CAD & Atherosclerosis

The suggestion that long-term endurance exercise may lead to a paradoxical increase in coronary atherosclerosis has been raised again by a new study.

In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.

The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.

“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.

The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.

Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”

The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.

“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.

“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”

On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”

In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”

He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”

However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”

Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”

He noted that the Master@Heart study as an “important contribution” to the field.

“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”

It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”

He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”

However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”

Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.

But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.

“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”

In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.

He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.

The Master@Heart study aimed to look at this question in a more comprehensive way.

The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.

Maximal oxygen uptake (VO_2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO_2max than nonathletes (159 vs. 155 vs. 122).

There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).

The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.

Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).

In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:

• More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
• More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
• More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
• More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
• More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
• More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
• More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)

In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.

Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).

In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.

“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.

“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”

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

The suggestion that long-term endurance exercise may lead to a paradoxical increase in coronary atherosclerosis has been raised again by a new study.

In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.

The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.

“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.

The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.

Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”

The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.

“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.

“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”

On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”

In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”

He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”

However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”

Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”

He noted that the Master@Heart study as an “important contribution” to the field.

“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”

It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”

He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”

However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”

Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.

But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.

“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”

In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.

He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.

The Master@Heart study aimed to look at this question in a more comprehensive way.

The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.

Maximal oxygen uptake (VO_2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO_2max than nonathletes (159 vs. 155 vs. 122).

There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).

The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.

Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).

In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:

• More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
• More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
• More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
• More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
• More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
• More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
• More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)

In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.

Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).

In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.

“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.

“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”

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

The suggestion that long-term endurance exercise may lead to a paradoxical increase in coronary atherosclerosis has been raised again by a new study.

In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.

The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.

“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.

The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.

Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”

The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.

“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.

“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”

On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”

In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”

He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”

However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”

Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”

He noted that the Master@Heart study as an “important contribution” to the field.

“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”

It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”

He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”

However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”

Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.

But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.

“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”

In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.

He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.

The Master@Heart study aimed to look at this question in a more comprehensive way.

The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.

Maximal oxygen uptake (VO_2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO_2max than nonathletes (159 vs. 155 vs. 122).

There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).

The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.

Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).

In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:

• More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
• More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
• More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
• More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
• More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
• More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
• More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)

In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.

Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).

In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.

“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.

“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”

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

Evidence from three studies in sports cardiology presented at ACC 2023 piqued my interest. Not only because I love endurance sport but because the studies reported data that upset prevailing ideas.

LIVE HCM: Surprising result No. 1

Rachel Lampert, MD, from Yale University, New Haven, Conn., presented results of the LIVE-HCM observational study of vigorous exercise in more than 1,600 patients with hypertrophic cardiomyopathy (40% female). The investigators aimed to determine whether engagement in vigorous exercise, including competitive sports, is associated with increased risk for life-threatening ventricular arrhythmia and/or mortality in patients with HCM.

Because of the myocardial disease, HCM comes with a risk for ventricular arrhythmia. Prevailing wisdom held that vigorous exercise in these patients would be hazardous. It was all expert opinion; there were no data. Now there are.

Dr. Lampert and colleagues recruited patients from 42 international HCM centers. Patients self-enrolled and the researchers created three groups based on self-reported levels of exercise – vigorous, moderate, and sedentary. The main comparison was between vigorous versus nonvigorous exercisers (including moderate and sedentary). The two groups were mostly matched on baseline characteristics and typical of patients with HCM.

The primary endpoint was a composite of death, resuscitated cardiac arrest, syncope likely caused by an arrhythmia, or an appropriate shock from an ICD.

The event rates were low in all groups and almost identical in vigorous versus nonvigorous exercisers. Sub-group analyses found no increased risk in HCM patients who identified as competitive athletes.

Dr. Lampert said these data “do not support universal restriction of vigorous exercise in patients with HCM.”
 

Return to play: Surprising result No. 2

Undergraduate student Katherine Martinez from Loyola University, Chicago, presented an observational analysis of 76 elite athletes with genetic heart disease who gained a return-to-play approval from four expert centers in the United States.

The three-step, return-to-play protocol from these specialized centers deserves emphasis. First was the initial evaluation, including two ECGs, 24-hour ECG monitor, echocardiography, and treadmill exercise testing. Second was a discussion between clinicians and patients regarding the athlete’s situation. The third step was to inform coaches and staff of the team and instruct athletes to obtain a personal AED, stay replenished with electrolytes, avoid QT-prolonging drugs, and continue with annual follow-up.

Slightly more than half of these patients had HCM and almost a third had long QT syndrome. Nearly one-third had an ICD implant and 22 were women.

Of the 76 athletes, 73 chose to return to play; however, 4 of these remained disqualified because of their team’s decision. Of the remaining 69, only 3 had one or more breakthrough cardiac events during 200 patient-years of follow-up.

These comprised one male Division I basketball player with HCM who had an ICD shock while moving furniture; another male Division 1 hockey player with long QT syndrome who was taking beta-blockers experienced syncope while coming off the bench and while cooking; and a third male professional hockey player with HCM, on beta-blockers, had syncope without exertion.

The authors concluded that when there was careful evaluation by experts and shared decision-making, a specific plan to return to sport can be put into place for the highest-level athletes.
 

Masters@Heart: Surprising result No. 3

Ruben De Bosscher MD, PhD, from KU Leuven (Belgium), presented the Masters@Heart study on behalf of a Belgian team of researchers. The question they asked was whether lifelong endurance exercise is associated with more coronary atherosclerosis than standard “normal” exercise levels.

That question brings up the paradox of exercise, which is that numerous observational studies find that exercise strongly associates with lower rates of cardiovascular events, but imaging studies also report high rates of coronary artery calcium in endurance athletes, especially in those who have run multiple marathons.

Masters@Heart investigators sought to explore this paradox by performing detailed coronary imaging in three groups – lifelong athletes, late-onset athletes (after age 30 years), and super-healthy controls. Through advertisements they obtained about 1,100 middle-aged male volunteers (mean age, 55 years). Of these, 605 men were selected at random to participate to reduce the chance of enrolling people who responded to the ads because of health concerns.

Investigators assigned those selected based on self-report of exercise. The control group was notable for their good health: they were free of any risk factors, took (almost) no meds, exercised regularly but not excessively (about 3 hours per week) and had a VO₂ max of 122% of predicted.

The groups were well matched on baseline characteristics. Cycling predominated as the exercise of choice (this is a Belgian study after all). All patients had an extensive evaluation including coronary CT imaging.

European Heart Journal published the provocative results.

• Lifelong exercisers had a significantly higher CAC burden than controls, which confirms previous work.
• Lifelong exercisers had a higher percentage of multiple coronary plaques, plaques of at least 50%, and proximal plaques.
• There were no significant differences in the mixture of plaque types in the three groups. About two thirds of the plaques in each group were calcified and the remainder were deemed noncalcified or mixed.
• When looking only at noncalcified plaques, lifelong exercisers tended to have a higher prevalence of multiple plaques, plaques of at least 50%, and proximal plaques.
• So named “vulnerable” plaques were extremely infrequent in all three groups.

The authors concluded that lifelong endurance sport relative to a generic healthy lifestyle was not associated with more favorable coronary plaque composition.
 

Comments

Each of these three studies provided data where there was none. That is always a good thing.

The major theme from the first two studies is that expert opinion was too cautious. Doctors have long held the idea that patients with genetic heart disease, especially hypertrophic cardiomyopathy, are vulnerable, fragile even, when it comes to vigorous sport.

This new evidence upends this belief, as long as return to sport occurs in the setting of robust patient education and expert evaluation and surveillance.

Paternalism in prohibiting participation in sport because of genetic heart disease has joined the long list of medical reversals.

Masters@Heart provides a slightly different message. It finds that lifelong high-level exercise does not prevent coronary atherosclerosis in men. And, more provocatively, if replicated, might even show that long-term exposure to the biochemical, inflammatory, or hormonal effects of endurance training may actually be atherogenic. Like all good science, these findings raise more questions to explore in the realm of atherogenesis.

Two of the main limitations of the Belgian study was that the control arm was quite healthy; had the comparison arm been typical of sedentary controls in say, the Southeastern United States, the coronary lesions found in longtime exercisers may have looked more favorable. The more significant limitation is the lack of outcomes. Images of coronary arteries remain a surrogate marker. It’s possible that, like statins, higher levels of exercise may stabilize plaque and actually lower the risk for events.

The Belgian authors suggest – as many have – a J-curve of exercise benefits, wherein too little exercise is clearly bad, but too much exercise may also increase risk. In other words, for maximizing health, there may be a Goldilocks amount of exercise.

The problem with this idea comes in its pragmatic translation. The number of lifelong high-level, middle-aged endurance athletes that cite heart health reasons for their affliction is ... almost zero. Nearly everyone I have met in the endurance sport fraternity harbors no notion that racing a bike or running multiple marathons per year is a healthy endeavor.

Paternalism, therefore, would also fall in the realm of limiting lifelong exercise in addicted middle-aged athletes.

Via email, sports cardiologist Michael Emery, MD, reiterated the main immediate message from Masters@Heart: “Exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear honestly).”

I for one cannot give up on endurance exercise. I won’t likely race anymore but I am like the lab rat who needs to run on the wheel. Whether this affects my coronary plaque burden matters not to me.

Dr. Mandrola is a clinical electrophysiologist at Baptist Medical Associates, Louisville, Ky. He reported no conflicts of interest.

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

Evidence from three studies in sports cardiology presented at ACC 2023 piqued my interest. Not only because I love endurance sport but because the studies reported data that upset prevailing ideas.

LIVE HCM: Surprising result No. 1

Rachel Lampert, MD, from Yale University, New Haven, Conn., presented results of the LIVE-HCM observational study of vigorous exercise in more than 1,600 patients with hypertrophic cardiomyopathy (40% female). The investigators aimed to determine whether engagement in vigorous exercise, including competitive sports, is associated with increased risk for life-threatening ventricular arrhythmia and/or mortality in patients with HCM.

Because of the myocardial disease, HCM comes with a risk for ventricular arrhythmia. Prevailing wisdom held that vigorous exercise in these patients would be hazardous. It was all expert opinion; there were no data. Now there are.

Dr. Lampert and colleagues recruited patients from 42 international HCM centers. Patients self-enrolled and the researchers created three groups based on self-reported levels of exercise – vigorous, moderate, and sedentary. The main comparison was between vigorous versus nonvigorous exercisers (including moderate and sedentary). The two groups were mostly matched on baseline characteristics and typical of patients with HCM.

The primary endpoint was a composite of death, resuscitated cardiac arrest, syncope likely caused by an arrhythmia, or an appropriate shock from an ICD.

The event rates were low in all groups and almost identical in vigorous versus nonvigorous exercisers. Sub-group analyses found no increased risk in HCM patients who identified as competitive athletes.

Dr. Lampert said these data “do not support universal restriction of vigorous exercise in patients with HCM.”
 

Return to play: Surprising result No. 2

Undergraduate student Katherine Martinez from Loyola University, Chicago, presented an observational analysis of 76 elite athletes with genetic heart disease who gained a return-to-play approval from four expert centers in the United States.

The three-step, return-to-play protocol from these specialized centers deserves emphasis. First was the initial evaluation, including two ECGs, 24-hour ECG monitor, echocardiography, and treadmill exercise testing. Second was a discussion between clinicians and patients regarding the athlete’s situation. The third step was to inform coaches and staff of the team and instruct athletes to obtain a personal AED, stay replenished with electrolytes, avoid QT-prolonging drugs, and continue with annual follow-up.

Slightly more than half of these patients had HCM and almost a third had long QT syndrome. Nearly one-third had an ICD implant and 22 were women.

Of the 76 athletes, 73 chose to return to play; however, 4 of these remained disqualified because of their team’s decision. Of the remaining 69, only 3 had one or more breakthrough cardiac events during 200 patient-years of follow-up.

These comprised one male Division I basketball player with HCM who had an ICD shock while moving furniture; another male Division 1 hockey player with long QT syndrome who was taking beta-blockers experienced syncope while coming off the bench and while cooking; and a third male professional hockey player with HCM, on beta-blockers, had syncope without exertion.

The authors concluded that when there was careful evaluation by experts and shared decision-making, a specific plan to return to sport can be put into place for the highest-level athletes.
 

Masters@Heart: Surprising result No. 3

Ruben De Bosscher MD, PhD, from KU Leuven (Belgium), presented the Masters@Heart study on behalf of a Belgian team of researchers. The question they asked was whether lifelong endurance exercise is associated with more coronary atherosclerosis than standard “normal” exercise levels.

That question brings up the paradox of exercise, which is that numerous observational studies find that exercise strongly associates with lower rates of cardiovascular events, but imaging studies also report high rates of coronary artery calcium in endurance athletes, especially in those who have run multiple marathons.

Masters@Heart investigators sought to explore this paradox by performing detailed coronary imaging in three groups – lifelong athletes, late-onset athletes (after age 30 years), and super-healthy controls. Through advertisements they obtained about 1,100 middle-aged male volunteers (mean age, 55 years). Of these, 605 men were selected at random to participate to reduce the chance of enrolling people who responded to the ads because of health concerns.

Investigators assigned those selected based on self-report of exercise. The control group was notable for their good health: they were free of any risk factors, took (almost) no meds, exercised regularly but not excessively (about 3 hours per week) and had a VO₂ max of 122% of predicted.

The groups were well matched on baseline characteristics. Cycling predominated as the exercise of choice (this is a Belgian study after all). All patients had an extensive evaluation including coronary CT imaging.

European Heart Journal published the provocative results.

• Lifelong exercisers had a significantly higher CAC burden than controls, which confirms previous work.
• Lifelong exercisers had a higher percentage of multiple coronary plaques, plaques of at least 50%, and proximal plaques.
• There were no significant differences in the mixture of plaque types in the three groups. About two thirds of the plaques in each group were calcified and the remainder were deemed noncalcified or mixed.
• When looking only at noncalcified plaques, lifelong exercisers tended to have a higher prevalence of multiple plaques, plaques of at least 50%, and proximal plaques.
• So named “vulnerable” plaques were extremely infrequent in all three groups.

The authors concluded that lifelong endurance sport relative to a generic healthy lifestyle was not associated with more favorable coronary plaque composition.
 

Comments

Each of these three studies provided data where there was none. That is always a good thing.

The major theme from the first two studies is that expert opinion was too cautious. Doctors have long held the idea that patients with genetic heart disease, especially hypertrophic cardiomyopathy, are vulnerable, fragile even, when it comes to vigorous sport.

This new evidence upends this belief, as long as return to sport occurs in the setting of robust patient education and expert evaluation and surveillance.

Paternalism in prohibiting participation in sport because of genetic heart disease has joined the long list of medical reversals.

Masters@Heart provides a slightly different message. It finds that lifelong high-level exercise does not prevent coronary atherosclerosis in men. And, more provocatively, if replicated, might even show that long-term exposure to the biochemical, inflammatory, or hormonal effects of endurance training may actually be atherogenic. Like all good science, these findings raise more questions to explore in the realm of atherogenesis.

Two of the main limitations of the Belgian study was that the control arm was quite healthy; had the comparison arm been typical of sedentary controls in say, the Southeastern United States, the coronary lesions found in longtime exercisers may have looked more favorable. The more significant limitation is the lack of outcomes. Images of coronary arteries remain a surrogate marker. It’s possible that, like statins, higher levels of exercise may stabilize plaque and actually lower the risk for events.

The Belgian authors suggest – as many have – a J-curve of exercise benefits, wherein too little exercise is clearly bad, but too much exercise may also increase risk. In other words, for maximizing health, there may be a Goldilocks amount of exercise.

The problem with this idea comes in its pragmatic translation. The number of lifelong high-level, middle-aged endurance athletes that cite heart health reasons for their affliction is ... almost zero. Nearly everyone I have met in the endurance sport fraternity harbors no notion that racing a bike or running multiple marathons per year is a healthy endeavor.

Paternalism, therefore, would also fall in the realm of limiting lifelong exercise in addicted middle-aged athletes.

Via email, sports cardiologist Michael Emery, MD, reiterated the main immediate message from Masters@Heart: “Exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear honestly).”

I for one cannot give up on endurance exercise. I won’t likely race anymore but I am like the lab rat who needs to run on the wheel. Whether this affects my coronary plaque burden matters not to me.

Dr. Mandrola is a clinical electrophysiologist at Baptist Medical Associates, Louisville, Ky. He reported no conflicts of interest.

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

Evidence from three studies in sports cardiology presented at ACC 2023 piqued my interest. Not only because I love endurance sport but because the studies reported data that upset prevailing ideas.

LIVE HCM: Surprising result No. 1

Rachel Lampert, MD, from Yale University, New Haven, Conn., presented results of the LIVE-HCM observational study of vigorous exercise in more than 1,600 patients with hypertrophic cardiomyopathy (40% female). The investigators aimed to determine whether engagement in vigorous exercise, including competitive sports, is associated with increased risk for life-threatening ventricular arrhythmia and/or mortality in patients with HCM.

Because of the myocardial disease, HCM comes with a risk for ventricular arrhythmia. Prevailing wisdom held that vigorous exercise in these patients would be hazardous. It was all expert opinion; there were no data. Now there are.

Dr. Lampert and colleagues recruited patients from 42 international HCM centers. Patients self-enrolled and the researchers created three groups based on self-reported levels of exercise – vigorous, moderate, and sedentary. The main comparison was between vigorous versus nonvigorous exercisers (including moderate and sedentary). The two groups were mostly matched on baseline characteristics and typical of patients with HCM.

The primary endpoint was a composite of death, resuscitated cardiac arrest, syncope likely caused by an arrhythmia, or an appropriate shock from an ICD.

The event rates were low in all groups and almost identical in vigorous versus nonvigorous exercisers. Sub-group analyses found no increased risk in HCM patients who identified as competitive athletes.

Dr. Lampert said these data “do not support universal restriction of vigorous exercise in patients with HCM.”
 

Return to play: Surprising result No. 2

Undergraduate student Katherine Martinez from Loyola University, Chicago, presented an observational analysis of 76 elite athletes with genetic heart disease who gained a return-to-play approval from four expert centers in the United States.

The three-step, return-to-play protocol from these specialized centers deserves emphasis. First was the initial evaluation, including two ECGs, 24-hour ECG monitor, echocardiography, and treadmill exercise testing. Second was a discussion between clinicians and patients regarding the athlete’s situation. The third step was to inform coaches and staff of the team and instruct athletes to obtain a personal AED, stay replenished with electrolytes, avoid QT-prolonging drugs, and continue with annual follow-up.

Slightly more than half of these patients had HCM and almost a third had long QT syndrome. Nearly one-third had an ICD implant and 22 were women.

Of the 76 athletes, 73 chose to return to play; however, 4 of these remained disqualified because of their team’s decision. Of the remaining 69, only 3 had one or more breakthrough cardiac events during 200 patient-years of follow-up.

These comprised one male Division I basketball player with HCM who had an ICD shock while moving furniture; another male Division 1 hockey player with long QT syndrome who was taking beta-blockers experienced syncope while coming off the bench and while cooking; and a third male professional hockey player with HCM, on beta-blockers, had syncope without exertion.

The authors concluded that when there was careful evaluation by experts and shared decision-making, a specific plan to return to sport can be put into place for the highest-level athletes.
 

Masters@Heart: Surprising result No. 3

Ruben De Bosscher MD, PhD, from KU Leuven (Belgium), presented the Masters@Heart study on behalf of a Belgian team of researchers. The question they asked was whether lifelong endurance exercise is associated with more coronary atherosclerosis than standard “normal” exercise levels.

That question brings up the paradox of exercise, which is that numerous observational studies find that exercise strongly associates with lower rates of cardiovascular events, but imaging studies also report high rates of coronary artery calcium in endurance athletes, especially in those who have run multiple marathons.

Masters@Heart investigators sought to explore this paradox by performing detailed coronary imaging in three groups – lifelong athletes, late-onset athletes (after age 30 years), and super-healthy controls. Through advertisements they obtained about 1,100 middle-aged male volunteers (mean age, 55 years). Of these, 605 men were selected at random to participate to reduce the chance of enrolling people who responded to the ads because of health concerns.

Investigators assigned those selected based on self-report of exercise. The control group was notable for their good health: they were free of any risk factors, took (almost) no meds, exercised regularly but not excessively (about 3 hours per week) and had a VO₂ max of 122% of predicted.

The groups were well matched on baseline characteristics. Cycling predominated as the exercise of choice (this is a Belgian study after all). All patients had an extensive evaluation including coronary CT imaging.

European Heart Journal published the provocative results.

• Lifelong exercisers had a significantly higher CAC burden than controls, which confirms previous work.
• Lifelong exercisers had a higher percentage of multiple coronary plaques, plaques of at least 50%, and proximal plaques.
• There were no significant differences in the mixture of plaque types in the three groups. About two thirds of the plaques in each group were calcified and the remainder were deemed noncalcified or mixed.
• When looking only at noncalcified plaques, lifelong exercisers tended to have a higher prevalence of multiple plaques, plaques of at least 50%, and proximal plaques.
• So named “vulnerable” plaques were extremely infrequent in all three groups.

The authors concluded that lifelong endurance sport relative to a generic healthy lifestyle was not associated with more favorable coronary plaque composition.
 

Comments

Each of these three studies provided data where there was none. That is always a good thing.

The major theme from the first two studies is that expert opinion was too cautious. Doctors have long held the idea that patients with genetic heart disease, especially hypertrophic cardiomyopathy, are vulnerable, fragile even, when it comes to vigorous sport.

This new evidence upends this belief, as long as return to sport occurs in the setting of robust patient education and expert evaluation and surveillance.

Paternalism in prohibiting participation in sport because of genetic heart disease has joined the long list of medical reversals.

Masters@Heart provides a slightly different message. It finds that lifelong high-level exercise does not prevent coronary atherosclerosis in men. And, more provocatively, if replicated, might even show that long-term exposure to the biochemical, inflammatory, or hormonal effects of endurance training may actually be atherogenic. Like all good science, these findings raise more questions to explore in the realm of atherogenesis.

Two of the main limitations of the Belgian study was that the control arm was quite healthy; had the comparison arm been typical of sedentary controls in say, the Southeastern United States, the coronary lesions found in longtime exercisers may have looked more favorable. The more significant limitation is the lack of outcomes. Images of coronary arteries remain a surrogate marker. It’s possible that, like statins, higher levels of exercise may stabilize plaque and actually lower the risk for events.

The Belgian authors suggest – as many have – a J-curve of exercise benefits, wherein too little exercise is clearly bad, but too much exercise may also increase risk. In other words, for maximizing health, there may be a Goldilocks amount of exercise.

The problem with this idea comes in its pragmatic translation. The number of lifelong high-level, middle-aged endurance athletes that cite heart health reasons for their affliction is ... almost zero. Nearly everyone I have met in the endurance sport fraternity harbors no notion that racing a bike or running multiple marathons per year is a healthy endeavor.

Paternalism, therefore, would also fall in the realm of limiting lifelong exercise in addicted middle-aged athletes.

Via email, sports cardiologist Michael Emery, MD, reiterated the main immediate message from Masters@Heart: “Exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear honestly).”

I for one cannot give up on endurance exercise. I won’t likely race anymore but I am like the lab rat who needs to run on the wheel. Whether this affects my coronary plaque burden matters not to me.

Dr. Mandrola is a clinical electrophysiologist at Baptist Medical Associates, Louisville, Ky. He reported no conflicts of interest.

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

Childhood obesity is a risk factor for four of the five subtypes of adult-onset diabetes, emphasizing the importance of childhood weight control, according to a collaborative study from the Karolinska Institutet in Stockholm, the University of Bristol (England), and Sun Yat-Sen University in China.

“Our finding is that children who have a bigger body size than the average have increased risks of developing almost all subtypes of adult-onset diabetes, except for the mild age-related subtype,” lead author Yuxia Wei, a PhD student from the Karolinska Institutet, said in an interview. “This tells us that it is important to prevent overweight/obesity in children and important for pediatric patients to lose weight if they have already been overweight/obese,” she added, while acknowledging that the study did not examine whether childhood weight loss would prevent adult-onset diabetes.

The study, published online in Diabetologia, used Mendelian randomization (MR), with data from genome-wide association studies (GWAS) of childhood obesity and the five subtypes of adult-onset diabetes: latent autoimmune diabetes in adults (LADA, proxy for severe autoimmune diabetes), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD). MR is “a rather new but commonly used and established technique that uses genetic information to study the causal link between an environmental risk factor and a disease, while accounting for the influence of other risk factors,” Ms. Wei explained.

To identify genetic variations associated with obesity, the study used statistics from a GWAS of 453,169 Europeans who self-reported body size at age 10 years in the UK Biobank study. After adjustment for sex, age at baseline, type of genotyping array, and month of birth, they identified 295 independent single nucleotide polymorphisms (SNPs) for childhood body size.

The researchers also used data from two GWAS of European adults with newly diagnosed diabetes, or without diabetes, to identify SNPs in 8,581 individuals with LADA, 3,937 with SIDD, 3,874 with SIRD, 4,118 with MOD, and 5,605 with MARD.

They then used MR to assess the association of genetically predicted childhood body size with the different diabetes subtypes.

The analysis showed that, with the exception of MARD, all other adult-onset diabetes subtypes were causally associated with childhood obesity, with odds ratio of 1.62 for LADA, 2.11 for SIDD, 2.76 for SIRD, and 7.30 for MOD. However, a genetic correlation between childhood obesity and adult-onset diabetes was found only for MOD, and no other subtypes. “The weak genetic correlation between childhood obesity and adult diabetes indicates that the genes promoting childhood adiposity are largely distinct from those promoting diabetes during adulthood,” noted the authors.

The findings indicate that “childhood body size and MOD may share some genetic mutations,” added Ms. Wei. “That is to say, some genes may affect childhood body size and MOD simultaneously.” But the shared genes do demonstrate the causal effect of childhood obesity on MOD, she explained. The causal effect is demonstrated through the MR analysis.

Additionally, they noted that while “the link between childhood body size and SIRD is expected, given the adverse effects of adiposity on insulin sensitivity ... the smaller OR for SIRD than for MOD suggests that non–obesity-related and/or nongenetic effects may be the main factors underlying the development of SIRD.” Asked for her theory on how childhood body size could affect diabetes subtypes characterized by autoimmunity (LADA) or impaired insulin secretion (SIDD), Ms. Wei speculated that “excess fat around the pancreas can affect insulin secretion and that impaired insulin secretion is also an important problem for LADA.”

Another theory is that it might be “metabolic memory,” suggested Jordi Merino, PhD, of the University of Copenhagen and Harvard University, Boston, who was not involved in the research. “Being exposed to obesity during childhood will tell the body to produce more insulin/aberrant immunity responses later in life.”

Dr. Merino said that, overall, the study’s findings “highlight the long and lasting effect of early-life adiposity and metabolic alterations on different forms of adult-onset diabetes,” adding that this is the first evidence “that childhood adiposity is not only linked to the more traditional diabetes subtype consequence of increased insulin resistance but also subtypes driven by autoimmunity or impaired insulin secretion.” He explained that genetics is “only part of the story” driving increased diabetes risk and “we do not know much about other factors interacting with genetics, but the results from this Mendelian randomization analysis suggest that childhood obesity is a causal factor for all adult-onset diabetes subtypes. Identifying causal factors instead of associative factors is critical to implement more targeted preventive and therapeutic strategies.”

He acknowledged, “There is a long path for these results to be eventually implemented in clinical practice, but they can support early weight control strategies for preventing different diabetes subtypes.”

The study was supported by the Swedish Research Council, Research Council for Health, Working Life and Welfare, and Novo Nordisk Foundation. Ms. Wei received a scholarship from the China Scholarship Council. One coauthor is an employee of GlaxoSmithKline. Dr. Merino reported no conflicts of interest.

Childhood obesity is a risk factor for four of the five subtypes of adult-onset diabetes, emphasizing the importance of childhood weight control, according to a collaborative study from the Karolinska Institutet in Stockholm, the University of Bristol (England), and Sun Yat-Sen University in China.

“Our finding is that children who have a bigger body size than the average have increased risks of developing almost all subtypes of adult-onset diabetes, except for the mild age-related subtype,” lead author Yuxia Wei, a PhD student from the Karolinska Institutet, said in an interview. “This tells us that it is important to prevent overweight/obesity in children and important for pediatric patients to lose weight if they have already been overweight/obese,” she added, while acknowledging that the study did not examine whether childhood weight loss would prevent adult-onset diabetes.

The study, published online in Diabetologia, used Mendelian randomization (MR), with data from genome-wide association studies (GWAS) of childhood obesity and the five subtypes of adult-onset diabetes: latent autoimmune diabetes in adults (LADA, proxy for severe autoimmune diabetes), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD). MR is “a rather new but commonly used and established technique that uses genetic information to study the causal link between an environmental risk factor and a disease, while accounting for the influence of other risk factors,” Ms. Wei explained.

To identify genetic variations associated with obesity, the study used statistics from a GWAS of 453,169 Europeans who self-reported body size at age 10 years in the UK Biobank study. After adjustment for sex, age at baseline, type of genotyping array, and month of birth, they identified 295 independent single nucleotide polymorphisms (SNPs) for childhood body size.

The researchers also used data from two GWAS of European adults with newly diagnosed diabetes, or without diabetes, to identify SNPs in 8,581 individuals with LADA, 3,937 with SIDD, 3,874 with SIRD, 4,118 with MOD, and 5,605 with MARD.

They then used MR to assess the association of genetically predicted childhood body size with the different diabetes subtypes.

The analysis showed that, with the exception of MARD, all other adult-onset diabetes subtypes were causally associated with childhood obesity, with odds ratio of 1.62 for LADA, 2.11 for SIDD, 2.76 for SIRD, and 7.30 for MOD. However, a genetic correlation between childhood obesity and adult-onset diabetes was found only for MOD, and no other subtypes. “The weak genetic correlation between childhood obesity and adult diabetes indicates that the genes promoting childhood adiposity are largely distinct from those promoting diabetes during adulthood,” noted the authors.

The findings indicate that “childhood body size and MOD may share some genetic mutations,” added Ms. Wei. “That is to say, some genes may affect childhood body size and MOD simultaneously.” But the shared genes do demonstrate the causal effect of childhood obesity on MOD, she explained. The causal effect is demonstrated through the MR analysis.

Additionally, they noted that while “the link between childhood body size and SIRD is expected, given the adverse effects of adiposity on insulin sensitivity ... the smaller OR for SIRD than for MOD suggests that non–obesity-related and/or nongenetic effects may be the main factors underlying the development of SIRD.” Asked for her theory on how childhood body size could affect diabetes subtypes characterized by autoimmunity (LADA) or impaired insulin secretion (SIDD), Ms. Wei speculated that “excess fat around the pancreas can affect insulin secretion and that impaired insulin secretion is also an important problem for LADA.”

Another theory is that it might be “metabolic memory,” suggested Jordi Merino, PhD, of the University of Copenhagen and Harvard University, Boston, who was not involved in the research. “Being exposed to obesity during childhood will tell the body to produce more insulin/aberrant immunity responses later in life.”

Dr. Merino said that, overall, the study’s findings “highlight the long and lasting effect of early-life adiposity and metabolic alterations on different forms of adult-onset diabetes,” adding that this is the first evidence “that childhood adiposity is not only linked to the more traditional diabetes subtype consequence of increased insulin resistance but also subtypes driven by autoimmunity or impaired insulin secretion.” He explained that genetics is “only part of the story” driving increased diabetes risk and “we do not know much about other factors interacting with genetics, but the results from this Mendelian randomization analysis suggest that childhood obesity is a causal factor for all adult-onset diabetes subtypes. Identifying causal factors instead of associative factors is critical to implement more targeted preventive and therapeutic strategies.”

He acknowledged, “There is a long path for these results to be eventually implemented in clinical practice, but they can support early weight control strategies for preventing different diabetes subtypes.”

The study was supported by the Swedish Research Council, Research Council for Health, Working Life and Welfare, and Novo Nordisk Foundation. Ms. Wei received a scholarship from the China Scholarship Council. One coauthor is an employee of GlaxoSmithKline. Dr. Merino reported no conflicts of interest.

Childhood obesity is a risk factor for four of the five subtypes of adult-onset diabetes, emphasizing the importance of childhood weight control, according to a collaborative study from the Karolinska Institutet in Stockholm, the University of Bristol (England), and Sun Yat-Sen University in China.

“Our finding is that children who have a bigger body size than the average have increased risks of developing almost all subtypes of adult-onset diabetes, except for the mild age-related subtype,” lead author Yuxia Wei, a PhD student from the Karolinska Institutet, said in an interview. “This tells us that it is important to prevent overweight/obesity in children and important for pediatric patients to lose weight if they have already been overweight/obese,” she added, while acknowledging that the study did not examine whether childhood weight loss would prevent adult-onset diabetes.

The study, published online in Diabetologia, used Mendelian randomization (MR), with data from genome-wide association studies (GWAS) of childhood obesity and the five subtypes of adult-onset diabetes: latent autoimmune diabetes in adults (LADA, proxy for severe autoimmune diabetes), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD). MR is “a rather new but commonly used and established technique that uses genetic information to study the causal link between an environmental risk factor and a disease, while accounting for the influence of other risk factors,” Ms. Wei explained.

To identify genetic variations associated with obesity, the study used statistics from a GWAS of 453,169 Europeans who self-reported body size at age 10 years in the UK Biobank study. After adjustment for sex, age at baseline, type of genotyping array, and month of birth, they identified 295 independent single nucleotide polymorphisms (SNPs) for childhood body size.

The researchers also used data from two GWAS of European adults with newly diagnosed diabetes, or without diabetes, to identify SNPs in 8,581 individuals with LADA, 3,937 with SIDD, 3,874 with SIRD, 4,118 with MOD, and 5,605 with MARD.

They then used MR to assess the association of genetically predicted childhood body size with the different diabetes subtypes.

The analysis showed that, with the exception of MARD, all other adult-onset diabetes subtypes were causally associated with childhood obesity, with odds ratio of 1.62 for LADA, 2.11 for SIDD, 2.76 for SIRD, and 7.30 for MOD. However, a genetic correlation between childhood obesity and adult-onset diabetes was found only for MOD, and no other subtypes. “The weak genetic correlation between childhood obesity and adult diabetes indicates that the genes promoting childhood adiposity are largely distinct from those promoting diabetes during adulthood,” noted the authors.

The findings indicate that “childhood body size and MOD may share some genetic mutations,” added Ms. Wei. “That is to say, some genes may affect childhood body size and MOD simultaneously.” But the shared genes do demonstrate the causal effect of childhood obesity on MOD, she explained. The causal effect is demonstrated through the MR analysis.

Additionally, they noted that while “the link between childhood body size and SIRD is expected, given the adverse effects of adiposity on insulin sensitivity ... the smaller OR for SIRD than for MOD suggests that non–obesity-related and/or nongenetic effects may be the main factors underlying the development of SIRD.” Asked for her theory on how childhood body size could affect diabetes subtypes characterized by autoimmunity (LADA) or impaired insulin secretion (SIDD), Ms. Wei speculated that “excess fat around the pancreas can affect insulin secretion and that impaired insulin secretion is also an important problem for LADA.”

Another theory is that it might be “metabolic memory,” suggested Jordi Merino, PhD, of the University of Copenhagen and Harvard University, Boston, who was not involved in the research. “Being exposed to obesity during childhood will tell the body to produce more insulin/aberrant immunity responses later in life.”

Dr. Merino said that, overall, the study’s findings “highlight the long and lasting effect of early-life adiposity and metabolic alterations on different forms of adult-onset diabetes,” adding that this is the first evidence “that childhood adiposity is not only linked to the more traditional diabetes subtype consequence of increased insulin resistance but also subtypes driven by autoimmunity or impaired insulin secretion.” He explained that genetics is “only part of the story” driving increased diabetes risk and “we do not know much about other factors interacting with genetics, but the results from this Mendelian randomization analysis suggest that childhood obesity is a causal factor for all adult-onset diabetes subtypes. Identifying causal factors instead of associative factors is critical to implement more targeted preventive and therapeutic strategies.”

He acknowledged, “There is a long path for these results to be eventually implemented in clinical practice, but they can support early weight control strategies for preventing different diabetes subtypes.”

The study was supported by the Swedish Research Council, Research Council for Health, Working Life and Welfare, and Novo Nordisk Foundation. Ms. Wei received a scholarship from the China Scholarship Council. One coauthor is an employee of GlaxoSmithKline. Dr. Merino reported no conflicts of interest.

Consumption of a low-carbohydrate, high-fat diet, dubbed a “keto-like” diet, was associated with an increase in LDL levels and a twofold increase in the risk for future cardiovascular events, in a new observational study.

“To our knowledge this is the first study to demonstrate an association between a carbohydrate-restricted dietary platform and greater risk of atherosclerotic cardiovascular disease,” said study investigator Iulia Iatan, MD, PhD, University of British Columbia, Vancouver.

a_namenko/Getty Images

“Hypercholesterolemia occurring during a low-carb, high-fat diet should not be assumed to be benign,” she concluded.

Dr. Iatan presented the study March 5 at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

The presentation received much media attention, with headlines implying a causal relationship with cardiac events based on these observational results. But lipid expert Steven Nissen, MD, of the Cleveland Clinic, warned against paying much attention to the headlines or to the study’s conclusions.

In an interview, Dr. Nissen pointed out that the LDL increase in the “keto-like” diet group was relatively small and “certainly not enough to produce a doubling in cardiovascular risk.

“The people who were on the ‘keto-like’ diet in this study were different than those who were on the standard diet,” he said. “Those on the ‘keto-like’ diet were on it for a reason – they were more overweight, they had a higher incidence of diabetes, so their risk profile was completely different. Even though the researchers tried to adjust for other cardiovascular risk factors, there will be unmeasured confounding in a study like this.”

He said he doesn’t think this study “answers any significant questions in a way that we want to have them answered. I’m not a big fan of this type of diet, but I don’t think it doubles the risk of adverse cardiovascular events, and I don’t think this study tells us one way or another.” 

For the study, Dr. Iatan and colleagues defined a low-carbohydrate, high-fat diet as consisting of no more than 25% of total daily energy from carbohydrates and more than 45% of total daily calories from fat. This is somewhat higher in carbohydrates and lower in fat than a strict ketogenic diet but could be thought of as a ‘keto-like’ diet.

They analyzed data from the UK Biobank, a large-scale prospective database with health information from over half a million people living in the United Kingdom who were followed for at least 10 years.

On enrollment in the Biobank, participants completed a one-time, self-reported 24-hour diet questionnaire and, at the same time, had blood drawn to check their levels of cholesterol. The researchers identified 305 participants whose questionnaire responses indicated that they followed a low-carbohydrate, high-fat diet. These participants were matched by age and sex with 1,220 individuals who reported being on a standard diet.

Of the study population, 73% were women and the average age was 54 years. Those on a low carbohydrate/high fat diet had a higher average body mass index (27.7 vs. 26.7) and a higher incidence of diabetes (4.9% vs. 1.7%).

Results showed that compared with participants on a standard diet, those on the “keto-like” diet had significantly higher levels of both LDL cholesterol and apolipoprotein B (ApoB).

Levels of LDL were 3.80 mmol/L (147 mg/dL) in the keto-like group vs. 3.64 mmol/L (141 mg/dL) in the standard group (P = .004).  Levels of ApoB were 1.09 g/L (109 mg/dL) in the keto-like group and 1.04 g/L (104 mg/dL) in the standard group (P < .001).

After an average of 11.8 years of follow-up, 9.8% of participants on the low-carbohydrate/high-fat diet vs. 4.3% in the standard diet group experienced one of the events included in the composite event endpoint: Angina, myocardial infarction, coronary artery disease, ischemic stroke, peripheral arterial disease, or coronary/carotid revascularization.

After adjustment for other risk factors for heart disease – diabetes, hypertension, obesity, and smoking – individuals on a low-carbohydrate, high-fat diet were found to have a twofold risk of having a cardiovascular event (HR, 2.18; P < .001).
 

‘Closer monitoring needed’

“Our results have shown, I think for the first time, that there is an association between this increasingly popular dietary pattern and high LDL cholesterol and an increased future risk of cardiovascular events,” senior author Liam Brunham, MD, of the University of British Columbia, said in an interview. “This is concerning as there are many people out there following this type of diet, and I think it suggests there is a need for closer monitoring of these people.”

He explained that while it would be expected for cholesterol levels to rise on a high-fat diet, “there has been a perception by some that this is not worrisome as it is reflecting certain metabolic changes. What we’ve shown in this study is that if your cholesterol does increase significantly on this diet then you should not assume that this is not a problem.

“For some people with diabetes this diet can help lower blood sugar and some people can lose weight on it,” he noted, “but what our data show is that there is a subgroup of people who experience high levels of LDL and ApoB and that seems to be driving the risk.”

He pointed out that overall the mean level of LDL was only slightly increased in the individuals on the low-carb/high-fat diet but severe high cholesterol (more than 5 mmol/L or 190 mg/dL) was about doubled in that group (10% vs. 5%). And these patients had a sixfold increase in risk of cardiovascular disease (P < .001). 

“This suggests that there is a subgroup of people who are susceptible to this exacerbation of hypercholesterolemia in response to a low-carb/high-fat diet.”

Dr. Brunham said his advice would be that if people choose to follow this diet, they should have their cholesterol monitored, and manage their cardiovascular risk factors.

“I wouldn’t say it is not appropriate to follow this diet based on this study,” he added. “This is just an observational study. It is not definitive. But if people do want to follow this dietary pattern because they feel there would be some benefits, then they should be aware of the potential risks and take steps to mitigate those risks.”
 

Jury still out

Dr. Nissen said in his view “the jury was still out” on this type of diet. “I’m open to the possibility that, particularly in the short run, a ‘keto-like’ diet may help some people lose weight and that’s a good thing. But I do not generally recommend this type of diet.”

Rather, he advises patients to follow a Mediterranean diet, which has been proven to reduce cardiovascular events in a randomized study, the PREDIMED trial.  

“We can’t make decisions on what type of diet to recommend to patients based on observational studies like this where there is a lot of subtlety missing. But when studies like this are reported, the mass media seize on it. That’s not the way the public needs to be educated,” Dr. Nissen said. 

“We refer to this type of study as hypothesis-generating. It raises a hypothesis. It doesn’t answer the question. It is worth looking at the question of whether a ketogenic-like diet is harmful. We don’t know at present, and I don’t think we know any more after this study,” he added.

The authors of the study reported no relevant financial relationships.

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

Consumption of a low-carbohydrate, high-fat diet, dubbed a “keto-like” diet, was associated with an increase in LDL levels and a twofold increase in the risk for future cardiovascular events, in a new observational study.

“To our knowledge this is the first study to demonstrate an association between a carbohydrate-restricted dietary platform and greater risk of atherosclerotic cardiovascular disease,” said study investigator Iulia Iatan, MD, PhD, University of British Columbia, Vancouver.

a_namenko/Getty Images

“Hypercholesterolemia occurring during a low-carb, high-fat diet should not be assumed to be benign,” she concluded.

Dr. Iatan presented the study March 5 at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

The presentation received much media attention, with headlines implying a causal relationship with cardiac events based on these observational results. But lipid expert Steven Nissen, MD, of the Cleveland Clinic, warned against paying much attention to the headlines or to the study’s conclusions.

In an interview, Dr. Nissen pointed out that the LDL increase in the “keto-like” diet group was relatively small and “certainly not enough to produce a doubling in cardiovascular risk.

“The people who were on the ‘keto-like’ diet in this study were different than those who were on the standard diet,” he said. “Those on the ‘keto-like’ diet were on it for a reason – they were more overweight, they had a higher incidence of diabetes, so their risk profile was completely different. Even though the researchers tried to adjust for other cardiovascular risk factors, there will be unmeasured confounding in a study like this.”

He said he doesn’t think this study “answers any significant questions in a way that we want to have them answered. I’m not a big fan of this type of diet, but I don’t think it doubles the risk of adverse cardiovascular events, and I don’t think this study tells us one way or another.” 

For the study, Dr. Iatan and colleagues defined a low-carbohydrate, high-fat diet as consisting of no more than 25% of total daily energy from carbohydrates and more than 45% of total daily calories from fat. This is somewhat higher in carbohydrates and lower in fat than a strict ketogenic diet but could be thought of as a ‘keto-like’ diet.

They analyzed data from the UK Biobank, a large-scale prospective database with health information from over half a million people living in the United Kingdom who were followed for at least 10 years.

On enrollment in the Biobank, participants completed a one-time, self-reported 24-hour diet questionnaire and, at the same time, had blood drawn to check their levels of cholesterol. The researchers identified 305 participants whose questionnaire responses indicated that they followed a low-carbohydrate, high-fat diet. These participants were matched by age and sex with 1,220 individuals who reported being on a standard diet.

Of the study population, 73% were women and the average age was 54 years. Those on a low carbohydrate/high fat diet had a higher average body mass index (27.7 vs. 26.7) and a higher incidence of diabetes (4.9% vs. 1.7%).

Results showed that compared with participants on a standard diet, those on the “keto-like” diet had significantly higher levels of both LDL cholesterol and apolipoprotein B (ApoB).

Levels of LDL were 3.80 mmol/L (147 mg/dL) in the keto-like group vs. 3.64 mmol/L (141 mg/dL) in the standard group (P = .004).  Levels of ApoB were 1.09 g/L (109 mg/dL) in the keto-like group and 1.04 g/L (104 mg/dL) in the standard group (P < .001).

After an average of 11.8 years of follow-up, 9.8% of participants on the low-carbohydrate/high-fat diet vs. 4.3% in the standard diet group experienced one of the events included in the composite event endpoint: Angina, myocardial infarction, coronary artery disease, ischemic stroke, peripheral arterial disease, or coronary/carotid revascularization.

After adjustment for other risk factors for heart disease – diabetes, hypertension, obesity, and smoking – individuals on a low-carbohydrate, high-fat diet were found to have a twofold risk of having a cardiovascular event (HR, 2.18; P < .001).
 

‘Closer monitoring needed’

“Our results have shown, I think for the first time, that there is an association between this increasingly popular dietary pattern and high LDL cholesterol and an increased future risk of cardiovascular events,” senior author Liam Brunham, MD, of the University of British Columbia, said in an interview. “This is concerning as there are many people out there following this type of diet, and I think it suggests there is a need for closer monitoring of these people.”

He explained that while it would be expected for cholesterol levels to rise on a high-fat diet, “there has been a perception by some that this is not worrisome as it is reflecting certain metabolic changes. What we’ve shown in this study is that if your cholesterol does increase significantly on this diet then you should not assume that this is not a problem.

“For some people with diabetes this diet can help lower blood sugar and some people can lose weight on it,” he noted, “but what our data show is that there is a subgroup of people who experience high levels of LDL and ApoB and that seems to be driving the risk.”

He pointed out that overall the mean level of LDL was only slightly increased in the individuals on the low-carb/high-fat diet but severe high cholesterol (more than 5 mmol/L or 190 mg/dL) was about doubled in that group (10% vs. 5%). And these patients had a sixfold increase in risk of cardiovascular disease (P < .001). 

“This suggests that there is a subgroup of people who are susceptible to this exacerbation of hypercholesterolemia in response to a low-carb/high-fat diet.”

Dr. Brunham said his advice would be that if people choose to follow this diet, they should have their cholesterol monitored, and manage their cardiovascular risk factors.

“I wouldn’t say it is not appropriate to follow this diet based on this study,” he added. “This is just an observational study. It is not definitive. But if people do want to follow this dietary pattern because they feel there would be some benefits, then they should be aware of the potential risks and take steps to mitigate those risks.”
 

Jury still out

Dr. Nissen said in his view “the jury was still out” on this type of diet. “I’m open to the possibility that, particularly in the short run, a ‘keto-like’ diet may help some people lose weight and that’s a good thing. But I do not generally recommend this type of diet.”

Rather, he advises patients to follow a Mediterranean diet, which has been proven to reduce cardiovascular events in a randomized study, the PREDIMED trial.  

“We can’t make decisions on what type of diet to recommend to patients based on observational studies like this where there is a lot of subtlety missing. But when studies like this are reported, the mass media seize on it. That’s not the way the public needs to be educated,” Dr. Nissen said. 

“We refer to this type of study as hypothesis-generating. It raises a hypothesis. It doesn’t answer the question. It is worth looking at the question of whether a ketogenic-like diet is harmful. We don’t know at present, and I don’t think we know any more after this study,” he added.

The authors of the study reported no relevant financial relationships.

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

Consumption of a low-carbohydrate, high-fat diet, dubbed a “keto-like” diet, was associated with an increase in LDL levels and a twofold increase in the risk for future cardiovascular events, in a new observational study.

“To our knowledge this is the first study to demonstrate an association between a carbohydrate-restricted dietary platform and greater risk of atherosclerotic cardiovascular disease,” said study investigator Iulia Iatan, MD, PhD, University of British Columbia, Vancouver.

a_namenko/Getty Images

“Hypercholesterolemia occurring during a low-carb, high-fat diet should not be assumed to be benign,” she concluded.

Dr. Iatan presented the study March 5 at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

The presentation received much media attention, with headlines implying a causal relationship with cardiac events based on these observational results. But lipid expert Steven Nissen, MD, of the Cleveland Clinic, warned against paying much attention to the headlines or to the study’s conclusions.

In an interview, Dr. Nissen pointed out that the LDL increase in the “keto-like” diet group was relatively small and “certainly not enough to produce a doubling in cardiovascular risk.

“The people who were on the ‘keto-like’ diet in this study were different than those who were on the standard diet,” he said. “Those on the ‘keto-like’ diet were on it for a reason – they were more overweight, they had a higher incidence of diabetes, so their risk profile was completely different. Even though the researchers tried to adjust for other cardiovascular risk factors, there will be unmeasured confounding in a study like this.”

He said he doesn’t think this study “answers any significant questions in a way that we want to have them answered. I’m not a big fan of this type of diet, but I don’t think it doubles the risk of adverse cardiovascular events, and I don’t think this study tells us one way or another.” 

For the study, Dr. Iatan and colleagues defined a low-carbohydrate, high-fat diet as consisting of no more than 25% of total daily energy from carbohydrates and more than 45% of total daily calories from fat. This is somewhat higher in carbohydrates and lower in fat than a strict ketogenic diet but could be thought of as a ‘keto-like’ diet.

They analyzed data from the UK Biobank, a large-scale prospective database with health information from over half a million people living in the United Kingdom who were followed for at least 10 years.

On enrollment in the Biobank, participants completed a one-time, self-reported 24-hour diet questionnaire and, at the same time, had blood drawn to check their levels of cholesterol. The researchers identified 305 participants whose questionnaire responses indicated that they followed a low-carbohydrate, high-fat diet. These participants were matched by age and sex with 1,220 individuals who reported being on a standard diet.

Of the study population, 73% were women and the average age was 54 years. Those on a low carbohydrate/high fat diet had a higher average body mass index (27.7 vs. 26.7) and a higher incidence of diabetes (4.9% vs. 1.7%).

Results showed that compared with participants on a standard diet, those on the “keto-like” diet had significantly higher levels of both LDL cholesterol and apolipoprotein B (ApoB).

Levels of LDL were 3.80 mmol/L (147 mg/dL) in the keto-like group vs. 3.64 mmol/L (141 mg/dL) in the standard group (P = .004).  Levels of ApoB were 1.09 g/L (109 mg/dL) in the keto-like group and 1.04 g/L (104 mg/dL) in the standard group (P < .001).

After an average of 11.8 years of follow-up, 9.8% of participants on the low-carbohydrate/high-fat diet vs. 4.3% in the standard diet group experienced one of the events included in the composite event endpoint: Angina, myocardial infarction, coronary artery disease, ischemic stroke, peripheral arterial disease, or coronary/carotid revascularization.

After adjustment for other risk factors for heart disease – diabetes, hypertension, obesity, and smoking – individuals on a low-carbohydrate, high-fat diet were found to have a twofold risk of having a cardiovascular event (HR, 2.18; P < .001).
 

‘Closer monitoring needed’

“Our results have shown, I think for the first time, that there is an association between this increasingly popular dietary pattern and high LDL cholesterol and an increased future risk of cardiovascular events,” senior author Liam Brunham, MD, of the University of British Columbia, said in an interview. “This is concerning as there are many people out there following this type of diet, and I think it suggests there is a need for closer monitoring of these people.”

He explained that while it would be expected for cholesterol levels to rise on a high-fat diet, “there has been a perception by some that this is not worrisome as it is reflecting certain metabolic changes. What we’ve shown in this study is that if your cholesterol does increase significantly on this diet then you should not assume that this is not a problem.

“For some people with diabetes this diet can help lower blood sugar and some people can lose weight on it,” he noted, “but what our data show is that there is a subgroup of people who experience high levels of LDL and ApoB and that seems to be driving the risk.”

He pointed out that overall the mean level of LDL was only slightly increased in the individuals on the low-carb/high-fat diet but severe high cholesterol (more than 5 mmol/L or 190 mg/dL) was about doubled in that group (10% vs. 5%). And these patients had a sixfold increase in risk of cardiovascular disease (P < .001). 

“This suggests that there is a subgroup of people who are susceptible to this exacerbation of hypercholesterolemia in response to a low-carb/high-fat diet.”

Dr. Brunham said his advice would be that if people choose to follow this diet, they should have their cholesterol monitored, and manage their cardiovascular risk factors.

“I wouldn’t say it is not appropriate to follow this diet based on this study,” he added. “This is just an observational study. It is not definitive. But if people do want to follow this dietary pattern because they feel there would be some benefits, then they should be aware of the potential risks and take steps to mitigate those risks.”
 

Jury still out

Dr. Nissen said in his view “the jury was still out” on this type of diet. “I’m open to the possibility that, particularly in the short run, a ‘keto-like’ diet may help some people lose weight and that’s a good thing. But I do not generally recommend this type of diet.”

Rather, he advises patients to follow a Mediterranean diet, which has been proven to reduce cardiovascular events in a randomized study, the PREDIMED trial.  

“We can’t make decisions on what type of diet to recommend to patients based on observational studies like this where there is a lot of subtlety missing. But when studies like this are reported, the mass media seize on it. That’s not the way the public needs to be educated,” Dr. Nissen said. 

“We refer to this type of study as hypothesis-generating. It raises a hypothesis. It doesn’t answer the question. It is worth looking at the question of whether a ketogenic-like diet is harmful. We don’t know at present, and I don’t think we know any more after this study,” he added.

The authors of the study reported no relevant financial relationships.

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

At 6 months follow-up, a new-generation resorbable stent with a magnesium scaffold appears to perform at a level comparable to nonabsorbable drug-eluting stents (DES), according to first-in-man results presented as a late-breaker at the Cardiovascular Research Technologies conference, sponsored by MedStar Heart & Vascular Institute.

“IVUS [intravascular ultrasound] assessment demonstrated preservation of the scaffold area from post procedure up to 6 months with a low mean neointimal area,” reported Michael Haude, MD, PhD, director of the Heart & Vascular Center, Neuss, Germany.

Neointimal formation and late lumen loss (LLL) have been the Achilles’ heel of previous efforts to develop a viable fully absorbable stent, making these 6-month data highly encouraging.

Ted Bosworth/MDedge Cardiology

The tested device is the most recent iteration of the DREAMS (drug-eluting resorbable magnesium scaffold) technology. Relative to DREAMS 2G, the DREAMS 3G device has several design changes, including a higher radial force and reduced strut thickness.

The goal was to build on the promise of DREAMS 2G while avoiding its limitations.

“The problem with DREAMS 2G was that it showed low–target lesion failure and scaffold thrombosis rates in multiple trials, but in-scaffold LLL was not comparable to LLL values observed with historical PLLA [poly-L-lactic acid]–based scaffolds or contemporary DES,” Dr. Haude said.

The 6-month data with DREAMS 3G were drawn from the BIOMAG-I study. Patients with stable or unstable angina were enrolled if they had no angiographic evidence of thrombus at the target lesion. Patients were also required to have no more than two single de novo lesions requiring revascularization.

Of 116 patients enrolled, 115 were available for evaluation at 6 months. The study was not controlled, but outcomes were compared at 6 months to those observed with the DREAMS 2G device in the BIOSOLVE-II trial, published several years ago in the Lancet.

For the primary outcome of in-scaffold LLL at 6 months, the mean LLL from baseline at 6 months was more than 50% lower with the DREAMS 3G device in BIOMAG-I than DREAMS 2G in BIOSOLVE-II (0.21 vs. 0.44 mm). In a post hoc superiority analysis employing a weighted mean, a superiority analysis supported a highly significant difference in favor of the newer device (P < .0001).

More importantly, the low LLL in BIOMAG-I was not just favorable relative to previously evaluated bioabsorbable stents, but it appears to compete with nonabsorbable options at least after this length of follow-up.

In terms of LLL at 6 months, “these data suggested that DREAMS 3G “is now on the level of contemporary DES,” Dr. Haude said.

The relative difference in favor of DREAMS 3G was even greater at 6 months for the secondary endpoint of in-segment LLL (0.05 vs. 0.27 mm) with similar significance for the superiority margin in a post hoc analysis (P < .0001).

Serial optical coherence tomography (OCT) was conducted post procedure, and indicated that the struts “were well embedded in the vessel wall,” according to Dr. Haude. Only 4.4% of struts on average were malapposed. The total incomplete strut apposition area was on average 0.08 mm. At 6 months, most struts were no long discernible on OCT, documenting device resorption.

Clinical results at 6 months were supportive. There were no cases of definite or probable scaffold thrombosis, and there were no target vessel myocardial infarctions or cardiac deaths. There was one clinically driven target lesion revascularization.

DREAMS 3G has other features designed to make it easier to deploy, Dr. Haude said. For example, radiopaque markers are now situated on both ends of the stent, making it easier to see on imaging. There are also plans to make these stents available in 15 sizes to accommodate a broad range of anatomy.

The data were impressive for many of the panelists invited to discuss the results.

“For the first time, we are seeing a bioabsorbable device showing excellent healing and very little late lumen loss,” said Michael H. Joner, MD, professor of early clinical trials at the German Center for Cardiovascular Research, Munich. “The next step is some sort of direct comparison with a drug-eluting stent.”

Describing himself as “a little more skeptical,” Aoke V Finn, MD, medical director and chief scientific officer, CVPath Institute, University of Maryland, Baltimore, said he wants to know more about the speed of device degradation and to see more long-term results in terms of clinical events. Although he considers the data promising so far, he considers it too early to embark on a randomized trial.

Longer-term data are coming, according to Dr. Haude. In addition to the 12-month follow-up that will include OCT and IVUS evaluations, there are annual clinical follow-up analyses planned to 5 years.

Dr. Haude reports financial relationships with Biotronik, Cardiac Dimensions, OrbusNeich, and Philips. Dr. Joner reports no potential conflicts of interest. Dr. Finn reports financial relationships with 19 pharmaceutical companies including those that manufacture cardiovascular stents.

At 6 months follow-up, a new-generation resorbable stent with a magnesium scaffold appears to perform at a level comparable to nonabsorbable drug-eluting stents (DES), according to first-in-man results presented as a late-breaker at the Cardiovascular Research Technologies conference, sponsored by MedStar Heart & Vascular Institute.

“IVUS [intravascular ultrasound] assessment demonstrated preservation of the scaffold area from post procedure up to 6 months with a low mean neointimal area,” reported Michael Haude, MD, PhD, director of the Heart & Vascular Center, Neuss, Germany.

Neointimal formation and late lumen loss (LLL) have been the Achilles’ heel of previous efforts to develop a viable fully absorbable stent, making these 6-month data highly encouraging.

Ted Bosworth/MDedge Cardiology

The tested device is the most recent iteration of the DREAMS (drug-eluting resorbable magnesium scaffold) technology. Relative to DREAMS 2G, the DREAMS 3G device has several design changes, including a higher radial force and reduced strut thickness.

The goal was to build on the promise of DREAMS 2G while avoiding its limitations.

“The problem with DREAMS 2G was that it showed low–target lesion failure and scaffold thrombosis rates in multiple trials, but in-scaffold LLL was not comparable to LLL values observed with historical PLLA [poly-L-lactic acid]–based scaffolds or contemporary DES,” Dr. Haude said.

The 6-month data with DREAMS 3G were drawn from the BIOMAG-I study. Patients with stable or unstable angina were enrolled if they had no angiographic evidence of thrombus at the target lesion. Patients were also required to have no more than two single de novo lesions requiring revascularization.

Of 116 patients enrolled, 115 were available for evaluation at 6 months. The study was not controlled, but outcomes were compared at 6 months to those observed with the DREAMS 2G device in the BIOSOLVE-II trial, published several years ago in the Lancet.

For the primary outcome of in-scaffold LLL at 6 months, the mean LLL from baseline at 6 months was more than 50% lower with the DREAMS 3G device in BIOMAG-I than DREAMS 2G in BIOSOLVE-II (0.21 vs. 0.44 mm). In a post hoc superiority analysis employing a weighted mean, a superiority analysis supported a highly significant difference in favor of the newer device (P < .0001).

More importantly, the low LLL in BIOMAG-I was not just favorable relative to previously evaluated bioabsorbable stents, but it appears to compete with nonabsorbable options at least after this length of follow-up.

In terms of LLL at 6 months, “these data suggested that DREAMS 3G “is now on the level of contemporary DES,” Dr. Haude said.

The relative difference in favor of DREAMS 3G was even greater at 6 months for the secondary endpoint of in-segment LLL (0.05 vs. 0.27 mm) with similar significance for the superiority margin in a post hoc analysis (P < .0001).

Serial optical coherence tomography (OCT) was conducted post procedure, and indicated that the struts “were well embedded in the vessel wall,” according to Dr. Haude. Only 4.4% of struts on average were malapposed. The total incomplete strut apposition area was on average 0.08 mm. At 6 months, most struts were no long discernible on OCT, documenting device resorption.

Clinical results at 6 months were supportive. There were no cases of definite or probable scaffold thrombosis, and there were no target vessel myocardial infarctions or cardiac deaths. There was one clinically driven target lesion revascularization.

DREAMS 3G has other features designed to make it easier to deploy, Dr. Haude said. For example, radiopaque markers are now situated on both ends of the stent, making it easier to see on imaging. There are also plans to make these stents available in 15 sizes to accommodate a broad range of anatomy.

The data were impressive for many of the panelists invited to discuss the results.

“For the first time, we are seeing a bioabsorbable device showing excellent healing and very little late lumen loss,” said Michael H. Joner, MD, professor of early clinical trials at the German Center for Cardiovascular Research, Munich. “The next step is some sort of direct comparison with a drug-eluting stent.”

Describing himself as “a little more skeptical,” Aoke V Finn, MD, medical director and chief scientific officer, CVPath Institute, University of Maryland, Baltimore, said he wants to know more about the speed of device degradation and to see more long-term results in terms of clinical events. Although he considers the data promising so far, he considers it too early to embark on a randomized trial.

Longer-term data are coming, according to Dr. Haude. In addition to the 12-month follow-up that will include OCT and IVUS evaluations, there are annual clinical follow-up analyses planned to 5 years.

Dr. Haude reports financial relationships with Biotronik, Cardiac Dimensions, OrbusNeich, and Philips. Dr. Joner reports no potential conflicts of interest. Dr. Finn reports financial relationships with 19 pharmaceutical companies including those that manufacture cardiovascular stents.

At 6 months follow-up, a new-generation resorbable stent with a magnesium scaffold appears to perform at a level comparable to nonabsorbable drug-eluting stents (DES), according to first-in-man results presented as a late-breaker at the Cardiovascular Research Technologies conference, sponsored by MedStar Heart & Vascular Institute.

“IVUS [intravascular ultrasound] assessment demonstrated preservation of the scaffold area from post procedure up to 6 months with a low mean neointimal area,” reported Michael Haude, MD, PhD, director of the Heart & Vascular Center, Neuss, Germany.

Neointimal formation and late lumen loss (LLL) have been the Achilles’ heel of previous efforts to develop a viable fully absorbable stent, making these 6-month data highly encouraging.

Ted Bosworth/MDedge Cardiology

The tested device is the most recent iteration of the DREAMS (drug-eluting resorbable magnesium scaffold) technology. Relative to DREAMS 2G, the DREAMS 3G device has several design changes, including a higher radial force and reduced strut thickness.

The goal was to build on the promise of DREAMS 2G while avoiding its limitations.

“The problem with DREAMS 2G was that it showed low–target lesion failure and scaffold thrombosis rates in multiple trials, but in-scaffold LLL was not comparable to LLL values observed with historical PLLA [poly-L-lactic acid]–based scaffolds or contemporary DES,” Dr. Haude said.

The 6-month data with DREAMS 3G were drawn from the BIOMAG-I study. Patients with stable or unstable angina were enrolled if they had no angiographic evidence of thrombus at the target lesion. Patients were also required to have no more than two single de novo lesions requiring revascularization.

Of 116 patients enrolled, 115 were available for evaluation at 6 months. The study was not controlled, but outcomes were compared at 6 months to those observed with the DREAMS 2G device in the BIOSOLVE-II trial, published several years ago in the Lancet.

For the primary outcome of in-scaffold LLL at 6 months, the mean LLL from baseline at 6 months was more than 50% lower with the DREAMS 3G device in BIOMAG-I than DREAMS 2G in BIOSOLVE-II (0.21 vs. 0.44 mm). In a post hoc superiority analysis employing a weighted mean, a superiority analysis supported a highly significant difference in favor of the newer device (P < .0001).

More importantly, the low LLL in BIOMAG-I was not just favorable relative to previously evaluated bioabsorbable stents, but it appears to compete with nonabsorbable options at least after this length of follow-up.

In terms of LLL at 6 months, “these data suggested that DREAMS 3G “is now on the level of contemporary DES,” Dr. Haude said.

The relative difference in favor of DREAMS 3G was even greater at 6 months for the secondary endpoint of in-segment LLL (0.05 vs. 0.27 mm) with similar significance for the superiority margin in a post hoc analysis (P < .0001).

Serial optical coherence tomography (OCT) was conducted post procedure, and indicated that the struts “were well embedded in the vessel wall,” according to Dr. Haude. Only 4.4% of struts on average were malapposed. The total incomplete strut apposition area was on average 0.08 mm. At 6 months, most struts were no long discernible on OCT, documenting device resorption.

Clinical results at 6 months were supportive. There were no cases of definite or probable scaffold thrombosis, and there were no target vessel myocardial infarctions or cardiac deaths. There was one clinically driven target lesion revascularization.

DREAMS 3G has other features designed to make it easier to deploy, Dr. Haude said. For example, radiopaque markers are now situated on both ends of the stent, making it easier to see on imaging. There are also plans to make these stents available in 15 sizes to accommodate a broad range of anatomy.

The data were impressive for many of the panelists invited to discuss the results.

“For the first time, we are seeing a bioabsorbable device showing excellent healing and very little late lumen loss,” said Michael H. Joner, MD, professor of early clinical trials at the German Center for Cardiovascular Research, Munich. “The next step is some sort of direct comparison with a drug-eluting stent.”

Describing himself as “a little more skeptical,” Aoke V Finn, MD, medical director and chief scientific officer, CVPath Institute, University of Maryland, Baltimore, said he wants to know more about the speed of device degradation and to see more long-term results in terms of clinical events. Although he considers the data promising so far, he considers it too early to embark on a randomized trial.

Longer-term data are coming, according to Dr. Haude. In addition to the 12-month follow-up that will include OCT and IVUS evaluations, there are annual clinical follow-up analyses planned to 5 years.

Dr. Haude reports financial relationships with Biotronik, Cardiac Dimensions, OrbusNeich, and Philips. Dr. Joner reports no potential conflicts of interest. Dr. Finn reports financial relationships with 19 pharmaceutical companies including those that manufacture cardiovascular stents.

In February 2003, when Cardiology News published its first edition, there were a handful of articles reporting results from randomized clinical trials. These included a trial of bivalirudin for percutaneous coronary intervention (PCI) anticoagulation (REPLACE-2) and a small controlled pilot study of soy nuts for blood pressure reduction in postmenopausal women. Also included was a considered discussion of the ALLHAT findings.

These trials and the incremental gain they offered belie the enormous global impact the cardiology community has had in clinical research over the last several decades. In fact, more than any other medical specialty, cardiology has led the way in evidence-based practice.

“When you step back and take a look at the compendium of cardiology advances, it’s unbelievable how much we’ve accomplished in the last 20 years,” said Steven E. Nissen, MD.

Dr. Nissen, a prodigious researcher, is the chief academic officer at the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute, and holds the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at the Cleveland Clinic.
 

The needle mover: LDL lowering

“From a population health perspective, LDL cholesterol lowering is clearly the big winner,” said Christopher Cannon, MD, from Harvard Medical School and Brigham and Women’s Hospital, both in Boston, said in an interview.

“We’ve been at it with LDL cholesterol for about 50 years now, but I think things really accelerated over the last 20 years when the conversation shifted from just lowering LDL-C to recognizing that lower is better. This pushed us toward high-intensity statin treatment and add-on drugs to push LDL down further,” he said.

“Concurrent with this increase in the use of statins and other LDL-lowering drugs, cardiovascular death has fallen significantly, which in my mind is likely a result of better LDL lowering and getting people to stop smoking, which we’ve also done a better job of in the last 20 years,” said Dr. Cannon.

Indeed, until cardiovascular mortality started rising in 2020, the first year of the COVID-19 pandemic, mortality rates had been dropping steadily for several decades. The progress in the past 2 decades has been so fast, noted Dr. Cannon, that the American Heart Association’s stated goal in 1998 of reducing coronary heart disease, stroke, and risk by 25% by the year 2008 was accomplished about 4 years ahead of schedule.

Coincidentally, Dr. Cannon and Dr. Nissen were both important players in this advance. Dr. Cannon led the PROVE-IT trial, which showed in 2004 that an intensive lipid-lowering statin regimen offers greater protection against death or major cardiovascular events than does a standard regimen in patients with recent acute coronary syndrome.

That trial was published just months after REVERSAL, Dr. Nissen’s trial that showed for the first time that intensive lipid-lowering treatment reduced progression of coronary atherosclerosis, compared with a moderate lipid-lowering approach.

“Added to this, we have drugs like ezetimibe and the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor, and now they’re even using CRISPR gene editing to permanently switch off the gene that codes for PCSK9, testing this in people with familial hypercholesterolemia,” said Dr. Cannon. “In the preclinical study, they showed that with one treatment they lowered blood PCSK9 protein levels by 83% and LDL-C by 69%..”

At the same time as we’ve seen what works, we’ve also seen what doesn’t work, added Dr. Nissen. “Shortly after we saw the power of LDL lowering, everyone wanted to target HDL and we had epidemiological evidence suggesting this was a good idea, but several landmark trials testing the HDL hypothesis were complete failures.” Debate continues as to whether HDL cholesterol is a suitable target for prevention.

Not only has the recent past in lipidology been needle-moving, but the hits keep coming. Inclisiran, a first-in-class LDL cholesterol–lowering drug that shows potent lipid-lowering efficacy and excellent safety and tolerability in phase 3 study, received Food and Drug Administration approval in December 2021. The drugs twice-a-year dosing has been called a game changer for adherence.

And at the 2023 annual scientific sessions of the American College of Cardiology in March, Dr. Nissen presented results of the CLEAR Outcomes trial on bempedoic acid (Nexletol), a 14,000-patient, placebo-controlled trial of bempedoic acid in statin intolerant patients at high cardiovascular risk. Bempedoic acid is a novel compound that inhibits ATP citrate lyase, which catalyzes a step in the biosynthesis of cholesterol upstream of HMG-CoA reductase, the target of statins.

Findings revealed a significant reduction in risk for a composite 4-point major adverse cardiovascular events endpoint of time to first cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization. The trial marks the first time an oral nonstatin drug has met the MACE-4 primary endpoint, Dr. Nissen reported.

“We also have new therapies for lowering lipoprotein(a) and outcome trials underway for antisense and short interfering RNA targeting of Lp(a), which I frankly think herald a new era in which we can have these longer-acting directly targeted drugs that work at the translation level to prevent a protein that is not desirable,” added Dr. Nissen. “These drugs will undoubtedly change the face of atherosclerotic cardiovascular disease in the next 2 decades.”


 

Other important successes and equally important failures

Perhaps consideration of some of the treatments we didn’t have 20 years ago is more revealing than a list of advances. Two decades ago, there were no direct direct-acting anticoagulants on the market, “so no alternative to warfarin, which is difficult to use and associated with excess bleeding,” said Dr. Cannon. These days, warfarin is little used, mostly after valve replacement, Dr. Nissen added.

There were also no percutaneous options for the treatment of valvular heart disease and no catheter ablation of atrial fibrillation, “huge developments that are now being done everywhere,” Dr. Nissen said.

Also in the catheterization laboratory, there was also a far less sophisticated understanding of the optimal role of PCI in treating coronary artery disease.

“We’ve moved from what we called the ‘oculostenotic reflex’– if you see an obstruction, you treat it – to a far more nuanced understanding of who should and shouldn’t have PCI, such that now PCI has contracted to the point where most of the time it’s being done for urgent indications like ST-segment elevation MI or an unstable non-STEMI. And this is based on a solid evidence base, which is terribly important,” said Dr. Nissen.
 

The rise and fall of CVOTs

Certainly, the heart failure world has seen important advances in recent years, including the first mineralocorticoid receptor antagonist, spironolactone, shown in the 1999 RALES trial to be life prolonging in patients with heart failure with reduced ejection fraction and a first in class angiotensin neprilysin inhibitor, sacubitril/valsartan. But it’s a fair guess that heart failure has never seen anything like the sodium-glucose cotransporter 2 (SGLT2) inhibitors.

Likely very few in the cardiology world had ever heard of SGLT2 inhibition 20 years ago, even though the idea of SGLT2 inhibition dates back more than 150 years, to when a French chemist isolated a substance known as phlorizin from the bark of the apple tree and subsequent investigations found that ingestion of it caused glucosuria. The SGLT2 story is one of great serendipity and one in which Dr. Nissen played a prominent role. It also hints to something that has both come and gone in the last 20 years: the FDA-mandated cardiovascular outcome trial (CVOT).

It was Dr. Nissen’s meta-analysis published in 2007 that started the ball rolling for what has been dubbed the CVOT or cardiovascular outcomes trials.

His analysis suggested increased cardiovascular risk associated with the thiazolidinedione rosiglitazone (Avandia), then a best-selling diabetes drug.

“At the time, Avandia was the top selling diabetes drug in the world, and our meta-analysis was terribly controversial,” said Dr. Nissen. In 2008, he gave a presentation to the FDA where he suggested they should require properly powered trials to rule out excess cardiovascular risk for any new diabetes drugs.

Others also recognized that the findings of his meta-analysis hinted to a failure of the approval process and the postapproval monitoring process, something which had been seen previously, with cardiac safety concerns emerging over other antihyperglycemic medications. The FDA was also responding to concerns that, given the high prevalence of cardiovascular disease in diabetes, approving a drug with cardiovascular risk could be disastrous.

In 2008 they mandated the CVOT, one of which, the EMPA-REG OUTCOME trial, showed that the SGLT2 inhibitor empagliflozin significantly reduced the risk of a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 14% (P = .04), driven by a 38% relative risk reduction in cardiovascular death (P < .001).Treatment with empagliflozin was also associated with a 35% reduction in heart failure hospitalization and a 32% reduction in all-cause death in that trial.

Additional groundbreaking CVOTs of empagliflozin and other SGLT2 inhibitors went on to show significant cardiorenal benefits and risk reduction in patients across the spectrum of heart failure, including those with preserved ejection fraction and in those with kidney disease.

“I think it’s fair to say that, had the FDA not mandated CVOTs for all new diabetes drugs, then the SGLT2 inhibitors and the GLP-1 [glucagonlike peptide–1] receptor agonists would have been approved on the basis of trials involving a few thousand patients showing that they lowered blood sugar, and we might never have found out what we know now about their benefits in individuals with established cardiovascular disease, in heart failure, and their ability to help people lose weight,” said Dr. Nissen. “And, of course, Avandia is long gone, which is a good thing.”

Interestingly, the FDA no longer requires extensive cardiovascular testing for new glucose-lowering agents in the absence of specific safety signals, replacing the CVOT mandate with one requiring broader inclusion of patients with underlying CV disease, chronic kidney disease, and older patients in stage 3 clinical trials of new agents.

“The SGLT2 inhibitors are already hugely important and with the growing prevalence of diabetes, their role is just going to get bigger. And it looks like the same thing will happen with the GLP-1 receptor agonists and obesity. We don’t have the outcomes trials for semaglutide and tirzepatide yet in patients with obesity, but given every other trial of this class in patients with diabetes has shown cardiovascular benefit, assuming those trials do too, those drugs are going to be very important,” added Dr. Cannon.

“The truth is, everywhere you look in cardiology, there have been major advances,” Dr. Cannon said. “It’s a wonderful time to work in this field because we’re making important progress across the board and it doesn’t appear to be slowing down at all.”

Clinical research for the next 20 years

Twenty years ago, clinical research was relatively simple, or at least it seemed so. All that was needed was a basic understanding of the scientific method and randomized controlled trials (RCTs), a solid research question, a target sample of sufficient size to ensure statistical power, and some basic statistical analysis, et violà, evidence generation.

Turns out, that might have been in large part true because medicine was in a more simplistic age. While RCTs remain the cornerstone of determining the safety and efficacy of new therapeutic strategies, they traditionally have severely lacked in age, gender, ethnic, and racial diversity. These issues limit their clinical relevance, to the chagrin of the large proportion of the population (women, minorities, children, and anyone with comorbidities) not included in most studies.

RCTs have also grown exceedingly time consuming and expensive. “We really saw the limitations of our clinical trial system during the pandemic when so many of the randomized COVID-19 trials done in the United States had complex protocols with a focus on surrogate outcomes such that, with only the 500 patients they enrolled, they ended up showing nothing,” Dr. Cannon said in an interview.

“And then we looked at the RECOVERY trial program that Martin Landray, MBChB, PhD, and the folks at Oxford [England] University pioneered. They ran multiple trials for relatively little costs, used a pragmatic design, and asked simple straightforward questions, and included 10,000-15,000 patients in each trial and gave us answers quickly,” he said.

RECOVERY is an ongoing adaptive multicenter randomized controlled trial evaluating several potential treatments for COVID-19. The RECOVERY Collaborative are credited with running multiple streamlined and easy to administer trials that included more than 47,000 participants spread across almost 200 hospital sites in six countries. The trials resulted in finding four effective COVID-19 treatments and proving that five others clearly were not effective.

Importantly, only essential data were collected and, wherever possible, much of the follow-up information was derived from national electronic health records.

“Now the question is, Can the U.S. move to doing more of these pragmatic trials?” asked Dr. Cannon.
 

Time to be inclusive

Where the rules of generating evidence have changed and will continue to change over the next many years is inclusivity. Gone are the days when researchers can get away with running a randomized trial with, say, few minority patients, 20% representation of women, and no elderly patients with comorbidities.

“I’m proud of the fact that 48% of more than 14,000 participants in the CLEAR outcomes trial that I presented at the ACC meeting are women,” Dr. Nissen said in an interview.

“Should it have been like that 20 years ago? Yes, probably. But we weren’t as conscious of these things. Now we’re working very hard to enroll more women and more underrepresented groups into trials, and this is a good thing.”

In a joint statement entitled “Randomized trials fit for the 21st century,” the leadership of the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation urge investigators and professional societies to “promote trials that are relevant to a broad and varied population; assuring diversity of participants and funded researchers (e.g., with appropriate sex, age, racial, ethnic, and socioeconomic diversity).”

The statement also recognizes that the present clinical research model is “unsustainable” and encourages wider adoption of “highly streamlined” conduct like that taken by the RECOVERY investigators during the pandemic.
 

Stick with randomization

Some have suggested that loosening the standards for evidence generation in medicine to include observational data, big data, artificial intelligence, and alternative trial strategies, such as Mendelian randomization and causal inference of nonrandomized data, might help drive new treatments to the clinic faster. To this, Dr. Nissen and Dr. Cannon offer an emphatic no.

“The idea that you can use big data or any kind of nonrandomized data to replace randomized control trials is a bad idea, and the reason is that nonrandomized data is often bad data,” Dr. Nissen said in an interview.

“I can’t count how many bad studies we’ve seen that were enormous in size, and where they tried to control the variables to balance it out, and they still get the wrong answer,” he added. “The bottom line is that observational data has failed us over and over again.”

Not to say that observational studies have no value, it’s just not for determining which treatments are most efficacious or safe, said Dr. Cannon. “If you want to identify markers of disease or risk factors, you can use observational data like data collected from wearables and screen for patients who, say, might be at high risk of dying of COVID-19. Or even more directly, you can use a heart rate and temperature monitor to identify people who are about to test positive for COVID-19.

“But the findings of observational analyses, no matter how much you try to control for confounding, are only ever going to be hypothesis generating. They can’t be used to say this biomarker causes death from COVID or this blood thinner is better than that blood thinner.”

Concurring with this, the ESC, AHA, ACC, and WHF statement authors acknowledged the value of nonrandomized evidence in today’s big data, electronic world, but advocated for the “appropriate use of routine EHRs (i.e. ‘real-world’ data) within randomized trials, recognizing the huge potential of centrally or regionally held electronic health data for trial recruitment and follow-up, as well as to highlight the severe limitations of using observational analyses when the purpose is to draw causal inference about the risks and benefits of an intervention.”

In February 2003, when Cardiology News published its first edition, there were a handful of articles reporting results from randomized clinical trials. These included a trial of bivalirudin for percutaneous coronary intervention (PCI) anticoagulation (REPLACE-2) and a small controlled pilot study of soy nuts for blood pressure reduction in postmenopausal women. Also included was a considered discussion of the ALLHAT findings.

These trials and the incremental gain they offered belie the enormous global impact the cardiology community has had in clinical research over the last several decades. In fact, more than any other medical specialty, cardiology has led the way in evidence-based practice.

“When you step back and take a look at the compendium of cardiology advances, it’s unbelievable how much we’ve accomplished in the last 20 years,” said Steven E. Nissen, MD.

Dr. Nissen, a prodigious researcher, is the chief academic officer at the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute, and holds the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at the Cleveland Clinic.
 

The needle mover: LDL lowering

“From a population health perspective, LDL cholesterol lowering is clearly the big winner,” said Christopher Cannon, MD, from Harvard Medical School and Brigham and Women’s Hospital, both in Boston, said in an interview.

“We’ve been at it with LDL cholesterol for about 50 years now, but I think things really accelerated over the last 20 years when the conversation shifted from just lowering LDL-C to recognizing that lower is better. This pushed us toward high-intensity statin treatment and add-on drugs to push LDL down further,” he said.

“Concurrent with this increase in the use of statins and other LDL-lowering drugs, cardiovascular death has fallen significantly, which in my mind is likely a result of better LDL lowering and getting people to stop smoking, which we’ve also done a better job of in the last 20 years,” said Dr. Cannon.

Indeed, until cardiovascular mortality started rising in 2020, the first year of the COVID-19 pandemic, mortality rates had been dropping steadily for several decades. The progress in the past 2 decades has been so fast, noted Dr. Cannon, that the American Heart Association’s stated goal in 1998 of reducing coronary heart disease, stroke, and risk by 25% by the year 2008 was accomplished about 4 years ahead of schedule.

Coincidentally, Dr. Cannon and Dr. Nissen were both important players in this advance. Dr. Cannon led the PROVE-IT trial, which showed in 2004 that an intensive lipid-lowering statin regimen offers greater protection against death or major cardiovascular events than does a standard regimen in patients with recent acute coronary syndrome.

That trial was published just months after REVERSAL, Dr. Nissen’s trial that showed for the first time that intensive lipid-lowering treatment reduced progression of coronary atherosclerosis, compared with a moderate lipid-lowering approach.

“Added to this, we have drugs like ezetimibe and the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor, and now they’re even using CRISPR gene editing to permanently switch off the gene that codes for PCSK9, testing this in people with familial hypercholesterolemia,” said Dr. Cannon. “In the preclinical study, they showed that with one treatment they lowered blood PCSK9 protein levels by 83% and LDL-C by 69%..”

At the same time as we’ve seen what works, we’ve also seen what doesn’t work, added Dr. Nissen. “Shortly after we saw the power of LDL lowering, everyone wanted to target HDL and we had epidemiological evidence suggesting this was a good idea, but several landmark trials testing the HDL hypothesis were complete failures.” Debate continues as to whether HDL cholesterol is a suitable target for prevention.

Not only has the recent past in lipidology been needle-moving, but the hits keep coming. Inclisiran, a first-in-class LDL cholesterol–lowering drug that shows potent lipid-lowering efficacy and excellent safety and tolerability in phase 3 study, received Food and Drug Administration approval in December 2021. The drugs twice-a-year dosing has been called a game changer for adherence.

And at the 2023 annual scientific sessions of the American College of Cardiology in March, Dr. Nissen presented results of the CLEAR Outcomes trial on bempedoic acid (Nexletol), a 14,000-patient, placebo-controlled trial of bempedoic acid in statin intolerant patients at high cardiovascular risk. Bempedoic acid is a novel compound that inhibits ATP citrate lyase, which catalyzes a step in the biosynthesis of cholesterol upstream of HMG-CoA reductase, the target of statins.

Findings revealed a significant reduction in risk for a composite 4-point major adverse cardiovascular events endpoint of time to first cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization. The trial marks the first time an oral nonstatin drug has met the MACE-4 primary endpoint, Dr. Nissen reported.

“We also have new therapies for lowering lipoprotein(a) and outcome trials underway for antisense and short interfering RNA targeting of Lp(a), which I frankly think herald a new era in which we can have these longer-acting directly targeted drugs that work at the translation level to prevent a protein that is not desirable,” added Dr. Nissen. “These drugs will undoubtedly change the face of atherosclerotic cardiovascular disease in the next 2 decades.”


 

Other important successes and equally important failures

Perhaps consideration of some of the treatments we didn’t have 20 years ago is more revealing than a list of advances. Two decades ago, there were no direct direct-acting anticoagulants on the market, “so no alternative to warfarin, which is difficult to use and associated with excess bleeding,” said Dr. Cannon. These days, warfarin is little used, mostly after valve replacement, Dr. Nissen added.

There were also no percutaneous options for the treatment of valvular heart disease and no catheter ablation of atrial fibrillation, “huge developments that are now being done everywhere,” Dr. Nissen said.

Also in the catheterization laboratory, there was also a far less sophisticated understanding of the optimal role of PCI in treating coronary artery disease.

“We’ve moved from what we called the ‘oculostenotic reflex’– if you see an obstruction, you treat it – to a far more nuanced understanding of who should and shouldn’t have PCI, such that now PCI has contracted to the point where most of the time it’s being done for urgent indications like ST-segment elevation MI or an unstable non-STEMI. And this is based on a solid evidence base, which is terribly important,” said Dr. Nissen.
 

The rise and fall of CVOTs

Certainly, the heart failure world has seen important advances in recent years, including the first mineralocorticoid receptor antagonist, spironolactone, shown in the 1999 RALES trial to be life prolonging in patients with heart failure with reduced ejection fraction and a first in class angiotensin neprilysin inhibitor, sacubitril/valsartan. But it’s a fair guess that heart failure has never seen anything like the sodium-glucose cotransporter 2 (SGLT2) inhibitors.

Likely very few in the cardiology world had ever heard of SGLT2 inhibition 20 years ago, even though the idea of SGLT2 inhibition dates back more than 150 years, to when a French chemist isolated a substance known as phlorizin from the bark of the apple tree and subsequent investigations found that ingestion of it caused glucosuria. The SGLT2 story is one of great serendipity and one in which Dr. Nissen played a prominent role. It also hints to something that has both come and gone in the last 20 years: the FDA-mandated cardiovascular outcome trial (CVOT).

It was Dr. Nissen’s meta-analysis published in 2007 that started the ball rolling for what has been dubbed the CVOT or cardiovascular outcomes trials.

His analysis suggested increased cardiovascular risk associated with the thiazolidinedione rosiglitazone (Avandia), then a best-selling diabetes drug.

“At the time, Avandia was the top selling diabetes drug in the world, and our meta-analysis was terribly controversial,” said Dr. Nissen. In 2008, he gave a presentation to the FDA where he suggested they should require properly powered trials to rule out excess cardiovascular risk for any new diabetes drugs.

Others also recognized that the findings of his meta-analysis hinted to a failure of the approval process and the postapproval monitoring process, something which had been seen previously, with cardiac safety concerns emerging over other antihyperglycemic medications. The FDA was also responding to concerns that, given the high prevalence of cardiovascular disease in diabetes, approving a drug with cardiovascular risk could be disastrous.

In 2008 they mandated the CVOT, one of which, the EMPA-REG OUTCOME trial, showed that the SGLT2 inhibitor empagliflozin significantly reduced the risk of a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 14% (P = .04), driven by a 38% relative risk reduction in cardiovascular death (P < .001).Treatment with empagliflozin was also associated with a 35% reduction in heart failure hospitalization and a 32% reduction in all-cause death in that trial.

Additional groundbreaking CVOTs of empagliflozin and other SGLT2 inhibitors went on to show significant cardiorenal benefits and risk reduction in patients across the spectrum of heart failure, including those with preserved ejection fraction and in those with kidney disease.

“I think it’s fair to say that, had the FDA not mandated CVOTs for all new diabetes drugs, then the SGLT2 inhibitors and the GLP-1 [glucagonlike peptide–1] receptor agonists would have been approved on the basis of trials involving a few thousand patients showing that they lowered blood sugar, and we might never have found out what we know now about their benefits in individuals with established cardiovascular disease, in heart failure, and their ability to help people lose weight,” said Dr. Nissen. “And, of course, Avandia is long gone, which is a good thing.”

Interestingly, the FDA no longer requires extensive cardiovascular testing for new glucose-lowering agents in the absence of specific safety signals, replacing the CVOT mandate with one requiring broader inclusion of patients with underlying CV disease, chronic kidney disease, and older patients in stage 3 clinical trials of new agents.

“The SGLT2 inhibitors are already hugely important and with the growing prevalence of diabetes, their role is just going to get bigger. And it looks like the same thing will happen with the GLP-1 receptor agonists and obesity. We don’t have the outcomes trials for semaglutide and tirzepatide yet in patients with obesity, but given every other trial of this class in patients with diabetes has shown cardiovascular benefit, assuming those trials do too, those drugs are going to be very important,” added Dr. Cannon.

“The truth is, everywhere you look in cardiology, there have been major advances,” Dr. Cannon said. “It’s a wonderful time to work in this field because we’re making important progress across the board and it doesn’t appear to be slowing down at all.”

Clinical research for the next 20 years

Twenty years ago, clinical research was relatively simple, or at least it seemed so. All that was needed was a basic understanding of the scientific method and randomized controlled trials (RCTs), a solid research question, a target sample of sufficient size to ensure statistical power, and some basic statistical analysis, et violà, evidence generation.

Turns out, that might have been in large part true because medicine was in a more simplistic age. While RCTs remain the cornerstone of determining the safety and efficacy of new therapeutic strategies, they traditionally have severely lacked in age, gender, ethnic, and racial diversity. These issues limit their clinical relevance, to the chagrin of the large proportion of the population (women, minorities, children, and anyone with comorbidities) not included in most studies.

RCTs have also grown exceedingly time consuming and expensive. “We really saw the limitations of our clinical trial system during the pandemic when so many of the randomized COVID-19 trials done in the United States had complex protocols with a focus on surrogate outcomes such that, with only the 500 patients they enrolled, they ended up showing nothing,” Dr. Cannon said in an interview.

“And then we looked at the RECOVERY trial program that Martin Landray, MBChB, PhD, and the folks at Oxford [England] University pioneered. They ran multiple trials for relatively little costs, used a pragmatic design, and asked simple straightforward questions, and included 10,000-15,000 patients in each trial and gave us answers quickly,” he said.

RECOVERY is an ongoing adaptive multicenter randomized controlled trial evaluating several potential treatments for COVID-19. The RECOVERY Collaborative are credited with running multiple streamlined and easy to administer trials that included more than 47,000 participants spread across almost 200 hospital sites in six countries. The trials resulted in finding four effective COVID-19 treatments and proving that five others clearly were not effective.

Importantly, only essential data were collected and, wherever possible, much of the follow-up information was derived from national electronic health records.

“Now the question is, Can the U.S. move to doing more of these pragmatic trials?” asked Dr. Cannon.
 

Time to be inclusive

Where the rules of generating evidence have changed and will continue to change over the next many years is inclusivity. Gone are the days when researchers can get away with running a randomized trial with, say, few minority patients, 20% representation of women, and no elderly patients with comorbidities.

“I’m proud of the fact that 48% of more than 14,000 participants in the CLEAR outcomes trial that I presented at the ACC meeting are women,” Dr. Nissen said in an interview.

“Should it have been like that 20 years ago? Yes, probably. But we weren’t as conscious of these things. Now we’re working very hard to enroll more women and more underrepresented groups into trials, and this is a good thing.”

In a joint statement entitled “Randomized trials fit for the 21st century,” the leadership of the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation urge investigators and professional societies to “promote trials that are relevant to a broad and varied population; assuring diversity of participants and funded researchers (e.g., with appropriate sex, age, racial, ethnic, and socioeconomic diversity).”

The statement also recognizes that the present clinical research model is “unsustainable” and encourages wider adoption of “highly streamlined” conduct like that taken by the RECOVERY investigators during the pandemic.
 

Stick with randomization

Some have suggested that loosening the standards for evidence generation in medicine to include observational data, big data, artificial intelligence, and alternative trial strategies, such as Mendelian randomization and causal inference of nonrandomized data, might help drive new treatments to the clinic faster. To this, Dr. Nissen and Dr. Cannon offer an emphatic no.

“The idea that you can use big data or any kind of nonrandomized data to replace randomized control trials is a bad idea, and the reason is that nonrandomized data is often bad data,” Dr. Nissen said in an interview.

“I can’t count how many bad studies we’ve seen that were enormous in size, and where they tried to control the variables to balance it out, and they still get the wrong answer,” he added. “The bottom line is that observational data has failed us over and over again.”

Not to say that observational studies have no value, it’s just not for determining which treatments are most efficacious or safe, said Dr. Cannon. “If you want to identify markers of disease or risk factors, you can use observational data like data collected from wearables and screen for patients who, say, might be at high risk of dying of COVID-19. Or even more directly, you can use a heart rate and temperature monitor to identify people who are about to test positive for COVID-19.

“But the findings of observational analyses, no matter how much you try to control for confounding, are only ever going to be hypothesis generating. They can’t be used to say this biomarker causes death from COVID or this blood thinner is better than that blood thinner.”

Concurring with this, the ESC, AHA, ACC, and WHF statement authors acknowledged the value of nonrandomized evidence in today’s big data, electronic world, but advocated for the “appropriate use of routine EHRs (i.e. ‘real-world’ data) within randomized trials, recognizing the huge potential of centrally or regionally held electronic health data for trial recruitment and follow-up, as well as to highlight the severe limitations of using observational analyses when the purpose is to draw causal inference about the risks and benefits of an intervention.”

In February 2003, when Cardiology News published its first edition, there were a handful of articles reporting results from randomized clinical trials. These included a trial of bivalirudin for percutaneous coronary intervention (PCI) anticoagulation (REPLACE-2) and a small controlled pilot study of soy nuts for blood pressure reduction in postmenopausal women. Also included was a considered discussion of the ALLHAT findings.

These trials and the incremental gain they offered belie the enormous global impact the cardiology community has had in clinical research over the last several decades. In fact, more than any other medical specialty, cardiology has led the way in evidence-based practice.

“When you step back and take a look at the compendium of cardiology advances, it’s unbelievable how much we’ve accomplished in the last 20 years,” said Steven E. Nissen, MD.

Dr. Nissen, a prodigious researcher, is the chief academic officer at the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute, and holds the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at the Cleveland Clinic.
 

The needle mover: LDL lowering

“From a population health perspective, LDL cholesterol lowering is clearly the big winner,” said Christopher Cannon, MD, from Harvard Medical School and Brigham and Women’s Hospital, both in Boston, said in an interview.

“We’ve been at it with LDL cholesterol for about 50 years now, but I think things really accelerated over the last 20 years when the conversation shifted from just lowering LDL-C to recognizing that lower is better. This pushed us toward high-intensity statin treatment and add-on drugs to push LDL down further,” he said.

“Concurrent with this increase in the use of statins and other LDL-lowering drugs, cardiovascular death has fallen significantly, which in my mind is likely a result of better LDL lowering and getting people to stop smoking, which we’ve also done a better job of in the last 20 years,” said Dr. Cannon.

Indeed, until cardiovascular mortality started rising in 2020, the first year of the COVID-19 pandemic, mortality rates had been dropping steadily for several decades. The progress in the past 2 decades has been so fast, noted Dr. Cannon, that the American Heart Association’s stated goal in 1998 of reducing coronary heart disease, stroke, and risk by 25% by the year 2008 was accomplished about 4 years ahead of schedule.

Coincidentally, Dr. Cannon and Dr. Nissen were both important players in this advance. Dr. Cannon led the PROVE-IT trial, which showed in 2004 that an intensive lipid-lowering statin regimen offers greater protection against death or major cardiovascular events than does a standard regimen in patients with recent acute coronary syndrome.

That trial was published just months after REVERSAL, Dr. Nissen’s trial that showed for the first time that intensive lipid-lowering treatment reduced progression of coronary atherosclerosis, compared with a moderate lipid-lowering approach.

“Added to this, we have drugs like ezetimibe and the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor, and now they’re even using CRISPR gene editing to permanently switch off the gene that codes for PCSK9, testing this in people with familial hypercholesterolemia,” said Dr. Cannon. “In the preclinical study, they showed that with one treatment they lowered blood PCSK9 protein levels by 83% and LDL-C by 69%..”

At the same time as we’ve seen what works, we’ve also seen what doesn’t work, added Dr. Nissen. “Shortly after we saw the power of LDL lowering, everyone wanted to target HDL and we had epidemiological evidence suggesting this was a good idea, but several landmark trials testing the HDL hypothesis were complete failures.” Debate continues as to whether HDL cholesterol is a suitable target for prevention.

Not only has the recent past in lipidology been needle-moving, but the hits keep coming. Inclisiran, a first-in-class LDL cholesterol–lowering drug that shows potent lipid-lowering efficacy and excellent safety and tolerability in phase 3 study, received Food and Drug Administration approval in December 2021. The drugs twice-a-year dosing has been called a game changer for adherence.

And at the 2023 annual scientific sessions of the American College of Cardiology in March, Dr. Nissen presented results of the CLEAR Outcomes trial on bempedoic acid (Nexletol), a 14,000-patient, placebo-controlled trial of bempedoic acid in statin intolerant patients at high cardiovascular risk. Bempedoic acid is a novel compound that inhibits ATP citrate lyase, which catalyzes a step in the biosynthesis of cholesterol upstream of HMG-CoA reductase, the target of statins.

Findings revealed a significant reduction in risk for a composite 4-point major adverse cardiovascular events endpoint of time to first cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization. The trial marks the first time an oral nonstatin drug has met the MACE-4 primary endpoint, Dr. Nissen reported.

“We also have new therapies for lowering lipoprotein(a) and outcome trials underway for antisense and short interfering RNA targeting of Lp(a), which I frankly think herald a new era in which we can have these longer-acting directly targeted drugs that work at the translation level to prevent a protein that is not desirable,” added Dr. Nissen. “These drugs will undoubtedly change the face of atherosclerotic cardiovascular disease in the next 2 decades.”


 

Other important successes and equally important failures

Perhaps consideration of some of the treatments we didn’t have 20 years ago is more revealing than a list of advances. Two decades ago, there were no direct direct-acting anticoagulants on the market, “so no alternative to warfarin, which is difficult to use and associated with excess bleeding,” said Dr. Cannon. These days, warfarin is little used, mostly after valve replacement, Dr. Nissen added.

There were also no percutaneous options for the treatment of valvular heart disease and no catheter ablation of atrial fibrillation, “huge developments that are now being done everywhere,” Dr. Nissen said.

Also in the catheterization laboratory, there was also a far less sophisticated understanding of the optimal role of PCI in treating coronary artery disease.

“We’ve moved from what we called the ‘oculostenotic reflex’– if you see an obstruction, you treat it – to a far more nuanced understanding of who should and shouldn’t have PCI, such that now PCI has contracted to the point where most of the time it’s being done for urgent indications like ST-segment elevation MI or an unstable non-STEMI. And this is based on a solid evidence base, which is terribly important,” said Dr. Nissen.
 

The rise and fall of CVOTs

Certainly, the heart failure world has seen important advances in recent years, including the first mineralocorticoid receptor antagonist, spironolactone, shown in the 1999 RALES trial to be life prolonging in patients with heart failure with reduced ejection fraction and a first in class angiotensin neprilysin inhibitor, sacubitril/valsartan. But it’s a fair guess that heart failure has never seen anything like the sodium-glucose cotransporter 2 (SGLT2) inhibitors.

Likely very few in the cardiology world had ever heard of SGLT2 inhibition 20 years ago, even though the idea of SGLT2 inhibition dates back more than 150 years, to when a French chemist isolated a substance known as phlorizin from the bark of the apple tree and subsequent investigations found that ingestion of it caused glucosuria. The SGLT2 story is one of great serendipity and one in which Dr. Nissen played a prominent role. It also hints to something that has both come and gone in the last 20 years: the FDA-mandated cardiovascular outcome trial (CVOT).

It was Dr. Nissen’s meta-analysis published in 2007 that started the ball rolling for what has been dubbed the CVOT or cardiovascular outcomes trials.

His analysis suggested increased cardiovascular risk associated with the thiazolidinedione rosiglitazone (Avandia), then a best-selling diabetes drug.

“At the time, Avandia was the top selling diabetes drug in the world, and our meta-analysis was terribly controversial,” said Dr. Nissen. In 2008, he gave a presentation to the FDA where he suggested they should require properly powered trials to rule out excess cardiovascular risk for any new diabetes drugs.

Others also recognized that the findings of his meta-analysis hinted to a failure of the approval process and the postapproval monitoring process, something which had been seen previously, with cardiac safety concerns emerging over other antihyperglycemic medications. The FDA was also responding to concerns that, given the high prevalence of cardiovascular disease in diabetes, approving a drug with cardiovascular risk could be disastrous.

In 2008 they mandated the CVOT, one of which, the EMPA-REG OUTCOME trial, showed that the SGLT2 inhibitor empagliflozin significantly reduced the risk of a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 14% (P = .04), driven by a 38% relative risk reduction in cardiovascular death (P < .001).Treatment with empagliflozin was also associated with a 35% reduction in heart failure hospitalization and a 32% reduction in all-cause death in that trial.

Additional groundbreaking CVOTs of empagliflozin and other SGLT2 inhibitors went on to show significant cardiorenal benefits and risk reduction in patients across the spectrum of heart failure, including those with preserved ejection fraction and in those with kidney disease.

“I think it’s fair to say that, had the FDA not mandated CVOTs for all new diabetes drugs, then the SGLT2 inhibitors and the GLP-1 [glucagonlike peptide–1] receptor agonists would have been approved on the basis of trials involving a few thousand patients showing that they lowered blood sugar, and we might never have found out what we know now about their benefits in individuals with established cardiovascular disease, in heart failure, and their ability to help people lose weight,” said Dr. Nissen. “And, of course, Avandia is long gone, which is a good thing.”

Interestingly, the FDA no longer requires extensive cardiovascular testing for new glucose-lowering agents in the absence of specific safety signals, replacing the CVOT mandate with one requiring broader inclusion of patients with underlying CV disease, chronic kidney disease, and older patients in stage 3 clinical trials of new agents.

“The SGLT2 inhibitors are already hugely important and with the growing prevalence of diabetes, their role is just going to get bigger. And it looks like the same thing will happen with the GLP-1 receptor agonists and obesity. We don’t have the outcomes trials for semaglutide and tirzepatide yet in patients with obesity, but given every other trial of this class in patients with diabetes has shown cardiovascular benefit, assuming those trials do too, those drugs are going to be very important,” added Dr. Cannon.

“The truth is, everywhere you look in cardiology, there have been major advances,” Dr. Cannon said. “It’s a wonderful time to work in this field because we’re making important progress across the board and it doesn’t appear to be slowing down at all.”

Clinical research for the next 20 years

Twenty years ago, clinical research was relatively simple, or at least it seemed so. All that was needed was a basic understanding of the scientific method and randomized controlled trials (RCTs), a solid research question, a target sample of sufficient size to ensure statistical power, and some basic statistical analysis, et violà, evidence generation.

Turns out, that might have been in large part true because medicine was in a more simplistic age. While RCTs remain the cornerstone of determining the safety and efficacy of new therapeutic strategies, they traditionally have severely lacked in age, gender, ethnic, and racial diversity. These issues limit their clinical relevance, to the chagrin of the large proportion of the population (women, minorities, children, and anyone with comorbidities) not included in most studies.

RCTs have also grown exceedingly time consuming and expensive. “We really saw the limitations of our clinical trial system during the pandemic when so many of the randomized COVID-19 trials done in the United States had complex protocols with a focus on surrogate outcomes such that, with only the 500 patients they enrolled, they ended up showing nothing,” Dr. Cannon said in an interview.

“And then we looked at the RECOVERY trial program that Martin Landray, MBChB, PhD, and the folks at Oxford [England] University pioneered. They ran multiple trials for relatively little costs, used a pragmatic design, and asked simple straightforward questions, and included 10,000-15,000 patients in each trial and gave us answers quickly,” he said.

RECOVERY is an ongoing adaptive multicenter randomized controlled trial evaluating several potential treatments for COVID-19. The RECOVERY Collaborative are credited with running multiple streamlined and easy to administer trials that included more than 47,000 participants spread across almost 200 hospital sites in six countries. The trials resulted in finding four effective COVID-19 treatments and proving that five others clearly were not effective.

Importantly, only essential data were collected and, wherever possible, much of the follow-up information was derived from national electronic health records.

“Now the question is, Can the U.S. move to doing more of these pragmatic trials?” asked Dr. Cannon.
 

Time to be inclusive

Where the rules of generating evidence have changed and will continue to change over the next many years is inclusivity. Gone are the days when researchers can get away with running a randomized trial with, say, few minority patients, 20% representation of women, and no elderly patients with comorbidities.

“I’m proud of the fact that 48% of more than 14,000 participants in the CLEAR outcomes trial that I presented at the ACC meeting are women,” Dr. Nissen said in an interview.

“Should it have been like that 20 years ago? Yes, probably. But we weren’t as conscious of these things. Now we’re working very hard to enroll more women and more underrepresented groups into trials, and this is a good thing.”

In a joint statement entitled “Randomized trials fit for the 21st century,” the leadership of the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation urge investigators and professional societies to “promote trials that are relevant to a broad and varied population; assuring diversity of participants and funded researchers (e.g., with appropriate sex, age, racial, ethnic, and socioeconomic diversity).”

The statement also recognizes that the present clinical research model is “unsustainable” and encourages wider adoption of “highly streamlined” conduct like that taken by the RECOVERY investigators during the pandemic.
 

Stick with randomization

Some have suggested that loosening the standards for evidence generation in medicine to include observational data, big data, artificial intelligence, and alternative trial strategies, such as Mendelian randomization and causal inference of nonrandomized data, might help drive new treatments to the clinic faster. To this, Dr. Nissen and Dr. Cannon offer an emphatic no.

“The idea that you can use big data or any kind of nonrandomized data to replace randomized control trials is a bad idea, and the reason is that nonrandomized data is often bad data,” Dr. Nissen said in an interview.

“I can’t count how many bad studies we’ve seen that were enormous in size, and where they tried to control the variables to balance it out, and they still get the wrong answer,” he added. “The bottom line is that observational data has failed us over and over again.”

Not to say that observational studies have no value, it’s just not for determining which treatments are most efficacious or safe, said Dr. Cannon. “If you want to identify markers of disease or risk factors, you can use observational data like data collected from wearables and screen for patients who, say, might be at high risk of dying of COVID-19. Or even more directly, you can use a heart rate and temperature monitor to identify people who are about to test positive for COVID-19.

“But the findings of observational analyses, no matter how much you try to control for confounding, are only ever going to be hypothesis generating. They can’t be used to say this biomarker causes death from COVID or this blood thinner is better than that blood thinner.”

Concurring with this, the ESC, AHA, ACC, and WHF statement authors acknowledged the value of nonrandomized evidence in today’s big data, electronic world, but advocated for the “appropriate use of routine EHRs (i.e. ‘real-world’ data) within randomized trials, recognizing the huge potential of centrally or regionally held electronic health data for trial recruitment and follow-up, as well as to highlight the severe limitations of using observational analyses when the purpose is to draw causal inference about the risks and benefits of an intervention.”

Adults who follow a heart-healthy lifestyle are more likely to live longer and to be free of chronic health conditions, based on data from a pair of related studies from the United States and United Kingdom involving nearly 200,000 individuals.

FatCamera/Getty Images

The studies, presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting in Boston, assessed the impact of cardiovascular health on life expectancy and freedom from chronic diseases. Cardiovascular health (CVH) was based on the Life’s Essential 8 (LE8) score, a composite of health metrics released by the American Heart Association in 2022. The LE8 was developed to guide research and assessment of cardiovascular health, and includes diet, physical activity, tobacco/nicotine exposure, sleep, body mass index, non-HDL cholesterol, blood glucose, and blood pressure.

In one study, Xuan Wang, MD, a postdoctoral fellow and biostatistician in the department of epidemiology at Tulane University, New Orleans, and colleagues reviewed data from 136,599 adults in the United Kingdom Biobank who were free of cardiovascular disease, diabetes, cancer, and dementia at baseline, and for whom complete LE8 data were available.

CVH was classified as poor, intermediate, and ideal, defined as LE8 scores of less than 50, 50 to 80, and 80 or higher, respectively.

The goal of the study was to examine the role of CVH based on LE8 scores on the percentage of life expectancy free of chronic diseases.

Men and women with ideal CVH averaged 5.2 years and 6.3 years more of total life expectancy at age 50 years, compared with those with poor CVH. Out of total life expectancy, the percentage of life expectancy free of chronic diseases was 75.9% and 83.4% for men and women, respectively, compared with 64.9% and 69.4%, respectively, for men and women with poor CVH.

The researchers also found that disparities in the percentage of disease-free years for both men and women were reduced in the high CVH groups.

The findings were limited by several factors including the use of only CVD, diabetes, cancer, and dementia in the definition of “disease-free life expectancy,” the researchers noted in a press release accompanying the study. Other limitations include the lack of data on e-cigarettes, and the homogeneous White study population. More research is needed in diverse populations who experience a stronger impact from negative social determinants of health, they said.

In a second study, Hao Ma, MD, and colleagues reviewed data from 23,003 adults who participated in the National Health and Nutrition Examination Survey (NHANES) between 2005 and 2018 with mortality linked to the National Death Index through Dec. 31, 2019. The goal of the second study was to examine the association between CVH based on LE8 scores and life expectancy.

Over a median follow-up of 7.8 years, deaths occurred in 772 men and 587 women, said Dr. Ma, a postdoctoral fellow and biostatistician in epidemiology at Tulane University and coauthor on Dr. Wang’s study.

The estimated life expectancies at age 50 years for men with poor, intermediate, and ideal cardiovascular health based on the LE8 were 25.5 years, 31.2 years, and 33.1 years, respectively.

For women, the corresponding life expectancies for women at age 50 with poor, intermediate, and ideal CVH were 29.5 years, 34.2 years, and 38.4 years, respectively.

Men and women had similar gains in life expectancy from adhering to a heart-healthy lifestyle as defined by the LE8 score that reduced their risk of death from cardiovascular disease (41.8% and 44.1%, respectively).

Associations of cardiovascular health and life expectancy were similar for non-Hispanic Whites and non-Hispanic Blacks, but not among people of Mexican heritage, and more research is needed in diverse populations, the researchers wrote.

The study was limited by several factors including potential changes in cardiovascular health during the follow-up period, and by the limited analysis of racial and ethnic groups to non-Hispanic white, non-Hispanic Black, and people of Mexican heritage because of small sample sizes for other racial/ethnic groups, the researchers noted in a press release accompanying the study.

The message for clinicians and their patients is that adherence to cardiovascular health as defined by the LE8 will help not only extend life, but enhance quality of life, Dr. Xang and Dr. Ma said in an interview. “If your overall CVH score is low, we might be able to focus on one element first and improve them one by one,” they said. Sedentary lifestyle and an unhealthy diet are barriers to improving LE8 metrics that can be addressed, they added.

More research is needed to examine the effects of LE8 on high-risk patients, the researchers told this news organization. “No studies have yet focused on these patients with chronic diseases. We suspect that LE8 will play a role even in these high-risk groups,” they said. Further studies should include diverse populations and evaluations of the association between CVH change and health outcomes, they added.

“Overall, we see this 7.5-year difference [in life expectancy] going from poor to high cardiovascular health,” said Donald M. Lloyd-Jones, MD, of Northwestern University, Chicago, in a video accompanying the presentation of the study findings. The impact on life expectancy is yet another reason to motivate people to improve their cardiovascular health, said Dr. Lloyd-Jones, immediate past president of the American Heart Association and lead author on the writing group for Life’s Essential 8. “The earlier we do this, the better, and the greater the gains in life expectancy we’re likely to see in the U.S. population,” he said.

People maintaining high cardiovascular health into midlife are avoiding not only cardiovascular disease, but other chronic diseases of aging, Dr. Lloyd-Jones added. These conditions are delayed until much later in the lifespan, which allows people to enjoy better quality of life for more of their remaining years, he said.

The meeting was sponsored by the American Heart Association.

Both studies were supported by the National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health; the Fogarty International Center; and the Tulane Research Centers of Excellence Awards. The researchers had no financial conflicts to disclose.
 

Adults who follow a heart-healthy lifestyle are more likely to live longer and to be free of chronic health conditions, based on data from a pair of related studies from the United States and United Kingdom involving nearly 200,000 individuals.

FatCamera/Getty Images

The studies, presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting in Boston, assessed the impact of cardiovascular health on life expectancy and freedom from chronic diseases. Cardiovascular health (CVH) was based on the Life’s Essential 8 (LE8) score, a composite of health metrics released by the American Heart Association in 2022. The LE8 was developed to guide research and assessment of cardiovascular health, and includes diet, physical activity, tobacco/nicotine exposure, sleep, body mass index, non-HDL cholesterol, blood glucose, and blood pressure.

In one study, Xuan Wang, MD, a postdoctoral fellow and biostatistician in the department of epidemiology at Tulane University, New Orleans, and colleagues reviewed data from 136,599 adults in the United Kingdom Biobank who were free of cardiovascular disease, diabetes, cancer, and dementia at baseline, and for whom complete LE8 data were available.

CVH was classified as poor, intermediate, and ideal, defined as LE8 scores of less than 50, 50 to 80, and 80 or higher, respectively.

The goal of the study was to examine the role of CVH based on LE8 scores on the percentage of life expectancy free of chronic diseases.

Men and women with ideal CVH averaged 5.2 years and 6.3 years more of total life expectancy at age 50 years, compared with those with poor CVH. Out of total life expectancy, the percentage of life expectancy free of chronic diseases was 75.9% and 83.4% for men and women, respectively, compared with 64.9% and 69.4%, respectively, for men and women with poor CVH.

The researchers also found that disparities in the percentage of disease-free years for both men and women were reduced in the high CVH groups.

The findings were limited by several factors including the use of only CVD, diabetes, cancer, and dementia in the definition of “disease-free life expectancy,” the researchers noted in a press release accompanying the study. Other limitations include the lack of data on e-cigarettes, and the homogeneous White study population. More research is needed in diverse populations who experience a stronger impact from negative social determinants of health, they said.

In a second study, Hao Ma, MD, and colleagues reviewed data from 23,003 adults who participated in the National Health and Nutrition Examination Survey (NHANES) between 2005 and 2018 with mortality linked to the National Death Index through Dec. 31, 2019. The goal of the second study was to examine the association between CVH based on LE8 scores and life expectancy.

Over a median follow-up of 7.8 years, deaths occurred in 772 men and 587 women, said Dr. Ma, a postdoctoral fellow and biostatistician in epidemiology at Tulane University and coauthor on Dr. Wang’s study.

The estimated life expectancies at age 50 years for men with poor, intermediate, and ideal cardiovascular health based on the LE8 were 25.5 years, 31.2 years, and 33.1 years, respectively.

For women, the corresponding life expectancies for women at age 50 with poor, intermediate, and ideal CVH were 29.5 years, 34.2 years, and 38.4 years, respectively.

Men and women had similar gains in life expectancy from adhering to a heart-healthy lifestyle as defined by the LE8 score that reduced their risk of death from cardiovascular disease (41.8% and 44.1%, respectively).

Associations of cardiovascular health and life expectancy were similar for non-Hispanic Whites and non-Hispanic Blacks, but not among people of Mexican heritage, and more research is needed in diverse populations, the researchers wrote.

The study was limited by several factors including potential changes in cardiovascular health during the follow-up period, and by the limited analysis of racial and ethnic groups to non-Hispanic white, non-Hispanic Black, and people of Mexican heritage because of small sample sizes for other racial/ethnic groups, the researchers noted in a press release accompanying the study.

The message for clinicians and their patients is that adherence to cardiovascular health as defined by the LE8 will help not only extend life, but enhance quality of life, Dr. Xang and Dr. Ma said in an interview. “If your overall CVH score is low, we might be able to focus on one element first and improve them one by one,” they said. Sedentary lifestyle and an unhealthy diet are barriers to improving LE8 metrics that can be addressed, they added.

More research is needed to examine the effects of LE8 on high-risk patients, the researchers told this news organization. “No studies have yet focused on these patients with chronic diseases. We suspect that LE8 will play a role even in these high-risk groups,” they said. Further studies should include diverse populations and evaluations of the association between CVH change and health outcomes, they added.

“Overall, we see this 7.5-year difference [in life expectancy] going from poor to high cardiovascular health,” said Donald M. Lloyd-Jones, MD, of Northwestern University, Chicago, in a video accompanying the presentation of the study findings. The impact on life expectancy is yet another reason to motivate people to improve their cardiovascular health, said Dr. Lloyd-Jones, immediate past president of the American Heart Association and lead author on the writing group for Life’s Essential 8. “The earlier we do this, the better, and the greater the gains in life expectancy we’re likely to see in the U.S. population,” he said.

People maintaining high cardiovascular health into midlife are avoiding not only cardiovascular disease, but other chronic diseases of aging, Dr. Lloyd-Jones added. These conditions are delayed until much later in the lifespan, which allows people to enjoy better quality of life for more of their remaining years, he said.

The meeting was sponsored by the American Heart Association.

Both studies were supported by the National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health; the Fogarty International Center; and the Tulane Research Centers of Excellence Awards. The researchers had no financial conflicts to disclose.
 

Adults who follow a heart-healthy lifestyle are more likely to live longer and to be free of chronic health conditions, based on data from a pair of related studies from the United States and United Kingdom involving nearly 200,000 individuals.

FatCamera/Getty Images

The studies, presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting in Boston, assessed the impact of cardiovascular health on life expectancy and freedom from chronic diseases. Cardiovascular health (CVH) was based on the Life’s Essential 8 (LE8) score, a composite of health metrics released by the American Heart Association in 2022. The LE8 was developed to guide research and assessment of cardiovascular health, and includes diet, physical activity, tobacco/nicotine exposure, sleep, body mass index, non-HDL cholesterol, blood glucose, and blood pressure.

In one study, Xuan Wang, MD, a postdoctoral fellow and biostatistician in the department of epidemiology at Tulane University, New Orleans, and colleagues reviewed data from 136,599 adults in the United Kingdom Biobank who were free of cardiovascular disease, diabetes, cancer, and dementia at baseline, and for whom complete LE8 data were available.

CVH was classified as poor, intermediate, and ideal, defined as LE8 scores of less than 50, 50 to 80, and 80 or higher, respectively.

The goal of the study was to examine the role of CVH based on LE8 scores on the percentage of life expectancy free of chronic diseases.

Men and women with ideal CVH averaged 5.2 years and 6.3 years more of total life expectancy at age 50 years, compared with those with poor CVH. Out of total life expectancy, the percentage of life expectancy free of chronic diseases was 75.9% and 83.4% for men and women, respectively, compared with 64.9% and 69.4%, respectively, for men and women with poor CVH.

The researchers also found that disparities in the percentage of disease-free years for both men and women were reduced in the high CVH groups.

The findings were limited by several factors including the use of only CVD, diabetes, cancer, and dementia in the definition of “disease-free life expectancy,” the researchers noted in a press release accompanying the study. Other limitations include the lack of data on e-cigarettes, and the homogeneous White study population. More research is needed in diverse populations who experience a stronger impact from negative social determinants of health, they said.

In a second study, Hao Ma, MD, and colleagues reviewed data from 23,003 adults who participated in the National Health and Nutrition Examination Survey (NHANES) between 2005 and 2018 with mortality linked to the National Death Index through Dec. 31, 2019. The goal of the second study was to examine the association between CVH based on LE8 scores and life expectancy.

Over a median follow-up of 7.8 years, deaths occurred in 772 men and 587 women, said Dr. Ma, a postdoctoral fellow and biostatistician in epidemiology at Tulane University and coauthor on Dr. Wang’s study.

The estimated life expectancies at age 50 years for men with poor, intermediate, and ideal cardiovascular health based on the LE8 were 25.5 years, 31.2 years, and 33.1 years, respectively.

For women, the corresponding life expectancies for women at age 50 with poor, intermediate, and ideal CVH were 29.5 years, 34.2 years, and 38.4 years, respectively.

Men and women had similar gains in life expectancy from adhering to a heart-healthy lifestyle as defined by the LE8 score that reduced their risk of death from cardiovascular disease (41.8% and 44.1%, respectively).

Associations of cardiovascular health and life expectancy were similar for non-Hispanic Whites and non-Hispanic Blacks, but not among people of Mexican heritage, and more research is needed in diverse populations, the researchers wrote.

The study was limited by several factors including potential changes in cardiovascular health during the follow-up period, and by the limited analysis of racial and ethnic groups to non-Hispanic white, non-Hispanic Black, and people of Mexican heritage because of small sample sizes for other racial/ethnic groups, the researchers noted in a press release accompanying the study.

The message for clinicians and their patients is that adherence to cardiovascular health as defined by the LE8 will help not only extend life, but enhance quality of life, Dr. Xang and Dr. Ma said in an interview. “If your overall CVH score is low, we might be able to focus on one element first and improve them one by one,” they said. Sedentary lifestyle and an unhealthy diet are barriers to improving LE8 metrics that can be addressed, they added.

More research is needed to examine the effects of LE8 on high-risk patients, the researchers told this news organization. “No studies have yet focused on these patients with chronic diseases. We suspect that LE8 will play a role even in these high-risk groups,” they said. Further studies should include diverse populations and evaluations of the association between CVH change and health outcomes, they added.

“Overall, we see this 7.5-year difference [in life expectancy] going from poor to high cardiovascular health,” said Donald M. Lloyd-Jones, MD, of Northwestern University, Chicago, in a video accompanying the presentation of the study findings. The impact on life expectancy is yet another reason to motivate people to improve their cardiovascular health, said Dr. Lloyd-Jones, immediate past president of the American Heart Association and lead author on the writing group for Life’s Essential 8. “The earlier we do this, the better, and the greater the gains in life expectancy we’re likely to see in the U.S. population,” he said.

People maintaining high cardiovascular health into midlife are avoiding not only cardiovascular disease, but other chronic diseases of aging, Dr. Lloyd-Jones added. These conditions are delayed until much later in the lifespan, which allows people to enjoy better quality of life for more of their remaining years, he said.

The meeting was sponsored by the American Heart Association.

Both studies were supported by the National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health; the Fogarty International Center; and the Tulane Research Centers of Excellence Awards. The researchers had no financial conflicts to disclose.
 

New data show a high and rising burden of most cardiovascular (CV) risk factors among young adults aged 20-44 years in the United States.

In this age group, over the past 10 years, there has been an increase in the prevalence of diabetes and obesity, no improvement in the prevalence of hypertension, and a decrease in the prevalence of hyperlipidemia.

Yet medical treatment rates for CV risk factors are “surprisingly” low among young adults, study investigator Rishi Wadhera, MD, with Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston, told this news organization.

Preventing a tsunami of heart disease

The findings stem from a cross-sectional study of 12,294 U.S. adults aged 20-44 years (mean age, 32; 51% women) who participated in National Health and Nutrition Examination Survey (NHANES) cycles for 2009-2010 to 2017-2020.

Overall, the prevalence of hypertension was 9.3% in 2009-2010 and increased to 11.5% in 2017-2020. The prevalence of diabetes rose from 3.0% to 4.1%, and the prevalence of obesity rose from 32.7% to 40.9%. The prevalence of hyperlipidemia decreased from 40.5% to 36.1%.

Black adults consistently had high rates of hypertension during the study period – 16.2% in 2009-2010 and 20.1% in 2017-2020 – and significant increases in hypertension occurred among Mexican American adults (from 6.5% to 9.5%) and other Hispanic adults (from 4.4% to 10.5%), while Mexican American adults had a significant uptick in diabetes (from 4.3% to 7.5%).

Equally concerning, said Dr. Wadhera, is the fact that only about 55% of young adults with hypertension were receiving antihypertensive medication, and just 1 in 2 young adults with diabetes were receiving treatment. “These low rates were driven, in part, by many young adults not being aware of their diagnosis,” he noted.

The NHANES data also show that the percentage of young adults who were treated for hypertension and who achieved blood pressure control did not change significantly over the study period (65.0% in 2009-2010 and 74.8% in 2017-2020). Blood sugar control among young adults being treated for diabetes remained suboptimal throughout the study period (45.5% in 2009-2010 and 56.6% in 2017-2020).

“The fact that blood pressure control and glycemic control are so poor is really worrisome,” Jeffrey Berger, MD, director of the Center for the Prevention of Cardiovascular Disease at NYU Langone Heart, who wasn’t involved in the study, told this news organization.

NYU Langone

Double down on screening

Dr. Wadhera said “we need to double down on efforts to screen for and treat cardiovascular risk factors like high blood pressure and diabetes in young adults. We need to intensify clinical and public health interventions focused on primordial and primary prevention in young adults now so that we can avoid a tsunami of cardiovascular disease in the long term.”

“It’s critically important that young adults speak with their health care provider about whether – and when – they should undergo screening for high blood pressure, diabetes, and high cholesterol,” Dr. Wadhera added.

Dr. Berger said one problem is that younger people often have a “superman or superwoman” view and don’t comprehend that they are at risk for some of these conditions. Studies such as this “reinforce the idea that it’s never too young to be checked out.”

As a cardiologist who specializes in cardiovascular prevention, Dr. Berger said he sometimes hears patients say things like, “I don’t ever want to need a cardiologist,” or “I hope I never need a cardiologist.”

“My response is, ‘There are many different types of cardiologists,’ and I think it would really be helpful for many people to see a prevention-focused cardiologist way before they have problems,” he said in an interview.

“As a system, medicine has become very good at treating patients with different diseases. I think we need to get better in terms of preventing some of these problems,” Dr. Berger added.

In their editorial, Dr. Allen and Dr. Wilkins say the “foundation of cardiovascular health begins early in life. These worsening trends in risk factors highlight the importance of focusing on prevention in adolescence and young adulthood in order to promote cardiovascular health across the lifetime.”

The study was funded by a grant from the National Heart, Lung, and Blood Institute. Dr. Wadhera has served as a consultant for Abbott and CVS Health. Dr. Wilkins has received personal fees from 3M. Dr. Berger has disclosed no relevant financial relationships.

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

New data show a high and rising burden of most cardiovascular (CV) risk factors among young adults aged 20-44 years in the United States.

In this age group, over the past 10 years, there has been an increase in the prevalence of diabetes and obesity, no improvement in the prevalence of hypertension, and a decrease in the prevalence of hyperlipidemia.

Yet medical treatment rates for CV risk factors are “surprisingly” low among young adults, study investigator Rishi Wadhera, MD, with Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston, told this news organization.

Preventing a tsunami of heart disease

The findings stem from a cross-sectional study of 12,294 U.S. adults aged 20-44 years (mean age, 32; 51% women) who participated in National Health and Nutrition Examination Survey (NHANES) cycles for 2009-2010 to 2017-2020.

Overall, the prevalence of hypertension was 9.3% in 2009-2010 and increased to 11.5% in 2017-2020. The prevalence of diabetes rose from 3.0% to 4.1%, and the prevalence of obesity rose from 32.7% to 40.9%. The prevalence of hyperlipidemia decreased from 40.5% to 36.1%.

Black adults consistently had high rates of hypertension during the study period – 16.2% in 2009-2010 and 20.1% in 2017-2020 – and significant increases in hypertension occurred among Mexican American adults (from 6.5% to 9.5%) and other Hispanic adults (from 4.4% to 10.5%), while Mexican American adults had a significant uptick in diabetes (from 4.3% to 7.5%).

Equally concerning, said Dr. Wadhera, is the fact that only about 55% of young adults with hypertension were receiving antihypertensive medication, and just 1 in 2 young adults with diabetes were receiving treatment. “These low rates were driven, in part, by many young adults not being aware of their diagnosis,” he noted.

The NHANES data also show that the percentage of young adults who were treated for hypertension and who achieved blood pressure control did not change significantly over the study period (65.0% in 2009-2010 and 74.8% in 2017-2020). Blood sugar control among young adults being treated for diabetes remained suboptimal throughout the study period (45.5% in 2009-2010 and 56.6% in 2017-2020).

“The fact that blood pressure control and glycemic control are so poor is really worrisome,” Jeffrey Berger, MD, director of the Center for the Prevention of Cardiovascular Disease at NYU Langone Heart, who wasn’t involved in the study, told this news organization.

NYU Langone

Double down on screening

Dr. Wadhera said “we need to double down on efforts to screen for and treat cardiovascular risk factors like high blood pressure and diabetes in young adults. We need to intensify clinical and public health interventions focused on primordial and primary prevention in young adults now so that we can avoid a tsunami of cardiovascular disease in the long term.”

“It’s critically important that young adults speak with their health care provider about whether – and when – they should undergo screening for high blood pressure, diabetes, and high cholesterol,” Dr. Wadhera added.

Dr. Berger said one problem is that younger people often have a “superman or superwoman” view and don’t comprehend that they are at risk for some of these conditions. Studies such as this “reinforce the idea that it’s never too young to be checked out.”

As a cardiologist who specializes in cardiovascular prevention, Dr. Berger said he sometimes hears patients say things like, “I don’t ever want to need a cardiologist,” or “I hope I never need a cardiologist.”

“My response is, ‘There are many different types of cardiologists,’ and I think it would really be helpful for many people to see a prevention-focused cardiologist way before they have problems,” he said in an interview.

“As a system, medicine has become very good at treating patients with different diseases. I think we need to get better in terms of preventing some of these problems,” Dr. Berger added.

In their editorial, Dr. Allen and Dr. Wilkins say the “foundation of cardiovascular health begins early in life. These worsening trends in risk factors highlight the importance of focusing on prevention in adolescence and young adulthood in order to promote cardiovascular health across the lifetime.”

The study was funded by a grant from the National Heart, Lung, and Blood Institute. Dr. Wadhera has served as a consultant for Abbott and CVS Health. Dr. Wilkins has received personal fees from 3M. Dr. Berger has disclosed no relevant financial relationships.

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

New data show a high and rising burden of most cardiovascular (CV) risk factors among young adults aged 20-44 years in the United States.

In this age group, over the past 10 years, there has been an increase in the prevalence of diabetes and obesity, no improvement in the prevalence of hypertension, and a decrease in the prevalence of hyperlipidemia.

Yet medical treatment rates for CV risk factors are “surprisingly” low among young adults, study investigator Rishi Wadhera, MD, with Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston, told this news organization.

Preventing a tsunami of heart disease

The findings stem from a cross-sectional study of 12,294 U.S. adults aged 20-44 years (mean age, 32; 51% women) who participated in National Health and Nutrition Examination Survey (NHANES) cycles for 2009-2010 to 2017-2020.

Overall, the prevalence of hypertension was 9.3% in 2009-2010 and increased to 11.5% in 2017-2020. The prevalence of diabetes rose from 3.0% to 4.1%, and the prevalence of obesity rose from 32.7% to 40.9%. The prevalence of hyperlipidemia decreased from 40.5% to 36.1%.

Black adults consistently had high rates of hypertension during the study period – 16.2% in 2009-2010 and 20.1% in 2017-2020 – and significant increases in hypertension occurred among Mexican American adults (from 6.5% to 9.5%) and other Hispanic adults (from 4.4% to 10.5%), while Mexican American adults had a significant uptick in diabetes (from 4.3% to 7.5%).

Equally concerning, said Dr. Wadhera, is the fact that only about 55% of young adults with hypertension were receiving antihypertensive medication, and just 1 in 2 young adults with diabetes were receiving treatment. “These low rates were driven, in part, by many young adults not being aware of their diagnosis,” he noted.

The NHANES data also show that the percentage of young adults who were treated for hypertension and who achieved blood pressure control did not change significantly over the study period (65.0% in 2009-2010 and 74.8% in 2017-2020). Blood sugar control among young adults being treated for diabetes remained suboptimal throughout the study period (45.5% in 2009-2010 and 56.6% in 2017-2020).

“The fact that blood pressure control and glycemic control are so poor is really worrisome,” Jeffrey Berger, MD, director of the Center for the Prevention of Cardiovascular Disease at NYU Langone Heart, who wasn’t involved in the study, told this news organization.

NYU Langone

Double down on screening

Dr. Wadhera said “we need to double down on efforts to screen for and treat cardiovascular risk factors like high blood pressure and diabetes in young adults. We need to intensify clinical and public health interventions focused on primordial and primary prevention in young adults now so that we can avoid a tsunami of cardiovascular disease in the long term.”

“It’s critically important that young adults speak with their health care provider about whether – and when – they should undergo screening for high blood pressure, diabetes, and high cholesterol,” Dr. Wadhera added.

Dr. Berger said one problem is that younger people often have a “superman or superwoman” view and don’t comprehend that they are at risk for some of these conditions. Studies such as this “reinforce the idea that it’s never too young to be checked out.”

As a cardiologist who specializes in cardiovascular prevention, Dr. Berger said he sometimes hears patients say things like, “I don’t ever want to need a cardiologist,” or “I hope I never need a cardiologist.”

“My response is, ‘There are many different types of cardiologists,’ and I think it would really be helpful for many people to see a prevention-focused cardiologist way before they have problems,” he said in an interview.

“As a system, medicine has become very good at treating patients with different diseases. I think we need to get better in terms of preventing some of these problems,” Dr. Berger added.

In their editorial, Dr. Allen and Dr. Wilkins say the “foundation of cardiovascular health begins early in life. These worsening trends in risk factors highlight the importance of focusing on prevention in adolescence and young adulthood in order to promote cardiovascular health across the lifetime.”

The study was funded by a grant from the National Heart, Lung, and Blood Institute. Dr. Wadhera has served as a consultant for Abbott and CVS Health. Dr. Wilkins has received personal fees from 3M. Dr. Berger has disclosed no relevant financial relationships.

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

NEW ORLEANS – Twenty cardiology clinics successfully intensified the medical care they gave patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) after receiving a simple and scalable investigational intervention that gave the clinics’ staffs guidance on best prescribing practices and implementation and also provided quality-improvement feedback.

Within a year, these clinics quadrupled optimal medical management of these patients, compared with control clinics, in a randomized trial involving a total of 43 clinics and 1,049 patients.

“This multifaceted intervention is effective in increasing the prescription of evidence-based therapies in adults with T2D and ASCVD,” Neha J. Pagidipati, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“The next step is to scale this intervention across cardiology practices” interested in improving the quality of care they deliver to these patients, added Dr. Pagidipati, a cardiologist specializing in cardiometabolic disease prevention at Duke University in Durham, N.C.

The goal is getting patients on triple therapy

The primary outcome of the COORDINATE-Diabetes trial was the change in the number of patients with T2D and ASCVD who received prescriptions for agents from three recommended medication classes and at recommended dosages: a high-intensity statin, a renin-angiotensin system inhibitor (RASi), and at least one agent from either of two classes that have both cardiovascular-protective and antihyperglycemic effects: the sodium-glucose cotransporter 2 (SGLT2) inhibitors, or the glucagonlike peptide 1 (GLP-1)–receptor agonists.

Among the 457 patients treated at the 20 cardiology clinics who received the quality-improvement intervention, 37.9% were on the promoted triple therapy after 12 months, compared with 14.5% of the 588 patients treated at the 23 clinics that continued with their usual care approach. This 23.4–percentage point increase in triple-class prescribing at recommended dosages represented a significant 4.4-fold increase in the goal prescribing endpoint after adjustment for possible confounders, Dr. Pagidipati reported.

Simultaneously with her report, the findings also appeared online in JAMA.

At baseline, 41%-50% of the patients were on both a high-intensity statin and a RASi, with a total of about 58%-67% on a high-intensity statin and about 70%-75% on a RASi. Fewer than 1% of patients were on SGLT2 inhibitors or GLP-1–receptor agonists at baseline. By design, no patient could be on all three categories of medication at baseline.

At their last follow-up visit (after 12 months for 97% of patients, or after 6 months for the remainder) 71% of the patients at practices that received the intervention were on a high-intensity statin, 81% were taking a RASi, and 60% were on an SGLT2 inhibitor or GLP-1–receptor agonist. Among the control patients, 58% were on a high-intensity statin, 68% on a RASi, and 36% were on one of the antihyperglycemic agents.

Effective interventions and the need for a champion

The clinics randomized to the active arm received instruction from a three-member team, either from an in-person or virtual one-time visit, on an intervention comprising several initiatives:

• Analysis of the barriers to evidence-based care at each clinic.
• Development of local interdisciplinary care pathways to address the identified barriers.
• Facilitation of care coordination among clinicians – particularly among cardiology, endocrinology, and primary care clinicians.
• Education of the clinic staff, including provision of educational materials.
• Auditing of clinic performance using specified metrics and feedback on the findings.

Clinics in the usual care group were given current clinical practice guidelines.

The investigational intervention was, by design, “low-tech and designed to be scalable,” explained Dr. Pagidipati, and once the COVID pandemic started the intervention team shifted to a virtual consultation with participating practices that was mostly front-loaded, followed by monthly phone calls to give clinics feedback on their progress.

Among the most helpful aspects of the intervention was involving the entire clinic staff, including pharmacists, nurses, and advanced care practitioners; boosting familiarity with the relevant medications and their appropriate use; and advice on navigating insurance-coverage barriers such as prior authorizations.

“What was most critical was having a local champion who took on making this effort an important part” of what the clinic was trying to do, she explained. “All it takes is passion, and the tenacity of a bulldog,” Dr. Pagidipati said.

Research advances often don’t translate into management changes

“We don’t do a great job of translating findings from trials to patient care, so any method we can use to improve that will improve practice,” commented Kristen B. Campbell, PharmD, a clinical pharmacist at Duke who was not involved in the study.

“Although the trial was not powered to look at patient outcomes, we think that patients will benefit” because all the recommended medication uses have been proven to help patients in prior trials, Dr. Campbell noted.

Mitchel L. Zoler/MDedge News

“A particular strength of this study was its simple design. All the interventions are low-tech and scalable.”

The low level of use of guideline-directed medical therapy in American adults with type 2 diabetes and atherosclerotic cardiovascular disease is “incredible,” said Christopher B. Granger, MD, a senior investigator on the study and a cardiologist and professor at Duke.

The researchers who ran the study are now focused on evaluating which cardiology clinics and patients had the most success from the intervention and are using that information to further refine implementation. They are also planning to encourage cardiology practices as well as other relevant medical groups to incorporate the intervention and implementation model used in the trial. The intervention program is detailed and available at no charge on the COORDINATE-Diabetes website.

COORDINATE-Diabetes received funding from Boehringer Ingelheim and Eli Lilly. Dr. Pagidipati has received personal fees from Boehringer Ingelheim, Lilly, AstraZeneca, Novartis, Novo Nordisk, Merck, and CRISPR Therapeutics, and she has received research grants from Amgen, Novartis, Novo Nordisk, and Eggland’s Best. Dr. Campbell had no disclosures. Dr. Granger has received personal fees and research funding from numerous companies.

NEW ORLEANS – Twenty cardiology clinics successfully intensified the medical care they gave patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) after receiving a simple and scalable investigational intervention that gave the clinics’ staffs guidance on best prescribing practices and implementation and also provided quality-improvement feedback.

Within a year, these clinics quadrupled optimal medical management of these patients, compared with control clinics, in a randomized trial involving a total of 43 clinics and 1,049 patients.

“This multifaceted intervention is effective in increasing the prescription of evidence-based therapies in adults with T2D and ASCVD,” Neha J. Pagidipati, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“The next step is to scale this intervention across cardiology practices” interested in improving the quality of care they deliver to these patients, added Dr. Pagidipati, a cardiologist specializing in cardiometabolic disease prevention at Duke University in Durham, N.C.

The goal is getting patients on triple therapy

The primary outcome of the COORDINATE-Diabetes trial was the change in the number of patients with T2D and ASCVD who received prescriptions for agents from three recommended medication classes and at recommended dosages: a high-intensity statin, a renin-angiotensin system inhibitor (RASi), and at least one agent from either of two classes that have both cardiovascular-protective and antihyperglycemic effects: the sodium-glucose cotransporter 2 (SGLT2) inhibitors, or the glucagonlike peptide 1 (GLP-1)–receptor agonists.

Among the 457 patients treated at the 20 cardiology clinics who received the quality-improvement intervention, 37.9% were on the promoted triple therapy after 12 months, compared with 14.5% of the 588 patients treated at the 23 clinics that continued with their usual care approach. This 23.4–percentage point increase in triple-class prescribing at recommended dosages represented a significant 4.4-fold increase in the goal prescribing endpoint after adjustment for possible confounders, Dr. Pagidipati reported.

Simultaneously with her report, the findings also appeared online in JAMA.

At baseline, 41%-50% of the patients were on both a high-intensity statin and a RASi, with a total of about 58%-67% on a high-intensity statin and about 70%-75% on a RASi. Fewer than 1% of patients were on SGLT2 inhibitors or GLP-1–receptor agonists at baseline. By design, no patient could be on all three categories of medication at baseline.

At their last follow-up visit (after 12 months for 97% of patients, or after 6 months for the remainder) 71% of the patients at practices that received the intervention were on a high-intensity statin, 81% were taking a RASi, and 60% were on an SGLT2 inhibitor or GLP-1–receptor agonist. Among the control patients, 58% were on a high-intensity statin, 68% on a RASi, and 36% were on one of the antihyperglycemic agents.

Effective interventions and the need for a champion

The clinics randomized to the active arm received instruction from a three-member team, either from an in-person or virtual one-time visit, on an intervention comprising several initiatives:

• Analysis of the barriers to evidence-based care at each clinic.
• Development of local interdisciplinary care pathways to address the identified barriers.
• Facilitation of care coordination among clinicians – particularly among cardiology, endocrinology, and primary care clinicians.
• Education of the clinic staff, including provision of educational materials.
• Auditing of clinic performance using specified metrics and feedback on the findings.

Clinics in the usual care group were given current clinical practice guidelines.

The investigational intervention was, by design, “low-tech and designed to be scalable,” explained Dr. Pagidipati, and once the COVID pandemic started the intervention team shifted to a virtual consultation with participating practices that was mostly front-loaded, followed by monthly phone calls to give clinics feedback on their progress.

Among the most helpful aspects of the intervention was involving the entire clinic staff, including pharmacists, nurses, and advanced care practitioners; boosting familiarity with the relevant medications and their appropriate use; and advice on navigating insurance-coverage barriers such as prior authorizations.

“What was most critical was having a local champion who took on making this effort an important part” of what the clinic was trying to do, she explained. “All it takes is passion, and the tenacity of a bulldog,” Dr. Pagidipati said.

Research advances often don’t translate into management changes

“We don’t do a great job of translating findings from trials to patient care, so any method we can use to improve that will improve practice,” commented Kristen B. Campbell, PharmD, a clinical pharmacist at Duke who was not involved in the study.

“Although the trial was not powered to look at patient outcomes, we think that patients will benefit” because all the recommended medication uses have been proven to help patients in prior trials, Dr. Campbell noted.

Mitchel L. Zoler/MDedge News

“A particular strength of this study was its simple design. All the interventions are low-tech and scalable.”

The low level of use of guideline-directed medical therapy in American adults with type 2 diabetes and atherosclerotic cardiovascular disease is “incredible,” said Christopher B. Granger, MD, a senior investigator on the study and a cardiologist and professor at Duke.

The researchers who ran the study are now focused on evaluating which cardiology clinics and patients had the most success from the intervention and are using that information to further refine implementation. They are also planning to encourage cardiology practices as well as other relevant medical groups to incorporate the intervention and implementation model used in the trial. The intervention program is detailed and available at no charge on the COORDINATE-Diabetes website.

COORDINATE-Diabetes received funding from Boehringer Ingelheim and Eli Lilly. Dr. Pagidipati has received personal fees from Boehringer Ingelheim, Lilly, AstraZeneca, Novartis, Novo Nordisk, Merck, and CRISPR Therapeutics, and she has received research grants from Amgen, Novartis, Novo Nordisk, and Eggland’s Best. Dr. Campbell had no disclosures. Dr. Granger has received personal fees and research funding from numerous companies.

NEW ORLEANS – Twenty cardiology clinics successfully intensified the medical care they gave patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) after receiving a simple and scalable investigational intervention that gave the clinics’ staffs guidance on best prescribing practices and implementation and also provided quality-improvement feedback.

Within a year, these clinics quadrupled optimal medical management of these patients, compared with control clinics, in a randomized trial involving a total of 43 clinics and 1,049 patients.

“This multifaceted intervention is effective in increasing the prescription of evidence-based therapies in adults with T2D and ASCVD,” Neha J. Pagidipati, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“The next step is to scale this intervention across cardiology practices” interested in improving the quality of care they deliver to these patients, added Dr. Pagidipati, a cardiologist specializing in cardiometabolic disease prevention at Duke University in Durham, N.C.

The goal is getting patients on triple therapy

The primary outcome of the COORDINATE-Diabetes trial was the change in the number of patients with T2D and ASCVD who received prescriptions for agents from three recommended medication classes and at recommended dosages: a high-intensity statin, a renin-angiotensin system inhibitor (RASi), and at least one agent from either of two classes that have both cardiovascular-protective and antihyperglycemic effects: the sodium-glucose cotransporter 2 (SGLT2) inhibitors, or the glucagonlike peptide 1 (GLP-1)–receptor agonists.

Among the 457 patients treated at the 20 cardiology clinics who received the quality-improvement intervention, 37.9% were on the promoted triple therapy after 12 months, compared with 14.5% of the 588 patients treated at the 23 clinics that continued with their usual care approach. This 23.4–percentage point increase in triple-class prescribing at recommended dosages represented a significant 4.4-fold increase in the goal prescribing endpoint after adjustment for possible confounders, Dr. Pagidipati reported.

Simultaneously with her report, the findings also appeared online in JAMA.

At baseline, 41%-50% of the patients were on both a high-intensity statin and a RASi, with a total of about 58%-67% on a high-intensity statin and about 70%-75% on a RASi. Fewer than 1% of patients were on SGLT2 inhibitors or GLP-1–receptor agonists at baseline. By design, no patient could be on all three categories of medication at baseline.

At their last follow-up visit (after 12 months for 97% of patients, or after 6 months for the remainder) 71% of the patients at practices that received the intervention were on a high-intensity statin, 81% were taking a RASi, and 60% were on an SGLT2 inhibitor or GLP-1–receptor agonist. Among the control patients, 58% were on a high-intensity statin, 68% on a RASi, and 36% were on one of the antihyperglycemic agents.

Effective interventions and the need for a champion

The clinics randomized to the active arm received instruction from a three-member team, either from an in-person or virtual one-time visit, on an intervention comprising several initiatives:

• Analysis of the barriers to evidence-based care at each clinic.
• Development of local interdisciplinary care pathways to address the identified barriers.
• Facilitation of care coordination among clinicians – particularly among cardiology, endocrinology, and primary care clinicians.
• Education of the clinic staff, including provision of educational materials.
• Auditing of clinic performance using specified metrics and feedback on the findings.

Clinics in the usual care group were given current clinical practice guidelines.

The investigational intervention was, by design, “low-tech and designed to be scalable,” explained Dr. Pagidipati, and once the COVID pandemic started the intervention team shifted to a virtual consultation with participating practices that was mostly front-loaded, followed by monthly phone calls to give clinics feedback on their progress.

Among the most helpful aspects of the intervention was involving the entire clinic staff, including pharmacists, nurses, and advanced care practitioners; boosting familiarity with the relevant medications and their appropriate use; and advice on navigating insurance-coverage barriers such as prior authorizations.

“What was most critical was having a local champion who took on making this effort an important part” of what the clinic was trying to do, she explained. “All it takes is passion, and the tenacity of a bulldog,” Dr. Pagidipati said.

Research advances often don’t translate into management changes

“We don’t do a great job of translating findings from trials to patient care, so any method we can use to improve that will improve practice,” commented Kristen B. Campbell, PharmD, a clinical pharmacist at Duke who was not involved in the study.

“Although the trial was not powered to look at patient outcomes, we think that patients will benefit” because all the recommended medication uses have been proven to help patients in prior trials, Dr. Campbell noted.

Mitchel L. Zoler/MDedge News

“A particular strength of this study was its simple design. All the interventions are low-tech and scalable.”

The low level of use of guideline-directed medical therapy in American adults with type 2 diabetes and atherosclerotic cardiovascular disease is “incredible,” said Christopher B. Granger, MD, a senior investigator on the study and a cardiologist and professor at Duke.

The researchers who ran the study are now focused on evaluating which cardiology clinics and patients had the most success from the intervention and are using that information to further refine implementation. They are also planning to encourage cardiology practices as well as other relevant medical groups to incorporate the intervention and implementation model used in the trial. The intervention program is detailed and available at no charge on the COORDINATE-Diabetes website.

COORDINATE-Diabetes received funding from Boehringer Ingelheim and Eli Lilly. Dr. Pagidipati has received personal fees from Boehringer Ingelheim, Lilly, AstraZeneca, Novartis, Novo Nordisk, Merck, and CRISPR Therapeutics, and she has received research grants from Amgen, Novartis, Novo Nordisk, and Eggland’s Best. Dr. Campbell had no disclosures. Dr. Granger has received personal fees and research funding from numerous companies.

NEW ORLEANS – Causal artificial intelligence (AI) can translate polygenic scores (PGS) and other genetic information into risk reduction strategies for coronary artery disease (CAD) that is tailored for each individual patient, according to an analysis presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Tested for LDL cholesterol (LDL-C) and systolic blood pressure (SBP), causal AI explained how much each of these risk factors must improve at the level of each individual patient “to overcome overall inherited risk,” reported Brian Ference, MD, MPhil, director of translational therapeutics, University of Cambridge (England).

Ted Bosworth/MDedge News

Unlike the “black box” risk assessments common to machine learning, which relies on disparate forms of information of often unknown relative significance, causal AI explains cause and effect. In the case of CAD, its ability to encode the biological causes means that it can “both predict outcomes and prescribe specific actions to change those outcomes,” Dr. Ference explained.

The concept is testable against observed biology using randomized evidence, which was the objective of the study Dr. Ference presented in the late-breaker session.
 

Causal AI trained on nearly 2 million patients

This study employed a causal AI platform trained on roughly 1.3 million participants in Mendelian randomization studies, as well as more than 500,000 participants in randomized clinical trials. The PGS estimate of inherited risk was constructed from almost 4.1 million variants from genomewide association studies.

To test the ability of causal AI to reveal how much LDL-C or SBP had to be reduced to overcome the inherited risk of CAD based on PGS, it was applied to 445,765 participants of European ancestry in the UK Biobank. The goal was to determine how much those with greater than average risk would need to lower their LDL-C or SBP to achieve average CAD risk.

When validated against observed rates of events, causal AI accurately characterized risk before estimating what reductions in LDL-C, SBP, or both would attenuate that risk.

Providing examples, Dr. Ference explained that a PGS in the 80^th percentile can be overcome by lowering LDL-C by 14 mg/dL. Alternatively, the 80^th percentile risk could also be overcome by simultaneously lowering LDL-C and SBP by 7 mg/dL and 2.5 mm Hg, respectively.

Required risk factor reductions increase with age because of the increased risk of the events. For example, while a 14.8 mg/dL reduction in LDL-C would be adequate to overcome risk defined by a PGS in the 80^th percentile at age 35, reductions of 18.2 mg/dL, 28.9 mg/dL, and 42.6 mg/dL would be required, respectively, at ages 45, 55, and 65 years. The values climb similarly for SBP.

Family history of CAD adds an independent variable that further contributes to the ability of causal AI to estimate risk and the degree of risk factor attenuation to overcome the risk.

Even though family history is equivalent to having PGS above the 95^th percentile, it is an independent and additive variable, according to Dr. Ference. As a result, inherited risk of CAD depends on both.

Still when family history is factored into the analysis, “causal AI accurately estimated the magnitude of lower LDL-C, SBP, or both needed to overcome overall inherited risk at all levels of higher or lower PGS,” he reported.

According to Dr. Ference, the value of causal AI is that it can generate very specific goals for each patient regarding modifiable risk factors. Causal effects of risk factors encoded in time units of exposure allow the patient and the clinician to understand the biology and the basis of the disease burden.
 

Treatments become understandable to patients

“Encoding biology creates algorithms that are deeply explainable because they reveal why a person is at risk, how to reduce that risk, and how much each person will benefit from specific actions to reduce risk,” Dr. Ference said.

A real-world, randomized trial to confirm that the information from causal AI can reduce the risk of CAD is expected to start in 2023, but Dr. Ference thinks that causal AI for managing CAD risk, independent of this planned trial, is essentially inevitable. PGS, which he thinks will be performed routinely in all individuals within 10 years, is only likely to improve. He foresees large advantages of this form of personalized medicine.

Ted Bosworth/MDedge News

Ami Bhatt, MD, chief innovation officer for the American College of Cardiology, Washington, agreed, seeing a direct relationship between precision health as the pathway to improvements in population health.

By explaining risk factors in terms of mechanisms and specific goals to ameliorate these risks, it “engages our patients with agency,” said Dr. Bhatt. She suggested that the information provided by causal AI has the potential to empower patients while creating a collaborative approach with clinicians to CAD prevention.

With patient-specific information provided in the context of the disease biology, “you increase the sense of transparency,” Dr. Bhatt said.

She suggested this direction of research is wholly consistent with initiatives such as those from the World Health Organization to improve precision medicine as a step toward equipping patients to manage their own health.

Dr. Ference reported financial relationships with Amgen, AstraZeneca, CiVi Pharma, Daiichi Sankyo, DalCOR, Esperion, Eli Lilly, Ionis Pharmaceuticals, KrKA, Medicines Company, Merck, Mylan, Novo Nordisk, Novartis, and Sanofi, and Viatris. Dr. Bhatt reported no potential conflicts of interest.

NEW ORLEANS – Causal artificial intelligence (AI) can translate polygenic scores (PGS) and other genetic information into risk reduction strategies for coronary artery disease (CAD) that is tailored for each individual patient, according to an analysis presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Tested for LDL cholesterol (LDL-C) and systolic blood pressure (SBP), causal AI explained how much each of these risk factors must improve at the level of each individual patient “to overcome overall inherited risk,” reported Brian Ference, MD, MPhil, director of translational therapeutics, University of Cambridge (England).

Ted Bosworth/MDedge News

Unlike the “black box” risk assessments common to machine learning, which relies on disparate forms of information of often unknown relative significance, causal AI explains cause and effect. In the case of CAD, its ability to encode the biological causes means that it can “both predict outcomes and prescribe specific actions to change those outcomes,” Dr. Ference explained.

The concept is testable against observed biology using randomized evidence, which was the objective of the study Dr. Ference presented in the late-breaker session.
 

Causal AI trained on nearly 2 million patients

This study employed a causal AI platform trained on roughly 1.3 million participants in Mendelian randomization studies, as well as more than 500,000 participants in randomized clinical trials. The PGS estimate of inherited risk was constructed from almost 4.1 million variants from genomewide association studies.

To test the ability of causal AI to reveal how much LDL-C or SBP had to be reduced to overcome the inherited risk of CAD based on PGS, it was applied to 445,765 participants of European ancestry in the UK Biobank. The goal was to determine how much those with greater than average risk would need to lower their LDL-C or SBP to achieve average CAD risk.

When validated against observed rates of events, causal AI accurately characterized risk before estimating what reductions in LDL-C, SBP, or both would attenuate that risk.

Providing examples, Dr. Ference explained that a PGS in the 80^th percentile can be overcome by lowering LDL-C by 14 mg/dL. Alternatively, the 80^th percentile risk could also be overcome by simultaneously lowering LDL-C and SBP by 7 mg/dL and 2.5 mm Hg, respectively.

Required risk factor reductions increase with age because of the increased risk of the events. For example, while a 14.8 mg/dL reduction in LDL-C would be adequate to overcome risk defined by a PGS in the 80^th percentile at age 35, reductions of 18.2 mg/dL, 28.9 mg/dL, and 42.6 mg/dL would be required, respectively, at ages 45, 55, and 65 years. The values climb similarly for SBP.

Family history of CAD adds an independent variable that further contributes to the ability of causal AI to estimate risk and the degree of risk factor attenuation to overcome the risk.

Even though family history is equivalent to having PGS above the 95^th percentile, it is an independent and additive variable, according to Dr. Ference. As a result, inherited risk of CAD depends on both.

Still when family history is factored into the analysis, “causal AI accurately estimated the magnitude of lower LDL-C, SBP, or both needed to overcome overall inherited risk at all levels of higher or lower PGS,” he reported.

According to Dr. Ference, the value of causal AI is that it can generate very specific goals for each patient regarding modifiable risk factors. Causal effects of risk factors encoded in time units of exposure allow the patient and the clinician to understand the biology and the basis of the disease burden.
 

Treatments become understandable to patients

“Encoding biology creates algorithms that are deeply explainable because they reveal why a person is at risk, how to reduce that risk, and how much each person will benefit from specific actions to reduce risk,” Dr. Ference said.

A real-world, randomized trial to confirm that the information from causal AI can reduce the risk of CAD is expected to start in 2023, but Dr. Ference thinks that causal AI for managing CAD risk, independent of this planned trial, is essentially inevitable. PGS, which he thinks will be performed routinely in all individuals within 10 years, is only likely to improve. He foresees large advantages of this form of personalized medicine.

Ted Bosworth/MDedge News

Ami Bhatt, MD, chief innovation officer for the American College of Cardiology, Washington, agreed, seeing a direct relationship between precision health as the pathway to improvements in population health.

By explaining risk factors in terms of mechanisms and specific goals to ameliorate these risks, it “engages our patients with agency,” said Dr. Bhatt. She suggested that the information provided by causal AI has the potential to empower patients while creating a collaborative approach with clinicians to CAD prevention.

With patient-specific information provided in the context of the disease biology, “you increase the sense of transparency,” Dr. Bhatt said.

She suggested this direction of research is wholly consistent with initiatives such as those from the World Health Organization to improve precision medicine as a step toward equipping patients to manage their own health.

Dr. Ference reported financial relationships with Amgen, AstraZeneca, CiVi Pharma, Daiichi Sankyo, DalCOR, Esperion, Eli Lilly, Ionis Pharmaceuticals, KrKA, Medicines Company, Merck, Mylan, Novo Nordisk, Novartis, and Sanofi, and Viatris. Dr. Bhatt reported no potential conflicts of interest.

NEW ORLEANS – Causal artificial intelligence (AI) can translate polygenic scores (PGS) and other genetic information into risk reduction strategies for coronary artery disease (CAD) that is tailored for each individual patient, according to an analysis presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Tested for LDL cholesterol (LDL-C) and systolic blood pressure (SBP), causal AI explained how much each of these risk factors must improve at the level of each individual patient “to overcome overall inherited risk,” reported Brian Ference, MD, MPhil, director of translational therapeutics, University of Cambridge (England).

Ted Bosworth/MDedge News

Unlike the “black box” risk assessments common to machine learning, which relies on disparate forms of information of often unknown relative significance, causal AI explains cause and effect. In the case of CAD, its ability to encode the biological causes means that it can “both predict outcomes and prescribe specific actions to change those outcomes,” Dr. Ference explained.

The concept is testable against observed biology using randomized evidence, which was the objective of the study Dr. Ference presented in the late-breaker session.
 

Causal AI trained on nearly 2 million patients

This study employed a causal AI platform trained on roughly 1.3 million participants in Mendelian randomization studies, as well as more than 500,000 participants in randomized clinical trials. The PGS estimate of inherited risk was constructed from almost 4.1 million variants from genomewide association studies.

To test the ability of causal AI to reveal how much LDL-C or SBP had to be reduced to overcome the inherited risk of CAD based on PGS, it was applied to 445,765 participants of European ancestry in the UK Biobank. The goal was to determine how much those with greater than average risk would need to lower their LDL-C or SBP to achieve average CAD risk.

When validated against observed rates of events, causal AI accurately characterized risk before estimating what reductions in LDL-C, SBP, or both would attenuate that risk.

Providing examples, Dr. Ference explained that a PGS in the 80^th percentile can be overcome by lowering LDL-C by 14 mg/dL. Alternatively, the 80^th percentile risk could also be overcome by simultaneously lowering LDL-C and SBP by 7 mg/dL and 2.5 mm Hg, respectively.

Required risk factor reductions increase with age because of the increased risk of the events. For example, while a 14.8 mg/dL reduction in LDL-C would be adequate to overcome risk defined by a PGS in the 80^th percentile at age 35, reductions of 18.2 mg/dL, 28.9 mg/dL, and 42.6 mg/dL would be required, respectively, at ages 45, 55, and 65 years. The values climb similarly for SBP.

Family history of CAD adds an independent variable that further contributes to the ability of causal AI to estimate risk and the degree of risk factor attenuation to overcome the risk.

Even though family history is equivalent to having PGS above the 95^th percentile, it is an independent and additive variable, according to Dr. Ference. As a result, inherited risk of CAD depends on both.

Still when family history is factored into the analysis, “causal AI accurately estimated the magnitude of lower LDL-C, SBP, or both needed to overcome overall inherited risk at all levels of higher or lower PGS,” he reported.

According to Dr. Ference, the value of causal AI is that it can generate very specific goals for each patient regarding modifiable risk factors. Causal effects of risk factors encoded in time units of exposure allow the patient and the clinician to understand the biology and the basis of the disease burden.
 

Treatments become understandable to patients

“Encoding biology creates algorithms that are deeply explainable because they reveal why a person is at risk, how to reduce that risk, and how much each person will benefit from specific actions to reduce risk,” Dr. Ference said.

A real-world, randomized trial to confirm that the information from causal AI can reduce the risk of CAD is expected to start in 2023, but Dr. Ference thinks that causal AI for managing CAD risk, independent of this planned trial, is essentially inevitable. PGS, which he thinks will be performed routinely in all individuals within 10 years, is only likely to improve. He foresees large advantages of this form of personalized medicine.

Ted Bosworth/MDedge News

Ami Bhatt, MD, chief innovation officer for the American College of Cardiology, Washington, agreed, seeing a direct relationship between precision health as the pathway to improvements in population health.

By explaining risk factors in terms of mechanisms and specific goals to ameliorate these risks, it “engages our patients with agency,” said Dr. Bhatt. She suggested that the information provided by causal AI has the potential to empower patients while creating a collaborative approach with clinicians to CAD prevention.

With patient-specific information provided in the context of the disease biology, “you increase the sense of transparency,” Dr. Bhatt said.

She suggested this direction of research is wholly consistent with initiatives such as those from the World Health Organization to improve precision medicine as a step toward equipping patients to manage their own health.

Dr. Ference reported financial relationships with Amgen, AstraZeneca, CiVi Pharma, Daiichi Sankyo, DalCOR, Esperion, Eli Lilly, Ionis Pharmaceuticals, KrKA, Medicines Company, Merck, Mylan, Novo Nordisk, Novartis, and Sanofi, and Viatris. Dr. Bhatt reported no potential conflicts of interest.