepatic venous pressure gradient did not significantly differ between the 2-mg/kg group (–0.28 mm Hg) and the placebo group (0.10 mm Hg) or between the 8-mg/kg group (–0.25 mm Hg) and the placebo group (P = .1 for both comparisons). Belapectin also did not significantly improve fibrosis, nonalcoholic fatty liver disease activity score, or the frequency of various complications of cirrhosis. “However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce hepatic venous pressure gradient and development of varices,” wrote Naga Chalasani, MD, of Indiana University in Indianapolis and his associates. The findings were published in Gastroenterology.

NASH leads to portal hypertension, variceal bleeding, ascites with bacterial peritonitis, hepatic encephalopathy, and liver-related death and is a leading reason for liver transplantation among women and men. Galectin-3, which is primarily secreted by macrophages, is elevated in patients with NASH and has been linked to the pathophysiology of liver fibrosis in mice. Belapectin (GR-MD-02), a complex carbohydrate that targets and disrupts galectin-3, has been found to reduce liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies.

For this double-blind trial, the researchers randomly assigned 162 patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient at least 6 mm Hg) to receive biweekly infusions of belapectin 2 mg/kg (54 patients), belapectin 8 mg/kg (54 patients), or placebo (54 patients). Patients were treated for 52 weeks. The primary endpoint was change from baseline in hepatic venous pressure gradient.

In a post-hoc analysis of the 81 patients who had no esophageal varices at baseline, 2 mg/kg belapectin was associated with an average 1.61-mm Hg reduction in hepatic venous pressure gradient from baseline (P = .02) and with a reduction in the development of new varices (P = .03).These effects did not extend to subgroups of patients with varices at baseline, clinically significant portal hypertension, or mild portal hypertension. Moreover, 2 mg/kg belapectin did not improve fibrosis, and the higher dose of belapectin (8 mg/kg) met neither the primary endpoint nor the secondary endpoints in the overall cohort or in subgroup analyses. In the subgroup with no varices at baseline, Galectin Technologies is proceeding to initiating a phase 3 clinical trial.

“Interestingly and somewhat unexpectedly, belapectin was associated with an improvement in hepatocyte ballooning,” which “is considered fundamental to the pathogenesis of disease progression in nonalcoholic steatohepatitis,” the researchers wrote. “The significance of such improvement in hepatocyte ballooning in the absence of improvement of other histological components, especially inflammation, is unknown.”

Galectin Therapeutics provided funding. Dr. Chalasani disclosed grant support from Galectin Therapeutics and relevant consulting relationships with NuSirt, AbbVie, Afimmune (DS Biopharma), and several other pharmaceutical companies. Sixteen coinvestigators also disclosed relationships with pharmaceutical companies, of whom eight disclosed consulting relationships, received research funding, or were employed by Galectin.

SOURCE: Chalasani N et al. Gastroenterology. 2019 Dec 5. doi: 10.1053/j.gastro.2019.11.296.

*This story was updated on 3/18/2020.

For patients with nonalcoholic steatohepatitis (NASH) with cirrhosis and portal hypertension, belapectin therapy was safe but did not significantly improve fibrosis or hepatic venous pressure gradient, compared with placebo, according to the results of a multicenter phase 2b study.

After 52 weeks of infusions, the change in hepatic venous pressure gradient did not significantly differ between the 2-mg/kg group (–0.28 mm Hg) and the placebo group (0.10 mm Hg) or between the 8-mg/kg group (–0.25 mm Hg) and the placebo group (P = .1 for both comparisons). Belapectin also did not significantly improve fibrosis, nonalcoholic fatty liver disease activity score, or the frequency of various complications of cirrhosis. “However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce hepatic venous pressure gradient and development of varices,” wrote Naga Chalasani, MD, of Indiana University in Indianapolis and his associates. The findings were published in Gastroenterology.

NASH leads to portal hypertension, variceal bleeding, ascites with bacterial peritonitis, hepatic encephalopathy, and liver-related death and is a leading reason for liver transplantation among women and men. Galectin-3, which is primarily secreted by macrophages, is elevated in patients with NASH and has been linked to the pathophysiology of liver fibrosis in mice. Belapectin (GR-MD-02), a complex carbohydrate that targets and disrupts galectin-3, has been found to reduce liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies.

For this double-blind trial, the researchers randomly assigned 162 patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient at least 6 mm Hg) to receive biweekly infusions of belapectin 2 mg/kg (54 patients), belapectin 8 mg/kg (54 patients), or placebo (54 patients). Patients were treated for 52 weeks. The primary endpoint was change from baseline in hepatic venous pressure gradient.

In a post-hoc analysis of the 81 patients who had no esophageal varices at baseline, 2 mg/kg belapectin was associated with an average 1.61-mm Hg reduction in hepatic venous pressure gradient from baseline (P = .02) and with a reduction in the development of new varices (P = .03).These effects did not extend to subgroups of patients with varices at baseline, clinically significant portal hypertension, or mild portal hypertension. Moreover, 2 mg/kg belapectin did not improve fibrosis, and the higher dose of belapectin (8 mg/kg) met neither the primary endpoint nor the secondary endpoints in the overall cohort or in subgroup analyses. In the subgroup with no varices at baseline, Galectin Technologies is proceeding to initiating a phase 3 clinical trial.

“Interestingly and somewhat unexpectedly, belapectin was associated with an improvement in hepatocyte ballooning,” which “is considered fundamental to the pathogenesis of disease progression in nonalcoholic steatohepatitis,” the researchers wrote. “The significance of such improvement in hepatocyte ballooning in the absence of improvement of other histological components, especially inflammation, is unknown.”

Galectin Therapeutics provided funding. Dr. Chalasani disclosed grant support from Galectin Therapeutics and relevant consulting relationships with NuSirt, AbbVie, Afimmune (DS Biopharma), and several other pharmaceutical companies. Sixteen coinvestigators also disclosed relationships with pharmaceutical companies, of whom eight disclosed consulting relationships, received research funding, or were employed by Galectin.

SOURCE: Chalasani N et al. Gastroenterology. 2019 Dec 5. doi: 10.1053/j.gastro.2019.11.296.

*This story was updated on 3/18/2020.

For patients with nonalcoholic steatohepatitis (NASH) with cirrhosis and portal hypertension, belapectin therapy was safe but did not significantly improve fibrosis or hepatic venous pressure gradient, compared with placebo, according to the results of a multicenter phase 2b study.

After 52 weeks of infusions, the change in hepatic venous pressure gradient did not significantly differ between the 2-mg/kg group (–0.28 mm Hg) and the placebo group (0.10 mm Hg) or between the 8-mg/kg group (–0.25 mm Hg) and the placebo group (P = .1 for both comparisons). Belapectin also did not significantly improve fibrosis, nonalcoholic fatty liver disease activity score, or the frequency of various complications of cirrhosis. “However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce hepatic venous pressure gradient and development of varices,” wrote Naga Chalasani, MD, of Indiana University in Indianapolis and his associates. The findings were published in Gastroenterology.

NASH leads to portal hypertension, variceal bleeding, ascites with bacterial peritonitis, hepatic encephalopathy, and liver-related death and is a leading reason for liver transplantation among women and men. Galectin-3, which is primarily secreted by macrophages, is elevated in patients with NASH and has been linked to the pathophysiology of liver fibrosis in mice. Belapectin (GR-MD-02), a complex carbohydrate that targets and disrupts galectin-3, has been found to reduce liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies.

For this double-blind trial, the researchers randomly assigned 162 patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient at least 6 mm Hg) to receive biweekly infusions of belapectin 2 mg/kg (54 patients), belapectin 8 mg/kg (54 patients), or placebo (54 patients). Patients were treated for 52 weeks. The primary endpoint was change from baseline in hepatic venous pressure gradient.

In a post-hoc analysis of the 81 patients who had no esophageal varices at baseline, 2 mg/kg belapectin was associated with an average 1.61-mm Hg reduction in hepatic venous pressure gradient from baseline (P = .02) and with a reduction in the development of new varices (P = .03).These effects did not extend to subgroups of patients with varices at baseline, clinically significant portal hypertension, or mild portal hypertension. Moreover, 2 mg/kg belapectin did not improve fibrosis, and the higher dose of belapectin (8 mg/kg) met neither the primary endpoint nor the secondary endpoints in the overall cohort or in subgroup analyses. In the subgroup with no varices at baseline, Galectin Technologies is proceeding to initiating a phase 3 clinical trial.

“Interestingly and somewhat unexpectedly, belapectin was associated with an improvement in hepatocyte ballooning,” which “is considered fundamental to the pathogenesis of disease progression in nonalcoholic steatohepatitis,” the researchers wrote. “The significance of such improvement in hepatocyte ballooning in the absence of improvement of other histological components, especially inflammation, is unknown.”

Galectin Therapeutics provided funding. Dr. Chalasani disclosed grant support from Galectin Therapeutics and relevant consulting relationships with NuSirt, AbbVie, Afimmune (DS Biopharma), and several other pharmaceutical companies. Sixteen coinvestigators also disclosed relationships with pharmaceutical companies, of whom eight disclosed consulting relationships, received research funding, or were employed by Galectin.

SOURCE: Chalasani N et al. Gastroenterology. 2019 Dec 5. doi: 10.1053/j.gastro.2019.11.296.

*This story was updated on 3/18/2020.

PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.

“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”

The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.

In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.

For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.

Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.

The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).

“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).

“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”

Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.

She reported having no financial disclosures. The study was funded by the National Institute on Aging.

[email protected]

SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.

PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.

“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”

The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.

In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.

For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.

Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.

The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).

“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).

“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”

Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.

She reported having no financial disclosures. The study was funded by the National Institute on Aging.

[email protected]

SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.

PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.

“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”

The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.

In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.

For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.

Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.

The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).

“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).

“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”

Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.

She reported having no financial disclosures. The study was funded by the National Institute on Aging.

[email protected]

SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.

NATIONAL HARBOR, MD. – If positive, a major ongoing phase 3 trial of CSL112, an agent designed to promote efflux of cholesterol from macrophages, is positioned to prove the HDL hypothesis, according to an outline of the rationale of the trial at CRT 2020 sponsored by MedStar Heart & Vascular Institute.

“Twenty papers now show better efflux means better outcomes independent of standard risk factors” and “we know this drug improves efflux,” explained C. Michael Gibson, MD, an interventional cardiologist at Beth Israel Deaconess Hospital, Boston.

The HDL hypothesis was derived from the Framingham Heart Study, which correlated high levels of HDL cholesterol with a reduced risk of adverse cardiovascular (CV) outcomes, according to Dr. Gibson. Just as elevated LDL proved to be a treatable risk factor for CV events, reduced HDL was the target of numerous trials to achieve the same types of benefits.

All have failed.

The problem has been in seeing HDL as a number without addressing its function, Dr. Gibson said. In essence, he believes “the HDL hypothesis not been really tested to date.”

CSL112 is a novel formulation of apolipoprotein A-1 (apoA-1) that has been purified from human plasma and reconstituted to form HDL. In the experimental and clinical setting, including the AEGIS I pilot study, weekly infusions of CSL112 have been associated with a degree of cholesterol efflux that predicts major CV risk reductions.

At the same time that the multinational event-driven AEGIS II trial will determine whether cholesterol efflux with CSL112 does translate into protection from CV events, it will also examine the HDL side of the lipid equation. Dr. Gibson said that it is specifically designed to circumvent the weaknesses of previous efforts to target HDL for reducing CV risk.

“The previous studies were conducted in the wrong patients with the wrong drugs given in the wrong doses at the wrong times,” said Dr. Gibson, who is also professor of medicine at Harvard Medical School, Boston.

One major difference from previous trials is that AEGIS II is enrolling patients with an acute coronary syndrome rather than stable atherosclerosis. Many of those being enrolled have had a recent event. Also, rather than raising HDL, the goal of CSL112 is to increase cholesterol efflux, which is now considered to be the key function of HDL. Furthermore, the time frame for the primary outcome, which is a composite of major adverse cardiac outcomes (MACE), is 90 days rather than several years.

In patients with ACS, “it is the early period of vulnerability where efflux of cholesterol really appears to have the greatest influence on outcomes,” Dr. Gibson explained.

The failure of previous efforts to treat HDL now appears to be based on an incomplete understanding of the goals, according to Dr. Gibson. The doomed cholesteryl ester transfer protein (CETP) drugs, for example, effectively increased HDL levels, but generated a form of HDL that “was not all that functional.”

He noted that niacin raises HDL but has off-target effects. Apo-A1 Milano, a mutant variation of apo-A1, is now understood to reduce the endogenous form, which Dr. Gibson said might explain its counterproductive effect on CV protection.

Using a garbage truck analogy to explain the growing appreciation of factors involved in cholesterol accumulation in the macrophage, Dr. Gibson characterized ABCA1, a transporter protein sitting on the surface of the macrophage, as the loader. He described LCAT (lecithin-cholesterol acyltransferase), an enzyme that converts cholesterol into cholesteryl ester, as the compactor. He sees CRL112 as an empty garbage truck sent into the macrophage to reverse the process.

“We are moving beyond thinking of HDL as a number to try to better appreciate its function,” Dr. Gibson said.

The AEGIS II trial was opened in March of 2018. It has a planned enrollment of 17,400 patients, with an estimated completion date of October 2021.

Dr. Gibson reports financial relationships with Bayer, Janssen, Johnson & Johnson, and CSL Behring, the sponsor of the AEGIS II trial.

NATIONAL HARBOR, MD. – If positive, a major ongoing phase 3 trial of CSL112, an agent designed to promote efflux of cholesterol from macrophages, is positioned to prove the HDL hypothesis, according to an outline of the rationale of the trial at CRT 2020 sponsored by MedStar Heart & Vascular Institute.

“Twenty papers now show better efflux means better outcomes independent of standard risk factors” and “we know this drug improves efflux,” explained C. Michael Gibson, MD, an interventional cardiologist at Beth Israel Deaconess Hospital, Boston.

The HDL hypothesis was derived from the Framingham Heart Study, which correlated high levels of HDL cholesterol with a reduced risk of adverse cardiovascular (CV) outcomes, according to Dr. Gibson. Just as elevated LDL proved to be a treatable risk factor for CV events, reduced HDL was the target of numerous trials to achieve the same types of benefits.

All have failed.

The problem has been in seeing HDL as a number without addressing its function, Dr. Gibson said. In essence, he believes “the HDL hypothesis not been really tested to date.”

CSL112 is a novel formulation of apolipoprotein A-1 (apoA-1) that has been purified from human plasma and reconstituted to form HDL. In the experimental and clinical setting, including the AEGIS I pilot study, weekly infusions of CSL112 have been associated with a degree of cholesterol efflux that predicts major CV risk reductions.

At the same time that the multinational event-driven AEGIS II trial will determine whether cholesterol efflux with CSL112 does translate into protection from CV events, it will also examine the HDL side of the lipid equation. Dr. Gibson said that it is specifically designed to circumvent the weaknesses of previous efforts to target HDL for reducing CV risk.

“The previous studies were conducted in the wrong patients with the wrong drugs given in the wrong doses at the wrong times,” said Dr. Gibson, who is also professor of medicine at Harvard Medical School, Boston.

One major difference from previous trials is that AEGIS II is enrolling patients with an acute coronary syndrome rather than stable atherosclerosis. Many of those being enrolled have had a recent event. Also, rather than raising HDL, the goal of CSL112 is to increase cholesterol efflux, which is now considered to be the key function of HDL. Furthermore, the time frame for the primary outcome, which is a composite of major adverse cardiac outcomes (MACE), is 90 days rather than several years.

In patients with ACS, “it is the early period of vulnerability where efflux of cholesterol really appears to have the greatest influence on outcomes,” Dr. Gibson explained.

The failure of previous efforts to treat HDL now appears to be based on an incomplete understanding of the goals, according to Dr. Gibson. The doomed cholesteryl ester transfer protein (CETP) drugs, for example, effectively increased HDL levels, but generated a form of HDL that “was not all that functional.”

He noted that niacin raises HDL but has off-target effects. Apo-A1 Milano, a mutant variation of apo-A1, is now understood to reduce the endogenous form, which Dr. Gibson said might explain its counterproductive effect on CV protection.

Using a garbage truck analogy to explain the growing appreciation of factors involved in cholesterol accumulation in the macrophage, Dr. Gibson characterized ABCA1, a transporter protein sitting on the surface of the macrophage, as the loader. He described LCAT (lecithin-cholesterol acyltransferase), an enzyme that converts cholesterol into cholesteryl ester, as the compactor. He sees CRL112 as an empty garbage truck sent into the macrophage to reverse the process.

“We are moving beyond thinking of HDL as a number to try to better appreciate its function,” Dr. Gibson said.

The AEGIS II trial was opened in March of 2018. It has a planned enrollment of 17,400 patients, with an estimated completion date of October 2021.

Dr. Gibson reports financial relationships with Bayer, Janssen, Johnson & Johnson, and CSL Behring, the sponsor of the AEGIS II trial.

NATIONAL HARBOR, MD. – If positive, a major ongoing phase 3 trial of CSL112, an agent designed to promote efflux of cholesterol from macrophages, is positioned to prove the HDL hypothesis, according to an outline of the rationale of the trial at CRT 2020 sponsored by MedStar Heart & Vascular Institute.

“Twenty papers now show better efflux means better outcomes independent of standard risk factors” and “we know this drug improves efflux,” explained C. Michael Gibson, MD, an interventional cardiologist at Beth Israel Deaconess Hospital, Boston.

The HDL hypothesis was derived from the Framingham Heart Study, which correlated high levels of HDL cholesterol with a reduced risk of adverse cardiovascular (CV) outcomes, according to Dr. Gibson. Just as elevated LDL proved to be a treatable risk factor for CV events, reduced HDL was the target of numerous trials to achieve the same types of benefits.

All have failed.

The problem has been in seeing HDL as a number without addressing its function, Dr. Gibson said. In essence, he believes “the HDL hypothesis not been really tested to date.”

CSL112 is a novel formulation of apolipoprotein A-1 (apoA-1) that has been purified from human plasma and reconstituted to form HDL. In the experimental and clinical setting, including the AEGIS I pilot study, weekly infusions of CSL112 have been associated with a degree of cholesterol efflux that predicts major CV risk reductions.

At the same time that the multinational event-driven AEGIS II trial will determine whether cholesterol efflux with CSL112 does translate into protection from CV events, it will also examine the HDL side of the lipid equation. Dr. Gibson said that it is specifically designed to circumvent the weaknesses of previous efforts to target HDL for reducing CV risk.

“The previous studies were conducted in the wrong patients with the wrong drugs given in the wrong doses at the wrong times,” said Dr. Gibson, who is also professor of medicine at Harvard Medical School, Boston.

One major difference from previous trials is that AEGIS II is enrolling patients with an acute coronary syndrome rather than stable atherosclerosis. Many of those being enrolled have had a recent event. Also, rather than raising HDL, the goal of CSL112 is to increase cholesterol efflux, which is now considered to be the key function of HDL. Furthermore, the time frame for the primary outcome, which is a composite of major adverse cardiac outcomes (MACE), is 90 days rather than several years.

In patients with ACS, “it is the early period of vulnerability where efflux of cholesterol really appears to have the greatest influence on outcomes,” Dr. Gibson explained.

The failure of previous efforts to treat HDL now appears to be based on an incomplete understanding of the goals, according to Dr. Gibson. The doomed cholesteryl ester transfer protein (CETP) drugs, for example, effectively increased HDL levels, but generated a form of HDL that “was not all that functional.”

He noted that niacin raises HDL but has off-target effects. Apo-A1 Milano, a mutant variation of apo-A1, is now understood to reduce the endogenous form, which Dr. Gibson said might explain its counterproductive effect on CV protection.

Using a garbage truck analogy to explain the growing appreciation of factors involved in cholesterol accumulation in the macrophage, Dr. Gibson characterized ABCA1, a transporter protein sitting on the surface of the macrophage, as the loader. He described LCAT (lecithin-cholesterol acyltransferase), an enzyme that converts cholesterol into cholesteryl ester, as the compactor. He sees CRL112 as an empty garbage truck sent into the macrophage to reverse the process.

“We are moving beyond thinking of HDL as a number to try to better appreciate its function,” Dr. Gibson said.

The AEGIS II trial was opened in March of 2018. It has a planned enrollment of 17,400 patients, with an estimated completion date of October 2021.

Dr. Gibson reports financial relationships with Bayer, Janssen, Johnson & Johnson, and CSL Behring, the sponsor of the AEGIS II trial.

Bempedoic acid, the first agent in a new class of drugs that reduce LDL cholesterol, received Food and Drug Administration approval on Feb. 21 for treating selected hypercholesterolemic patients and is a welcome addition to the medicine cabinet, say lipid experts.

MDedge News

However, it is a tertiary option at least until results from a 14,000 patient clinical-outcome trial of bempedoic acid come out, likely in 2022, they agreed.

“I’m excited to have a new tool in the toolkit for treating high-risk patients, but I will always reach first for the drugs proven to reduce clinical outcomes,” said Erin D. Michos, MD, director of Women’s Cardiovascular Health and associate director of Preventive Cardiology at Johns Hopkins Medicine in Baltimore. That sentiment, shared by other experts, should for the time being relegate bempedoic acid (Nexletol) to a backup role behind statins, ezetimibe, and the PCSK9 inhibitor antibodies that are all now on the U.S. market and all buttressed with evidence of their ability to cut cardiovascular disease death and other CVD outcomes from large outcome studies.

The existing evidence base for bempedoic acid rests primarily two multicenter, randomized, placebo-controlled clinical trials of bempedoic acid in patients with LDL levels above 70 mg/dL while on maximally tolerated lipid-lowering therapy. In CLEAR Harmony, results showed that treatment with bempedoic acid cut LDL-cholesterol levels by an average of 18% more compared with placebo (N Engl J Med 2019;380:1022-32). In CLEAR Wisdom, bempedoic acid reduced LDL cholesterol levels by 17% (JAMA. 2019;322[18]:1780-8).

While those two trials proved the drug’s ability to lower levels of LDL cholesterol, they lacked the power to address whether this effect cut the incidence of CVD events, a question that the CLEAR Outcomes trial aims to answer.

“I believe in the lipid hypothesis, but the main thing we need to see is whether bempedoic acid leads to a meaningful reduction in CVD events. The window for bempedoic acid will remain narrow until we see the outcomes results,” Dr. Michos said in an interview.

Bempedoic acid is a prodrug that’s activated in liver and targets the same cholesterol synthesis pathway as statins by inhibition of ATP-citrate lyase, an enzyme that’s upstream of HMG-CoA reductase, thereby enhancing LDL cholesterol clearance via up-regulation of LDL receptors

.

Combined treatment with bempedoic acid and ezetimibe “may be successful in avoiding [using] a PCSK9 inhibitor in some patients, and in particular patients with HeFH or those who are statin intolerant.” But like his colleagues, Dr. Eckel agreed that, for the moment, ezetimibe has an edge over bempedoic acid because of its more extensive evidence base. “If the combination of bempedoic acid and ezetimibe is not needed, the decision [of which one of these to use] needs to depend on the outcome trial results for ezetimibe,” he said. Other factors clinicians could apply if faced with choosing between these two agents include the significant reduction in high-sensitivity C-reactive protein that bempedoic acid produces; the downside that bempedoic acid can cause in some patients an early and persistent rise in serum uric acid levels that can trigger gout flares in patients with a history of gout or at risk for gout; and cost, he said.

Cost is the room-dwelling elephant that colors many decisions about which lipid-lowering drug to use for patients, with options running the price gamut from the generic and uniformly affordable statins and ezetimibe, to the notoriously pricey PCSK9 inhibitors that remain for many patients either prohibitively expensive or hard to get covered by some insurers. Bempedoic acid seems on track to fall somewhere between these two poles, although staff members from Esperion, the company that developed and will market bempedoic acid as Nexletol starting on March 30, declared in a conference call on Feb. 24 that “cost will not be an issue,” for indicated patients prescribed the drug. Company representatives cited a program of coupons, discounts, and rebates they have planned that they anticipate will allow patients who meet the labeled indications to have an out-of-pocket cost for bempedoic acid of “as low as” $10 for a 90-pill supply. They also noted their goal of getting bempedoic acid onto the lowest tier of the Medicare formulary.

How these steps actually play out in the fun house of U.S. prescription drug pricing and preauthorizations remains to be seen. “Out-of-pocket costs are not the real drivers” of drug access, noted Dr. Robinson. “Insurers will likely start with restricted access and prior authorization requirements, just as they did with ezetimibe when it was on patent and prior to having the results from a CVD outcomes trial.” For the time being, bempedoic acid can generally be seen as “expensive ezetimibe,” summed up Dr. Robinson.

Despite that somewhat dismissive characterization, experts are intrigued by the possibility of combining two moderately potent, oral, and safe lipid-lowering drugs in selected patients as a potential alternative to the still financially challenging PCSK9 inhibitors. Combining bempedoic acid and ezetimibe “has a lot of appeal,” said Dr. Michos. “Even though preauthorization has gotten better, it’s still a challenge to get a PCSK9 inhibitor approved.”

Much of her enthusiasm stems from a study reported last year that randomized 301 patients to treatment with bempedoic acid, ezetimibe, or both. The results showed that combined treatment has a similar safety profile to treatment with either drug alone, and produced a cut in LDL cholesterol that was roughly additive for the reductions produced by each drug by itself: Ezetimibe alone cut LDL by about 23%, bempedoic acid alone by about 17%, and the two dosed together once daily resulted in an average 36% drop (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864671). The results showed that, “in patients requiring intensive LDL cholesterol lowering, who cannot afford PCSK9 inhibitors, or have statin intolerance, bempedoic acid and ezetimibe are stronger together and can serve as an alternative approach for lipid management in ASCVD prevention,” wrote Dr. Michos and a coauthor in a commentary that appeared with the study results (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864672).

The concept of combined bempedoic acid and ezetimibe treatment is so appealing that the bempedoic acid manufacturer, Esperion, has already developed a single-pill formulation of the two drugs that received FDA marketing approval on February 26. A company statement said that marketing of this combined formulation, Nexlizet, will start in July 2020.

Although interest in bempedoic acid seems running high for patients included in the new FDA indication, Dr. Michos and others see possibly greater potential for what would now be off-label use for primary prevention in high-risk patients without HeFH, patients who generally don’t qualify for insurance coverage of a PCSK9 inhibitor.

“Use in primary prevention in [non-HeFH] patients with insufficient lowering of LDL cholesterol wouldn’t surprise me,” but a big concern will be out-of-pocket cost when off-label use precludes insurance coverage or discount eligibility, noted Dr. Eckel. An Esperion spokesperson said that the undiscounted, wholesale acquisition cost for bempedoic acid is expected to be roughly $10/pill, or about $300 for a 30-day supply, positioning it more or less midway between generic statins and ezetimibe and the list price for a PCSk9 inhibitor of roughly $500/month.

“I’m most excited about bempedoic acid in the off-label space, for patients who can’t get approved for a PCSK9 inhibitor, for treating patients with subclinical ASCVD, or really high-risk patients with multiple risk factors including diabetes,” especially when these patients are intolerant of a high-intensity statin regimen, said Dr. Michos. “I have a clinic full of patients” who can’t take their full, indicated dosage of a high-intensity statin, and when those patients also can’t get on treatment with a PCSK9 inhibitor then bempedoic acid will be an important part of their alternative regimen, she explained.

Dr. Michos had no disclosures. Dr. Robinson has received research funding from Esperion and from several other companies, and she has been a consultant to Amgen, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi. Dr. Eckel has received honoraria from Kowa, Merck, Novo Nordisk, and Sanofi/Regeneron.

This article was updated 2/27/20.

[email protected]

Bempedoic acid, the first agent in a new class of drugs that reduce LDL cholesterol, received Food and Drug Administration approval on Feb. 21 for treating selected hypercholesterolemic patients and is a welcome addition to the medicine cabinet, say lipid experts.

MDedge News

However, it is a tertiary option at least until results from a 14,000 patient clinical-outcome trial of bempedoic acid come out, likely in 2022, they agreed.

“I’m excited to have a new tool in the toolkit for treating high-risk patients, but I will always reach first for the drugs proven to reduce clinical outcomes,” said Erin D. Michos, MD, director of Women’s Cardiovascular Health and associate director of Preventive Cardiology at Johns Hopkins Medicine in Baltimore. That sentiment, shared by other experts, should for the time being relegate bempedoic acid (Nexletol) to a backup role behind statins, ezetimibe, and the PCSK9 inhibitor antibodies that are all now on the U.S. market and all buttressed with evidence of their ability to cut cardiovascular disease death and other CVD outcomes from large outcome studies.

The existing evidence base for bempedoic acid rests primarily two multicenter, randomized, placebo-controlled clinical trials of bempedoic acid in patients with LDL levels above 70 mg/dL while on maximally tolerated lipid-lowering therapy. In CLEAR Harmony, results showed that treatment with bempedoic acid cut LDL-cholesterol levels by an average of 18% more compared with placebo (N Engl J Med 2019;380:1022-32). In CLEAR Wisdom, bempedoic acid reduced LDL cholesterol levels by 17% (JAMA. 2019;322[18]:1780-8).

While those two trials proved the drug’s ability to lower levels of LDL cholesterol, they lacked the power to address whether this effect cut the incidence of CVD events, a question that the CLEAR Outcomes trial aims to answer.

“I believe in the lipid hypothesis, but the main thing we need to see is whether bempedoic acid leads to a meaningful reduction in CVD events. The window for bempedoic acid will remain narrow until we see the outcomes results,” Dr. Michos said in an interview.

Bempedoic acid is a prodrug that’s activated in liver and targets the same cholesterol synthesis pathway as statins by inhibition of ATP-citrate lyase, an enzyme that’s upstream of HMG-CoA reductase, thereby enhancing LDL cholesterol clearance via up-regulation of LDL receptors

.

Combined treatment with bempedoic acid and ezetimibe “may be successful in avoiding [using] a PCSK9 inhibitor in some patients, and in particular patients with HeFH or those who are statin intolerant.” But like his colleagues, Dr. Eckel agreed that, for the moment, ezetimibe has an edge over bempedoic acid because of its more extensive evidence base. “If the combination of bempedoic acid and ezetimibe is not needed, the decision [of which one of these to use] needs to depend on the outcome trial results for ezetimibe,” he said. Other factors clinicians could apply if faced with choosing between these two agents include the significant reduction in high-sensitivity C-reactive protein that bempedoic acid produces; the downside that bempedoic acid can cause in some patients an early and persistent rise in serum uric acid levels that can trigger gout flares in patients with a history of gout or at risk for gout; and cost, he said.

Cost is the room-dwelling elephant that colors many decisions about which lipid-lowering drug to use for patients, with options running the price gamut from the generic and uniformly affordable statins and ezetimibe, to the notoriously pricey PCSK9 inhibitors that remain for many patients either prohibitively expensive or hard to get covered by some insurers. Bempedoic acid seems on track to fall somewhere between these two poles, although staff members from Esperion, the company that developed and will market bempedoic acid as Nexletol starting on March 30, declared in a conference call on Feb. 24 that “cost will not be an issue,” for indicated patients prescribed the drug. Company representatives cited a program of coupons, discounts, and rebates they have planned that they anticipate will allow patients who meet the labeled indications to have an out-of-pocket cost for bempedoic acid of “as low as” $10 for a 90-pill supply. They also noted their goal of getting bempedoic acid onto the lowest tier of the Medicare formulary.

How these steps actually play out in the fun house of U.S. prescription drug pricing and preauthorizations remains to be seen. “Out-of-pocket costs are not the real drivers” of drug access, noted Dr. Robinson. “Insurers will likely start with restricted access and prior authorization requirements, just as they did with ezetimibe when it was on patent and prior to having the results from a CVD outcomes trial.” For the time being, bempedoic acid can generally be seen as “expensive ezetimibe,” summed up Dr. Robinson.

Despite that somewhat dismissive characterization, experts are intrigued by the possibility of combining two moderately potent, oral, and safe lipid-lowering drugs in selected patients as a potential alternative to the still financially challenging PCSK9 inhibitors. Combining bempedoic acid and ezetimibe “has a lot of appeal,” said Dr. Michos. “Even though preauthorization has gotten better, it’s still a challenge to get a PCSK9 inhibitor approved.”

Much of her enthusiasm stems from a study reported last year that randomized 301 patients to treatment with bempedoic acid, ezetimibe, or both. The results showed that combined treatment has a similar safety profile to treatment with either drug alone, and produced a cut in LDL cholesterol that was roughly additive for the reductions produced by each drug by itself: Ezetimibe alone cut LDL by about 23%, bempedoic acid alone by about 17%, and the two dosed together once daily resulted in an average 36% drop (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864671). The results showed that, “in patients requiring intensive LDL cholesterol lowering, who cannot afford PCSK9 inhibitors, or have statin intolerance, bempedoic acid and ezetimibe are stronger together and can serve as an alternative approach for lipid management in ASCVD prevention,” wrote Dr. Michos and a coauthor in a commentary that appeared with the study results (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864672).

The concept of combined bempedoic acid and ezetimibe treatment is so appealing that the bempedoic acid manufacturer, Esperion, has already developed a single-pill formulation of the two drugs that received FDA marketing approval on February 26. A company statement said that marketing of this combined formulation, Nexlizet, will start in July 2020.

Although interest in bempedoic acid seems running high for patients included in the new FDA indication, Dr. Michos and others see possibly greater potential for what would now be off-label use for primary prevention in high-risk patients without HeFH, patients who generally don’t qualify for insurance coverage of a PCSK9 inhibitor.

“Use in primary prevention in [non-HeFH] patients with insufficient lowering of LDL cholesterol wouldn’t surprise me,” but a big concern will be out-of-pocket cost when off-label use precludes insurance coverage or discount eligibility, noted Dr. Eckel. An Esperion spokesperson said that the undiscounted, wholesale acquisition cost for bempedoic acid is expected to be roughly $10/pill, or about $300 for a 30-day supply, positioning it more or less midway between generic statins and ezetimibe and the list price for a PCSk9 inhibitor of roughly $500/month.

“I’m most excited about bempedoic acid in the off-label space, for patients who can’t get approved for a PCSK9 inhibitor, for treating patients with subclinical ASCVD, or really high-risk patients with multiple risk factors including diabetes,” especially when these patients are intolerant of a high-intensity statin regimen, said Dr. Michos. “I have a clinic full of patients” who can’t take their full, indicated dosage of a high-intensity statin, and when those patients also can’t get on treatment with a PCSK9 inhibitor then bempedoic acid will be an important part of their alternative regimen, she explained.

Dr. Michos had no disclosures. Dr. Robinson has received research funding from Esperion and from several other companies, and she has been a consultant to Amgen, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi. Dr. Eckel has received honoraria from Kowa, Merck, Novo Nordisk, and Sanofi/Regeneron.

This article was updated 2/27/20.

[email protected]

Bempedoic acid, the first agent in a new class of drugs that reduce LDL cholesterol, received Food and Drug Administration approval on Feb. 21 for treating selected hypercholesterolemic patients and is a welcome addition to the medicine cabinet, say lipid experts.

MDedge News

However, it is a tertiary option at least until results from a 14,000 patient clinical-outcome trial of bempedoic acid come out, likely in 2022, they agreed.

“I’m excited to have a new tool in the toolkit for treating high-risk patients, but I will always reach first for the drugs proven to reduce clinical outcomes,” said Erin D. Michos, MD, director of Women’s Cardiovascular Health and associate director of Preventive Cardiology at Johns Hopkins Medicine in Baltimore. That sentiment, shared by other experts, should for the time being relegate bempedoic acid (Nexletol) to a backup role behind statins, ezetimibe, and the PCSK9 inhibitor antibodies that are all now on the U.S. market and all buttressed with evidence of their ability to cut cardiovascular disease death and other CVD outcomes from large outcome studies.

The existing evidence base for bempedoic acid rests primarily two multicenter, randomized, placebo-controlled clinical trials of bempedoic acid in patients with LDL levels above 70 mg/dL while on maximally tolerated lipid-lowering therapy. In CLEAR Harmony, results showed that treatment with bempedoic acid cut LDL-cholesterol levels by an average of 18% more compared with placebo (N Engl J Med 2019;380:1022-32). In CLEAR Wisdom, bempedoic acid reduced LDL cholesterol levels by 17% (JAMA. 2019;322[18]:1780-8).

While those two trials proved the drug’s ability to lower levels of LDL cholesterol, they lacked the power to address whether this effect cut the incidence of CVD events, a question that the CLEAR Outcomes trial aims to answer.

“I believe in the lipid hypothesis, but the main thing we need to see is whether bempedoic acid leads to a meaningful reduction in CVD events. The window for bempedoic acid will remain narrow until we see the outcomes results,” Dr. Michos said in an interview.

Bempedoic acid is a prodrug that’s activated in liver and targets the same cholesterol synthesis pathway as statins by inhibition of ATP-citrate lyase, an enzyme that’s upstream of HMG-CoA reductase, thereby enhancing LDL cholesterol clearance via up-regulation of LDL receptors

.

Combined treatment with bempedoic acid and ezetimibe “may be successful in avoiding [using] a PCSK9 inhibitor in some patients, and in particular patients with HeFH or those who are statin intolerant.” But like his colleagues, Dr. Eckel agreed that, for the moment, ezetimibe has an edge over bempedoic acid because of its more extensive evidence base. “If the combination of bempedoic acid and ezetimibe is not needed, the decision [of which one of these to use] needs to depend on the outcome trial results for ezetimibe,” he said. Other factors clinicians could apply if faced with choosing between these two agents include the significant reduction in high-sensitivity C-reactive protein that bempedoic acid produces; the downside that bempedoic acid can cause in some patients an early and persistent rise in serum uric acid levels that can trigger gout flares in patients with a history of gout or at risk for gout; and cost, he said.

Cost is the room-dwelling elephant that colors many decisions about which lipid-lowering drug to use for patients, with options running the price gamut from the generic and uniformly affordable statins and ezetimibe, to the notoriously pricey PCSK9 inhibitors that remain for many patients either prohibitively expensive or hard to get covered by some insurers. Bempedoic acid seems on track to fall somewhere between these two poles, although staff members from Esperion, the company that developed and will market bempedoic acid as Nexletol starting on March 30, declared in a conference call on Feb. 24 that “cost will not be an issue,” for indicated patients prescribed the drug. Company representatives cited a program of coupons, discounts, and rebates they have planned that they anticipate will allow patients who meet the labeled indications to have an out-of-pocket cost for bempedoic acid of “as low as” $10 for a 90-pill supply. They also noted their goal of getting bempedoic acid onto the lowest tier of the Medicare formulary.

How these steps actually play out in the fun house of U.S. prescription drug pricing and preauthorizations remains to be seen. “Out-of-pocket costs are not the real drivers” of drug access, noted Dr. Robinson. “Insurers will likely start with restricted access and prior authorization requirements, just as they did with ezetimibe when it was on patent and prior to having the results from a CVD outcomes trial.” For the time being, bempedoic acid can generally be seen as “expensive ezetimibe,” summed up Dr. Robinson.

Despite that somewhat dismissive characterization, experts are intrigued by the possibility of combining two moderately potent, oral, and safe lipid-lowering drugs in selected patients as a potential alternative to the still financially challenging PCSK9 inhibitors. Combining bempedoic acid and ezetimibe “has a lot of appeal,” said Dr. Michos. “Even though preauthorization has gotten better, it’s still a challenge to get a PCSK9 inhibitor approved.”

Much of her enthusiasm stems from a study reported last year that randomized 301 patients to treatment with bempedoic acid, ezetimibe, or both. The results showed that combined treatment has a similar safety profile to treatment with either drug alone, and produced a cut in LDL cholesterol that was roughly additive for the reductions produced by each drug by itself: Ezetimibe alone cut LDL by about 23%, bempedoic acid alone by about 17%, and the two dosed together once daily resulted in an average 36% drop (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864671). The results showed that, “in patients requiring intensive LDL cholesterol lowering, who cannot afford PCSK9 inhibitors, or have statin intolerance, bempedoic acid and ezetimibe are stronger together and can serve as an alternative approach for lipid management in ASCVD prevention,” wrote Dr. Michos and a coauthor in a commentary that appeared with the study results (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864672).

The concept of combined bempedoic acid and ezetimibe treatment is so appealing that the bempedoic acid manufacturer, Esperion, has already developed a single-pill formulation of the two drugs that received FDA marketing approval on February 26. A company statement said that marketing of this combined formulation, Nexlizet, will start in July 2020.

Although interest in bempedoic acid seems running high for patients included in the new FDA indication, Dr. Michos and others see possibly greater potential for what would now be off-label use for primary prevention in high-risk patients without HeFH, patients who generally don’t qualify for insurance coverage of a PCSK9 inhibitor.

“Use in primary prevention in [non-HeFH] patients with insufficient lowering of LDL cholesterol wouldn’t surprise me,” but a big concern will be out-of-pocket cost when off-label use precludes insurance coverage or discount eligibility, noted Dr. Eckel. An Esperion spokesperson said that the undiscounted, wholesale acquisition cost for bempedoic acid is expected to be roughly $10/pill, or about $300 for a 30-day supply, positioning it more or less midway between generic statins and ezetimibe and the list price for a PCSk9 inhibitor of roughly $500/month.

“I’m most excited about bempedoic acid in the off-label space, for patients who can’t get approved for a PCSK9 inhibitor, for treating patients with subclinical ASCVD, or really high-risk patients with multiple risk factors including diabetes,” especially when these patients are intolerant of a high-intensity statin regimen, said Dr. Michos. “I have a clinic full of patients” who can’t take their full, indicated dosage of a high-intensity statin, and when those patients also can’t get on treatment with a PCSK9 inhibitor then bempedoic acid will be an important part of their alternative regimen, she explained.

Dr. Michos had no disclosures. Dr. Robinson has received research funding from Esperion and from several other companies, and she has been a consultant to Amgen, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi. Dr. Eckel has received honoraria from Kowa, Merck, Novo Nordisk, and Sanofi/Regeneron.

This article was updated 2/27/20.

[email protected]

The Food and Drug Administration has approved bempedoic acid (Nexletol) for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional LDL cholesterol lowering.

The oral adenosine triphosphate–citrate lyase (ACL) inhibitor is indicated as an adjunct to diet and maximally tolerated statin therapy in these patients, and approved at the 180 mg once daily dose, the agency announced today.

The safety and efficacy of bempedoic acid were demonstrated over 52 weeks in two multicenter randomized, clinical trials involving 3,009 adults with HeFH or established ASCVD on maximally tolerated statin therapy.

The difference between bempedoic acid and placebo for the primary outcome of change in LDL cholesterol from baseline to week 12 was –18% in the first trial, CLEAR Harmony (95% confidence interval, –20% to –16%; P less than .001), and –17% in the second trial, CLEAR Wisdom (95% CI, –21% to –14%; P less than .001).

The label notes that the effect on cardiovascular morbidity and mortality has not been determined. The label also includes warnings stating that bempedoic acid may increase blood uric acid levels and is associated with an increased risk of tendon rupture or injury.

In clinical trials, 26% of bempedoic acid–treated patients with normal baseline uric acid values versus 9.5% of placebo-treated patients experienced hyperuricemia one or more times, and 3.5% of patients experienced clinically significant hyperuricemia reported as an adverse reaction versus 1.1% with placebo, according to the label. Gout was reported in 1.5% of patients treated with bempedoic acid and 0.4% of those treated with placebo.

Also in clinical trials, the risk of tendon rupture was 0.5% with bempedoic acid and 0% with placebo. Tendon rupture involved the rotator cuff, biceps tendon, or Achilles tendon, and occurred within weeks to months of starting the drug. Rupture may “occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders,” the label states.

The label also advises that patients avoid concomitant use of bempedoic acid with simvastatin greater than 20 mg or pravastatin greater than 40 mg because it causes an increase in statin concentrations and may increase the risk of related myopathy.

A decision is expected shortly on a new drug application submitted by Esperion for an LDL cholesterol–lowering indication for bempedoic acid 180 mg/ezetimibe 10 mg combination tablet.

Full prescribing information is available online.

This article first appeared on Medscape.com.

The Food and Drug Administration has approved bempedoic acid (Nexletol) for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional LDL cholesterol lowering.

The oral adenosine triphosphate–citrate lyase (ACL) inhibitor is indicated as an adjunct to diet and maximally tolerated statin therapy in these patients, and approved at the 180 mg once daily dose, the agency announced today.

The safety and efficacy of bempedoic acid were demonstrated over 52 weeks in two multicenter randomized, clinical trials involving 3,009 adults with HeFH or established ASCVD on maximally tolerated statin therapy.

The difference between bempedoic acid and placebo for the primary outcome of change in LDL cholesterol from baseline to week 12 was –18% in the first trial, CLEAR Harmony (95% confidence interval, –20% to –16%; P less than .001), and –17% in the second trial, CLEAR Wisdom (95% CI, –21% to –14%; P less than .001).

The label notes that the effect on cardiovascular morbidity and mortality has not been determined. The label also includes warnings stating that bempedoic acid may increase blood uric acid levels and is associated with an increased risk of tendon rupture or injury.

In clinical trials, 26% of bempedoic acid–treated patients with normal baseline uric acid values versus 9.5% of placebo-treated patients experienced hyperuricemia one or more times, and 3.5% of patients experienced clinically significant hyperuricemia reported as an adverse reaction versus 1.1% with placebo, according to the label. Gout was reported in 1.5% of patients treated with bempedoic acid and 0.4% of those treated with placebo.

Also in clinical trials, the risk of tendon rupture was 0.5% with bempedoic acid and 0% with placebo. Tendon rupture involved the rotator cuff, biceps tendon, or Achilles tendon, and occurred within weeks to months of starting the drug. Rupture may “occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders,” the label states.

The label also advises that patients avoid concomitant use of bempedoic acid with simvastatin greater than 20 mg or pravastatin greater than 40 mg because it causes an increase in statin concentrations and may increase the risk of related myopathy.

A decision is expected shortly on a new drug application submitted by Esperion for an LDL cholesterol–lowering indication for bempedoic acid 180 mg/ezetimibe 10 mg combination tablet.

Full prescribing information is available online.

This article first appeared on Medscape.com.

The Food and Drug Administration has approved bempedoic acid (Nexletol) for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional LDL cholesterol lowering.

The oral adenosine triphosphate–citrate lyase (ACL) inhibitor is indicated as an adjunct to diet and maximally tolerated statin therapy in these patients, and approved at the 180 mg once daily dose, the agency announced today.

The safety and efficacy of bempedoic acid were demonstrated over 52 weeks in two multicenter randomized, clinical trials involving 3,009 adults with HeFH or established ASCVD on maximally tolerated statin therapy.

The difference between bempedoic acid and placebo for the primary outcome of change in LDL cholesterol from baseline to week 12 was –18% in the first trial, CLEAR Harmony (95% confidence interval, –20% to –16%; P less than .001), and –17% in the second trial, CLEAR Wisdom (95% CI, –21% to –14%; P less than .001).

The label notes that the effect on cardiovascular morbidity and mortality has not been determined. The label also includes warnings stating that bempedoic acid may increase blood uric acid levels and is associated with an increased risk of tendon rupture or injury.

In clinical trials, 26% of bempedoic acid–treated patients with normal baseline uric acid values versus 9.5% of placebo-treated patients experienced hyperuricemia one or more times, and 3.5% of patients experienced clinically significant hyperuricemia reported as an adverse reaction versus 1.1% with placebo, according to the label. Gout was reported in 1.5% of patients treated with bempedoic acid and 0.4% of those treated with placebo.

Also in clinical trials, the risk of tendon rupture was 0.5% with bempedoic acid and 0% with placebo. Tendon rupture involved the rotator cuff, biceps tendon, or Achilles tendon, and occurred within weeks to months of starting the drug. Rupture may “occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders,” the label states.

The label also advises that patients avoid concomitant use of bempedoic acid with simvastatin greater than 20 mg or pravastatin greater than 40 mg because it causes an increase in statin concentrations and may increase the risk of related myopathy.

A decision is expected shortly on a new drug application submitted by Esperion for an LDL cholesterol–lowering indication for bempedoic acid 180 mg/ezetimibe 10 mg combination tablet.

Full prescribing information is available online.

This article first appeared on Medscape.com.

Alcohol use is associated with hepatic steatosis, even after exclusion of heavy drinkers. Binge drinking was associated with a particularly high risk. The results are drawn from a retrospective analysis of the Framingham Heart Study and indicate a possible connection between alcohol use and nonalcoholic fatty liver disease (NAFLD). If confirmed prospectively, the results suggest that alcohol use could be a target for prevention and treatment of presumed NAFLD.

The study was led by Michelle Long, MD, of Boston University, and was published in Clinical Gastroenterology and Hepatology.

Previous studies have produced mixed results with respect to alcohol consumption and NAFLD, with some reporting increased risk with alcohol consumption, and some a beneficial effect of moderate alcohol consumption. Most such studies focused on average daily or weekly alcohol intake, without examining individual differences in alcohol use behavior.

The current work included 2,475 participants from the Offspring and Third Generation Cohorts of the multidetector CT (MDCT) substudy of the Framingham Heart Study. The researchers excluded heavy drinkers, defined as those who had more than 21 drinks (men) or 14 drinks (women) per week.

Of the sample, 17.3% had hepatic steatosis as measured by MDCT. The risk of hepatic steatosis increased from 15.3% to 54.3% along increasing categories of alcohol use.

With each standard deviation increase in the number of alcohol drinks per week, the risk of hepatic steatosis increased by 15% (adjusted odds ratio, 1.15; 95% CI, 1.02-1.29). Of subjects with presumed NAFLD, 25.4% were binge drinkers, defined as four or more drinks per day in women and five or more in men.

A pattern of risky weekly drinking – defined as 8 or more drinks for women or 15 or more for men – was associated with a 45% increase in odds of hepatic steatosis (aOR, 1.45; 95% CI, 1.06-1.98).

An analysis of only current drinkers showed stronger associations between hepatic steatosis and the number of alcoholic drinks per week, risky weekly drinking, and maximum number of drinks in 24 hours.

When the researchers broke down the analysis by beer, wine, or spirit drinkers, they only found a statistically significant association between alcohol consumption and hepatic steatosis in beer drinkers.

The study authors received funding from a range of nonindustry sources. They reported having no relevant financial disclosures.

SOURCE: Long M et al. Clin Gastroenterol Hepatol. 2019 Nov 14. doi: 10.1016/j.cgh.2019.11.022

Alcohol use is associated with hepatic steatosis, even after exclusion of heavy drinkers. Binge drinking was associated with a particularly high risk. The results are drawn from a retrospective analysis of the Framingham Heart Study and indicate a possible connection between alcohol use and nonalcoholic fatty liver disease (NAFLD). If confirmed prospectively, the results suggest that alcohol use could be a target for prevention and treatment of presumed NAFLD.

The study was led by Michelle Long, MD, of Boston University, and was published in Clinical Gastroenterology and Hepatology.

Previous studies have produced mixed results with respect to alcohol consumption and NAFLD, with some reporting increased risk with alcohol consumption, and some a beneficial effect of moderate alcohol consumption. Most such studies focused on average daily or weekly alcohol intake, without examining individual differences in alcohol use behavior.

The current work included 2,475 participants from the Offspring and Third Generation Cohorts of the multidetector CT (MDCT) substudy of the Framingham Heart Study. The researchers excluded heavy drinkers, defined as those who had more than 21 drinks (men) or 14 drinks (women) per week.

Of the sample, 17.3% had hepatic steatosis as measured by MDCT. The risk of hepatic steatosis increased from 15.3% to 54.3% along increasing categories of alcohol use.

With each standard deviation increase in the number of alcohol drinks per week, the risk of hepatic steatosis increased by 15% (adjusted odds ratio, 1.15; 95% CI, 1.02-1.29). Of subjects with presumed NAFLD, 25.4% were binge drinkers, defined as four or more drinks per day in women and five or more in men.

A pattern of risky weekly drinking – defined as 8 or more drinks for women or 15 or more for men – was associated with a 45% increase in odds of hepatic steatosis (aOR, 1.45; 95% CI, 1.06-1.98).

An analysis of only current drinkers showed stronger associations between hepatic steatosis and the number of alcoholic drinks per week, risky weekly drinking, and maximum number of drinks in 24 hours.

When the researchers broke down the analysis by beer, wine, or spirit drinkers, they only found a statistically significant association between alcohol consumption and hepatic steatosis in beer drinkers.

The study authors received funding from a range of nonindustry sources. They reported having no relevant financial disclosures.

SOURCE: Long M et al. Clin Gastroenterol Hepatol. 2019 Nov 14. doi: 10.1016/j.cgh.2019.11.022

Alcohol use is associated with hepatic steatosis, even after exclusion of heavy drinkers. Binge drinking was associated with a particularly high risk. The results are drawn from a retrospective analysis of the Framingham Heart Study and indicate a possible connection between alcohol use and nonalcoholic fatty liver disease (NAFLD). If confirmed prospectively, the results suggest that alcohol use could be a target for prevention and treatment of presumed NAFLD.

The study was led by Michelle Long, MD, of Boston University, and was published in Clinical Gastroenterology and Hepatology.

Previous studies have produced mixed results with respect to alcohol consumption and NAFLD, with some reporting increased risk with alcohol consumption, and some a beneficial effect of moderate alcohol consumption. Most such studies focused on average daily or weekly alcohol intake, without examining individual differences in alcohol use behavior.

The current work included 2,475 participants from the Offspring and Third Generation Cohorts of the multidetector CT (MDCT) substudy of the Framingham Heart Study. The researchers excluded heavy drinkers, defined as those who had more than 21 drinks (men) or 14 drinks (women) per week.

Of the sample, 17.3% had hepatic steatosis as measured by MDCT. The risk of hepatic steatosis increased from 15.3% to 54.3% along increasing categories of alcohol use.

With each standard deviation increase in the number of alcohol drinks per week, the risk of hepatic steatosis increased by 15% (adjusted odds ratio, 1.15; 95% CI, 1.02-1.29). Of subjects with presumed NAFLD, 25.4% were binge drinkers, defined as four or more drinks per day in women and five or more in men.

A pattern of risky weekly drinking – defined as 8 or more drinks for women or 15 or more for men – was associated with a 45% increase in odds of hepatic steatosis (aOR, 1.45; 95% CI, 1.06-1.98).

An analysis of only current drinkers showed stronger associations between hepatic steatosis and the number of alcoholic drinks per week, risky weekly drinking, and maximum number of drinks in 24 hours.

When the researchers broke down the analysis by beer, wine, or spirit drinkers, they only found a statistically significant association between alcohol consumption and hepatic steatosis in beer drinkers.

The study authors received funding from a range of nonindustry sources. They reported having no relevant financial disclosures.

SOURCE: Long M et al. Clin Gastroenterol Hepatol. 2019 Nov 14. doi: 10.1016/j.cgh.2019.11.022

SNOWMASS, COLO. – Physical activity is potent medicine, and it doesn’t take all that much of it to derive the maximum cardiovascular benefit: namely, the equivalent of a brisk hour-long walk 5 days/week or jogging at a 10-minute-per-mile pace for half an hour twice weekly, Robert A. Vogel, MD, asserted at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Bruce Jancin/MDedge News

“I’m not telling you to run marathons. A message for your patients is, ‘You don’t have to do a lot, but you have to do something,’ ” said Dr. Vogel, a cardiologist at the University of Colorado at Denver, Aurora, with a longstanding interest in preventive cardiology.

He presented selected highlights from the massive evidence base underlying the recommendations put forth in the current comprehensive U.S. Department of Health & Human Services Physical Activity Guidelines for Americans.

One particularly compelling chunk of evidence comes from a Taiwanese government–funded prospective cohort study of more than 416,000 individuals followed for an average of 8 years. A key finding: 15 minutes of moderate-intensity physical activity daily was associated with a 14% reduction in the relative risk of all-cause mortality and a 19% reduction in death caused by cardiovascular disease, compared with that of inactive individuals. Moreover, each additional 15 minutes of daily moderate exercise further reduced mortality by 4%. These benefits extended across the full age spectrum of both sexes and applied to patients with cardiovascular disease (Lancet. 2011 Oct 1;378[9798]:1244-53).

“That’s a very impressive result for modest physical activity,” the cardiologist commented.

Data on more than 50,000 adult participants in the Aerobics Center Longitudinal Study based at the Cooper Clinic in Dallas show that vigorous exercise in the form of running at 6 mph for half an hour twice weekly, or a total of 10 metabolic equivalent of task hours (MET-HR) per week, was associated with a roughly 40% reduction in cardiovascular disease mortality. Importantly, 20, 40, or 50 MET-HR/week of vigorous exercise conferred no further survival benefit (J Am Coll Cardiol. 2014 Aug 5;64[5]:472-81). The same group showed that the sweet spot for moderate physical activity in terms of reduced cardiovascular mortality was brisk walking for an hour daily 5 days/week, for a total of 20 MET-HR, which was also associated with roughly a 40% risk reduction compared to inactivity. At that point the benefit plateaued, with no further mortality reduction noted with additional MET-HR of moderate exercise.

“For more than that, we have no evidence of additional cardiovascular benefit. It’s not going to get you to the Tokyo Olympics, but that’s what we need to be doing,” Dr. Vogel observed.

In another report from the Aerobics Center Longitudinal Study, investigators found that moderate-level cardiorespiratory fitness as defined by METs was associated with a 44% reduction in the risk of sudden cardiac death in men and women after adjustment for potential confounders, while high-level cardiorespiratory fitness was associated with a closely similar 48% reduction in risk. This applied to individuals who were hypertensive, overweight, and/or had poor health status, as well as to others (Mayo Clin Proc. 2016 Jul;91[7]:849-57).


 

All activity counts

Exercise physiologists speak of NEPA – nonexercise physical activity – such as taking out the garbage. Swedish investigators followed more than 4,200 individuals for an average of 12.5 years and found that high NEPA activity was independently associated with a 30% reduction in all-cause mortality and a 27% lower risk of a first cardiovascular disease event, compared with low NEPA. High NEPA in regular exercisers was associated with a lower rate of metabolic syndrome than in low-NEPA regular exercisers (Br J Sports Med. 2014 Feb;48[3]:233-8).

Don’t just sit there – stand!

The current federal physical activity guidelines place a new emphasis on the detrimental effects of sitting. A report on more than 221,000 participants in the Australian 45 and Up Study, with close to 1 million person-years of follow-up, demonstrated a linear inverse relationship between standing time per day and all-cause mortality. In a multivariate analysis adjusted for potential confounders, individuals who stood for 2-5 hours per day had a 10% lower risk of all-cause mortality than did those who stood for less than 2 hours. Standing for 5-8 hours was associated with a 15% relative risk reduction. And standing for more than 8 hours daily was linked to a 24% reduction in risk (Prev Med. 2014 Dec;69:187-91).

And it’s not just total daily sitting time that’s a risk factor. Prolonged, uninterrupted sedentary time was also associated with a dose-dependent increase in all-cause mortality in a prospective cohort study of nearly 8,000 U.S. adults (Ann Intern Med. 2017 Oct 3;167[7]:465-75).

“If you can’t walk around, talk to your patients standing up. That activity of getting out of your chair is lifesaving,” the cardiologist advised.
 

Get strong

Muscle-strengthening activity on at least 2 days/week is recommended in the federal guidelines because it’s independently associated with decreased all-cause mortality, even in individuals getting sufficient aerobic exercise, as shown in a large national study with 15-years’ follow-up (Prev Med. 2016 Jun;87:121-127).

“As we get older, we tend to forget about muscle. I work with the National Football League. These folks are pretty strong, but we never see diabetes in these very big players, who are often well over 300 lb. They’ve got a lot of muscle. If you want to prevent diabetes, be strong. It’s a very important factor,” Dr. Vogel said.
 

For the time constrained

Jogging is more time-efficient than brisk walking as a way to attain the maximum cardiovascular benefit of exercise. And the so-called “Weekend Warrior” study of nearly 64,000 U.K. adults showed that it’s okay to cram the full week’s worth of exercise into one or two sessions and be done with it. Compared with the inactive study participants, the weekend warriors had a 40% reduction in cardiovascular disease mortality, while individuals who split their physical activity up into three or more sessions per week had a nearly identical 41% relative risk reduction (JAMA Intern Med. 2017 Mar 1;177[3]:335-42).

Interval training is a standard way for athletes in training to improve their endurance by alternating short, intense exercise with brief recovery periods. It’s also a time saver: In one classic bicycling study, physically active men were randomized to standardized 2-week programs of sprint interval training or high-volume endurance training on the bike. The training time required to pass a rigorous cycling time trial test was 90% lower in the interval training group (J Physiol. 2006 Sep 15;575(Pt 3):901-11).

The same principle is applicable to the nonathlete interested in physical activity for heart health.

“When I run a couple of miles, I walk for 5 minutes, then maybe run for three-quarters of a mile, then walk again, then run. In interval training you get your heart rate up, and you drop it down. It’s a very good form of exercise. As a vascular biologist I know that if you put endothelial cells in a Petri dish and spin them real fast continuously, you will not get as good an improvement in endothelial function as if you spin the dish, stop it, spin it, stop it,” Dr. Vogel said.
 

High-volume exercise is safe, even with high coronary calcium

A clinically significant coronary artery calcification score of 100 Agatston units or more is no reason not to exercise. A Cooper Clinic report on nearly 22,000 middle-aged men without baseline cardiovascular disease who were followed for a mean of 10.4 years concluded that those in the highest-volume exercise group, many of whom were marathon runners and engaged in the equivalent of running for at least 5-6 hours/week at a pace of 10 minutes per mile, were 11% more likely to have an elevated baseline coronary artery calcification score than those who exercised less. But these highest-volume exercisers with elevated coronary calcium – their mean level was 807 Agatston units – had risks of all-cause and cardiovascular mortality that weren’t significantly different from those of men with elevated coronary calcium who exercised more moderately (JAMA Cardiol. 2019 Feb 1;4[2]:174-81).

Cardiac rehab

Dr. Vogel had harsh words for his physician colleagues with respect to the widespread underprescribing of cardiac rehabilitation programs.

“You guys are doing a crappy job with exercise in our most vulnerable patients: those who’ve had cardiovascular events,” he charged. “Cardiac rehabilitation is a Class I recommendation in our guidelines. And yet utilization in the United States is just 10%-20%. No other Class I recommendation is in that ballpark.”

A meta-analysis of 34 randomized trials totaling more than 6,000 post-MI patients concluded that those randomized to exercise-based cardiac rehabilitation had a 47% reduction in the risk of reinfarction, 36% lower cardiac mortality, and a 26% reduction in all-cause mortality (Am Heart J. 2011 Oct;162[4]:571-584.e2).

“The data show that cardiac rehabilitation is as effective as anything else we do in cardiovascular medicine. I understand that patients live far away, they don’t like to exercise – I’ve heard every excuse. But I am charging you with the responsibility of meeting a Class I recommendation that gets patients to live longer,” he declared.

Medicare now covers an enhanced, 72-session program called Intensive Cardiac Rehabilitation that teaches comprehensive lifestyle change and provides reasonable reimbursement. “It’s a good thing for our patients,” Dr. Vogel commented.
 

Yoga

For patients who are reluctant to pound the pavement, yoga may provide an alternative form of physical activity with tangible cardiovascular benefits. Dr. Vogel pointed to the Yoga-CaRe trial presented at the 2018 scientific sessions of the American Heart Association. Yoga-CaRe randomized 3,959 post-MI patients at 29 centers in India to a program of 13 supervised in-hospital yoga classes followed by yoga at home, or to a control group with three educational sessions. The rate of major adverse cardiovascular events over 42 months of follow-up was cut in half, compared with controls, in the 27% of participants who attended at least 10 of the 13 yoga classes. Their quality of life scores were higher, too.

Dr. Vogel reported serving as a paid consultant to the National Football League and the Pritikin Longevity Center. He is on the speaker’s bureau for Sanofi and Regeneron.

[email protected]

SNOWMASS, COLO. – Physical activity is potent medicine, and it doesn’t take all that much of it to derive the maximum cardiovascular benefit: namely, the equivalent of a brisk hour-long walk 5 days/week or jogging at a 10-minute-per-mile pace for half an hour twice weekly, Robert A. Vogel, MD, asserted at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Bruce Jancin/MDedge News

“I’m not telling you to run marathons. A message for your patients is, ‘You don’t have to do a lot, but you have to do something,’ ” said Dr. Vogel, a cardiologist at the University of Colorado at Denver, Aurora, with a longstanding interest in preventive cardiology.

He presented selected highlights from the massive evidence base underlying the recommendations put forth in the current comprehensive U.S. Department of Health & Human Services Physical Activity Guidelines for Americans.

One particularly compelling chunk of evidence comes from a Taiwanese government–funded prospective cohort study of more than 416,000 individuals followed for an average of 8 years. A key finding: 15 minutes of moderate-intensity physical activity daily was associated with a 14% reduction in the relative risk of all-cause mortality and a 19% reduction in death caused by cardiovascular disease, compared with that of inactive individuals. Moreover, each additional 15 minutes of daily moderate exercise further reduced mortality by 4%. These benefits extended across the full age spectrum of both sexes and applied to patients with cardiovascular disease (Lancet. 2011 Oct 1;378[9798]:1244-53).

“That’s a very impressive result for modest physical activity,” the cardiologist commented.

Data on more than 50,000 adult participants in the Aerobics Center Longitudinal Study based at the Cooper Clinic in Dallas show that vigorous exercise in the form of running at 6 mph for half an hour twice weekly, or a total of 10 metabolic equivalent of task hours (MET-HR) per week, was associated with a roughly 40% reduction in cardiovascular disease mortality. Importantly, 20, 40, or 50 MET-HR/week of vigorous exercise conferred no further survival benefit (J Am Coll Cardiol. 2014 Aug 5;64[5]:472-81). The same group showed that the sweet spot for moderate physical activity in terms of reduced cardiovascular mortality was brisk walking for an hour daily 5 days/week, for a total of 20 MET-HR, which was also associated with roughly a 40% risk reduction compared to inactivity. At that point the benefit plateaued, with no further mortality reduction noted with additional MET-HR of moderate exercise.

“For more than that, we have no evidence of additional cardiovascular benefit. It’s not going to get you to the Tokyo Olympics, but that’s what we need to be doing,” Dr. Vogel observed.

In another report from the Aerobics Center Longitudinal Study, investigators found that moderate-level cardiorespiratory fitness as defined by METs was associated with a 44% reduction in the risk of sudden cardiac death in men and women after adjustment for potential confounders, while high-level cardiorespiratory fitness was associated with a closely similar 48% reduction in risk. This applied to individuals who were hypertensive, overweight, and/or had poor health status, as well as to others (Mayo Clin Proc. 2016 Jul;91[7]:849-57).


 

All activity counts

Exercise physiologists speak of NEPA – nonexercise physical activity – such as taking out the garbage. Swedish investigators followed more than 4,200 individuals for an average of 12.5 years and found that high NEPA activity was independently associated with a 30% reduction in all-cause mortality and a 27% lower risk of a first cardiovascular disease event, compared with low NEPA. High NEPA in regular exercisers was associated with a lower rate of metabolic syndrome than in low-NEPA regular exercisers (Br J Sports Med. 2014 Feb;48[3]:233-8).

Don’t just sit there – stand!

The current federal physical activity guidelines place a new emphasis on the detrimental effects of sitting. A report on more than 221,000 participants in the Australian 45 and Up Study, with close to 1 million person-years of follow-up, demonstrated a linear inverse relationship between standing time per day and all-cause mortality. In a multivariate analysis adjusted for potential confounders, individuals who stood for 2-5 hours per day had a 10% lower risk of all-cause mortality than did those who stood for less than 2 hours. Standing for 5-8 hours was associated with a 15% relative risk reduction. And standing for more than 8 hours daily was linked to a 24% reduction in risk (Prev Med. 2014 Dec;69:187-91).

And it’s not just total daily sitting time that’s a risk factor. Prolonged, uninterrupted sedentary time was also associated with a dose-dependent increase in all-cause mortality in a prospective cohort study of nearly 8,000 U.S. adults (Ann Intern Med. 2017 Oct 3;167[7]:465-75).

“If you can’t walk around, talk to your patients standing up. That activity of getting out of your chair is lifesaving,” the cardiologist advised.
 

Get strong

Muscle-strengthening activity on at least 2 days/week is recommended in the federal guidelines because it’s independently associated with decreased all-cause mortality, even in individuals getting sufficient aerobic exercise, as shown in a large national study with 15-years’ follow-up (Prev Med. 2016 Jun;87:121-127).

“As we get older, we tend to forget about muscle. I work with the National Football League. These folks are pretty strong, but we never see diabetes in these very big players, who are often well over 300 lb. They’ve got a lot of muscle. If you want to prevent diabetes, be strong. It’s a very important factor,” Dr. Vogel said.
 

For the time constrained

Jogging is more time-efficient than brisk walking as a way to attain the maximum cardiovascular benefit of exercise. And the so-called “Weekend Warrior” study of nearly 64,000 U.K. adults showed that it’s okay to cram the full week’s worth of exercise into one or two sessions and be done with it. Compared with the inactive study participants, the weekend warriors had a 40% reduction in cardiovascular disease mortality, while individuals who split their physical activity up into three or more sessions per week had a nearly identical 41% relative risk reduction (JAMA Intern Med. 2017 Mar 1;177[3]:335-42).

Interval training is a standard way for athletes in training to improve their endurance by alternating short, intense exercise with brief recovery periods. It’s also a time saver: In one classic bicycling study, physically active men were randomized to standardized 2-week programs of sprint interval training or high-volume endurance training on the bike. The training time required to pass a rigorous cycling time trial test was 90% lower in the interval training group (J Physiol. 2006 Sep 15;575(Pt 3):901-11).

The same principle is applicable to the nonathlete interested in physical activity for heart health.

“When I run a couple of miles, I walk for 5 minutes, then maybe run for three-quarters of a mile, then walk again, then run. In interval training you get your heart rate up, and you drop it down. It’s a very good form of exercise. As a vascular biologist I know that if you put endothelial cells in a Petri dish and spin them real fast continuously, you will not get as good an improvement in endothelial function as if you spin the dish, stop it, spin it, stop it,” Dr. Vogel said.
 

High-volume exercise is safe, even with high coronary calcium

A clinically significant coronary artery calcification score of 100 Agatston units or more is no reason not to exercise. A Cooper Clinic report on nearly 22,000 middle-aged men without baseline cardiovascular disease who were followed for a mean of 10.4 years concluded that those in the highest-volume exercise group, many of whom were marathon runners and engaged in the equivalent of running for at least 5-6 hours/week at a pace of 10 minutes per mile, were 11% more likely to have an elevated baseline coronary artery calcification score than those who exercised less. But these highest-volume exercisers with elevated coronary calcium – their mean level was 807 Agatston units – had risks of all-cause and cardiovascular mortality that weren’t significantly different from those of men with elevated coronary calcium who exercised more moderately (JAMA Cardiol. 2019 Feb 1;4[2]:174-81).

Cardiac rehab

Dr. Vogel had harsh words for his physician colleagues with respect to the widespread underprescribing of cardiac rehabilitation programs.

“You guys are doing a crappy job with exercise in our most vulnerable patients: those who’ve had cardiovascular events,” he charged. “Cardiac rehabilitation is a Class I recommendation in our guidelines. And yet utilization in the United States is just 10%-20%. No other Class I recommendation is in that ballpark.”

A meta-analysis of 34 randomized trials totaling more than 6,000 post-MI patients concluded that those randomized to exercise-based cardiac rehabilitation had a 47% reduction in the risk of reinfarction, 36% lower cardiac mortality, and a 26% reduction in all-cause mortality (Am Heart J. 2011 Oct;162[4]:571-584.e2).

“The data show that cardiac rehabilitation is as effective as anything else we do in cardiovascular medicine. I understand that patients live far away, they don’t like to exercise – I’ve heard every excuse. But I am charging you with the responsibility of meeting a Class I recommendation that gets patients to live longer,” he declared.

Medicare now covers an enhanced, 72-session program called Intensive Cardiac Rehabilitation that teaches comprehensive lifestyle change and provides reasonable reimbursement. “It’s a good thing for our patients,” Dr. Vogel commented.
 

Yoga

For patients who are reluctant to pound the pavement, yoga may provide an alternative form of physical activity with tangible cardiovascular benefits. Dr. Vogel pointed to the Yoga-CaRe trial presented at the 2018 scientific sessions of the American Heart Association. Yoga-CaRe randomized 3,959 post-MI patients at 29 centers in India to a program of 13 supervised in-hospital yoga classes followed by yoga at home, or to a control group with three educational sessions. The rate of major adverse cardiovascular events over 42 months of follow-up was cut in half, compared with controls, in the 27% of participants who attended at least 10 of the 13 yoga classes. Their quality of life scores were higher, too.

Dr. Vogel reported serving as a paid consultant to the National Football League and the Pritikin Longevity Center. He is on the speaker’s bureau for Sanofi and Regeneron.

[email protected]

SNOWMASS, COLO. – Physical activity is potent medicine, and it doesn’t take all that much of it to derive the maximum cardiovascular benefit: namely, the equivalent of a brisk hour-long walk 5 days/week or jogging at a 10-minute-per-mile pace for half an hour twice weekly, Robert A. Vogel, MD, asserted at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Bruce Jancin/MDedge News

“I’m not telling you to run marathons. A message for your patients is, ‘You don’t have to do a lot, but you have to do something,’ ” said Dr. Vogel, a cardiologist at the University of Colorado at Denver, Aurora, with a longstanding interest in preventive cardiology.

He presented selected highlights from the massive evidence base underlying the recommendations put forth in the current comprehensive U.S. Department of Health & Human Services Physical Activity Guidelines for Americans.

One particularly compelling chunk of evidence comes from a Taiwanese government–funded prospective cohort study of more than 416,000 individuals followed for an average of 8 years. A key finding: 15 minutes of moderate-intensity physical activity daily was associated with a 14% reduction in the relative risk of all-cause mortality and a 19% reduction in death caused by cardiovascular disease, compared with that of inactive individuals. Moreover, each additional 15 minutes of daily moderate exercise further reduced mortality by 4%. These benefits extended across the full age spectrum of both sexes and applied to patients with cardiovascular disease (Lancet. 2011 Oct 1;378[9798]:1244-53).

“That’s a very impressive result for modest physical activity,” the cardiologist commented.

Data on more than 50,000 adult participants in the Aerobics Center Longitudinal Study based at the Cooper Clinic in Dallas show that vigorous exercise in the form of running at 6 mph for half an hour twice weekly, or a total of 10 metabolic equivalent of task hours (MET-HR) per week, was associated with a roughly 40% reduction in cardiovascular disease mortality. Importantly, 20, 40, or 50 MET-HR/week of vigorous exercise conferred no further survival benefit (J Am Coll Cardiol. 2014 Aug 5;64[5]:472-81). The same group showed that the sweet spot for moderate physical activity in terms of reduced cardiovascular mortality was brisk walking for an hour daily 5 days/week, for a total of 20 MET-HR, which was also associated with roughly a 40% risk reduction compared to inactivity. At that point the benefit plateaued, with no further mortality reduction noted with additional MET-HR of moderate exercise.

“For more than that, we have no evidence of additional cardiovascular benefit. It’s not going to get you to the Tokyo Olympics, but that’s what we need to be doing,” Dr. Vogel observed.

In another report from the Aerobics Center Longitudinal Study, investigators found that moderate-level cardiorespiratory fitness as defined by METs was associated with a 44% reduction in the risk of sudden cardiac death in men and women after adjustment for potential confounders, while high-level cardiorespiratory fitness was associated with a closely similar 48% reduction in risk. This applied to individuals who were hypertensive, overweight, and/or had poor health status, as well as to others (Mayo Clin Proc. 2016 Jul;91[7]:849-57).


 

All activity counts

Exercise physiologists speak of NEPA – nonexercise physical activity – such as taking out the garbage. Swedish investigators followed more than 4,200 individuals for an average of 12.5 years and found that high NEPA activity was independently associated with a 30% reduction in all-cause mortality and a 27% lower risk of a first cardiovascular disease event, compared with low NEPA. High NEPA in regular exercisers was associated with a lower rate of metabolic syndrome than in low-NEPA regular exercisers (Br J Sports Med. 2014 Feb;48[3]:233-8).

Don’t just sit there – stand!

The current federal physical activity guidelines place a new emphasis on the detrimental effects of sitting. A report on more than 221,000 participants in the Australian 45 and Up Study, with close to 1 million person-years of follow-up, demonstrated a linear inverse relationship between standing time per day and all-cause mortality. In a multivariate analysis adjusted for potential confounders, individuals who stood for 2-5 hours per day had a 10% lower risk of all-cause mortality than did those who stood for less than 2 hours. Standing for 5-8 hours was associated with a 15% relative risk reduction. And standing for more than 8 hours daily was linked to a 24% reduction in risk (Prev Med. 2014 Dec;69:187-91).

And it’s not just total daily sitting time that’s a risk factor. Prolonged, uninterrupted sedentary time was also associated with a dose-dependent increase in all-cause mortality in a prospective cohort study of nearly 8,000 U.S. adults (Ann Intern Med. 2017 Oct 3;167[7]:465-75).

“If you can’t walk around, talk to your patients standing up. That activity of getting out of your chair is lifesaving,” the cardiologist advised.
 

Get strong

Muscle-strengthening activity on at least 2 days/week is recommended in the federal guidelines because it’s independently associated with decreased all-cause mortality, even in individuals getting sufficient aerobic exercise, as shown in a large national study with 15-years’ follow-up (Prev Med. 2016 Jun;87:121-127).

“As we get older, we tend to forget about muscle. I work with the National Football League. These folks are pretty strong, but we never see diabetes in these very big players, who are often well over 300 lb. They’ve got a lot of muscle. If you want to prevent diabetes, be strong. It’s a very important factor,” Dr. Vogel said.
 

For the time constrained

Jogging is more time-efficient than brisk walking as a way to attain the maximum cardiovascular benefit of exercise. And the so-called “Weekend Warrior” study of nearly 64,000 U.K. adults showed that it’s okay to cram the full week’s worth of exercise into one or two sessions and be done with it. Compared with the inactive study participants, the weekend warriors had a 40% reduction in cardiovascular disease mortality, while individuals who split their physical activity up into three or more sessions per week had a nearly identical 41% relative risk reduction (JAMA Intern Med. 2017 Mar 1;177[3]:335-42).

Interval training is a standard way for athletes in training to improve their endurance by alternating short, intense exercise with brief recovery periods. It’s also a time saver: In one classic bicycling study, physically active men were randomized to standardized 2-week programs of sprint interval training or high-volume endurance training on the bike. The training time required to pass a rigorous cycling time trial test was 90% lower in the interval training group (J Physiol. 2006 Sep 15;575(Pt 3):901-11).

The same principle is applicable to the nonathlete interested in physical activity for heart health.

“When I run a couple of miles, I walk for 5 minutes, then maybe run for three-quarters of a mile, then walk again, then run. In interval training you get your heart rate up, and you drop it down. It’s a very good form of exercise. As a vascular biologist I know that if you put endothelial cells in a Petri dish and spin them real fast continuously, you will not get as good an improvement in endothelial function as if you spin the dish, stop it, spin it, stop it,” Dr. Vogel said.
 

High-volume exercise is safe, even with high coronary calcium

A clinically significant coronary artery calcification score of 100 Agatston units or more is no reason not to exercise. A Cooper Clinic report on nearly 22,000 middle-aged men without baseline cardiovascular disease who were followed for a mean of 10.4 years concluded that those in the highest-volume exercise group, many of whom were marathon runners and engaged in the equivalent of running for at least 5-6 hours/week at a pace of 10 minutes per mile, were 11% more likely to have an elevated baseline coronary artery calcification score than those who exercised less. But these highest-volume exercisers with elevated coronary calcium – their mean level was 807 Agatston units – had risks of all-cause and cardiovascular mortality that weren’t significantly different from those of men with elevated coronary calcium who exercised more moderately (JAMA Cardiol. 2019 Feb 1;4[2]:174-81).

Cardiac rehab

Dr. Vogel had harsh words for his physician colleagues with respect to the widespread underprescribing of cardiac rehabilitation programs.

“You guys are doing a crappy job with exercise in our most vulnerable patients: those who’ve had cardiovascular events,” he charged. “Cardiac rehabilitation is a Class I recommendation in our guidelines. And yet utilization in the United States is just 10%-20%. No other Class I recommendation is in that ballpark.”

A meta-analysis of 34 randomized trials totaling more than 6,000 post-MI patients concluded that those randomized to exercise-based cardiac rehabilitation had a 47% reduction in the risk of reinfarction, 36% lower cardiac mortality, and a 26% reduction in all-cause mortality (Am Heart J. 2011 Oct;162[4]:571-584.e2).

“The data show that cardiac rehabilitation is as effective as anything else we do in cardiovascular medicine. I understand that patients live far away, they don’t like to exercise – I’ve heard every excuse. But I am charging you with the responsibility of meeting a Class I recommendation that gets patients to live longer,” he declared.

Medicare now covers an enhanced, 72-session program called Intensive Cardiac Rehabilitation that teaches comprehensive lifestyle change and provides reasonable reimbursement. “It’s a good thing for our patients,” Dr. Vogel commented.
 

Yoga

For patients who are reluctant to pound the pavement, yoga may provide an alternative form of physical activity with tangible cardiovascular benefits. Dr. Vogel pointed to the Yoga-CaRe trial presented at the 2018 scientific sessions of the American Heart Association. Yoga-CaRe randomized 3,959 post-MI patients at 29 centers in India to a program of 13 supervised in-hospital yoga classes followed by yoga at home, or to a control group with three educational sessions. The rate of major adverse cardiovascular events over 42 months of follow-up was cut in half, compared with controls, in the 27% of participants who attended at least 10 of the 13 yoga classes. Their quality of life scores were higher, too.

Dr. Vogel reported serving as a paid consultant to the National Football League and the Pritikin Longevity Center. He is on the speaker’s bureau for Sanofi and Regeneron.

[email protected]