Lipid Disorders

High levels of triglyceride molecules in LDL cholesterol are “robustly” linked with an increased risk of atherosclerotic cardiovascular disease, according to a study that used two different methods in two separate cohorts from a large European population study plus a meta-analysis to verify the results.

“There have been some studies in the past, as you can see from our meta-analysis, that found a similar association, but I don’t think most people are convinced that there is really this relationship, and certainly I was not convinced,” lead investigator Børge G. Nordestgaard, MD, DMSc, professor at the University of Copenhagen, said in an interview.

The study enrolled 68,290 patients from the Copenhagen General Population study; 38,081 were assigned to direct automated assay to measure their LDL triglycerides and 30,208 had nuclear magnetic resonance (NMR) spectroscopy. Median follow-up was 3 and 9.2 years for the respective cohorts.

LDL triglycerides carry higher ASCVD risk

In the automated assay group, each 0.1-mmol/L (9 mg/dL)–higher direct LDL triglycerides carried a 22%-38% higher risk for the following outcomes: ASCVD (hazard ratio, 1.26; 95% confidence interval, 1.17-1.35); ischemic heart disease (HR, 1.27; 95% CI, 1.16-1.39); myocardial infarction (HR, 1.28; 95% CI, 1.11-1.48); ischemic stroke (HR, 1.22; 95% CI, 1.08-1.38); and peripheral artery disease (HR, 1.38; 95% CI, 1.21-1.58).

In the group that had NMR spectroscopy to measure LDL triglycerides, risks were similar, ranging from HRs of 1.13 (95% CI, 1.05-1.23) for ischemic stroke to 1.41 (95% CI, 1.31-1.52) for myocardial infarction. The investigators noted that apolipoprotein B levels didn’t entirely explain these results.

The meta-analysis included 18 studies that evaluated varying cardiovascular disease outcomes. It compared random-effects risk ratios for the highest quartile vs. the lowest quartile of LDL triglycerides. They were 1.50 (95% CI, 1.35-1.66) for ASCVD (four studies, 71,526 individuals, 8,576 events); 1.62 (95% CI, 1.37-1.93) for ischemic heart disease (six studies, 107,538 individuals, 9,734 events); 1.30 (95% CI, 1.13-1.49) for ischemic stroke (four studies, 78,026 individuals, 4,273 events); and 1.53 (95% CI, 1.29-1.81) for peripheral artery disease (four studies, 107,511 individuals, 1,848 events). The study was published online in the Journal of the American College of Cardiology.

Results confirm hypothesis the study sought to disprove

The purpose of the study was to actually disprove the hypothesis that the study ended up confirming, Dr. Nordestgaard said. “When we started this study, my idea was that we wanted to show that LDL triglyceride was not related to these diseases, because that didn’t make sense to me,” he said. “I’m so used to the thinking that the cholesterol content of these particles drive atherosclerosis and therefore atherosclerotic cardiovascular disease.”

He noted that LDL can carry both cholesterol and triglycerides, and that larger remnant lipoproteins can carry a substantial amount of triglycerides and a lesser amount of cholesterol. “Those remnants actually transfer into LDL, so they somewhat bring the triglycerides molecules into LDL,” Dr. Nordestgaard said.

The direct automated assay test used in the study to measure LDL triglycerides is not approved for use in the United States by the Food and Drug Administration, according to Denka, the manufacturer of the test.

The use of the Copenhagen General Population Study cohorts is a strength of the study because it has 100% follow-up with all patients, Dr. Nordestgaard said. The meta-analysis is another strength. “So we can show real clearly, not only in our two prospective studies, but also added to the former ones in the literature: All say exactly the same thing: High LDL triglycerides carry a high risk for ASCVD and its components.”

A limitation Dr. Nordestgaard acknowledged: The study doesn’t explain the causal relationship between high LDL triglycerides and ASCVD. But the study provides “very sound evidence that there’s a relationship,” he added. The study population was also a White, Danish population that lacked ethnic and racial diversity.

Next step is finding a treatment

The Danish study essentially confirms what the Atherosclerosis Risk in Community Study (ARIC) found with regard to LDL triglycerides, said Christie M. Ballantyne, MD, chief of cardiology at Baylor College of Medicine in Houston, and an ARIC investigator. 

This study is the “first step” to coming up with a test to identify risk, he said. “These data are pretty convincing, when you throw in the data in this study plus all the meta-analyses data, that LDL triglycerides, when they’re elevated, identify individuals at increased risk for an atherosclerotic cardiovascular event.”

The next step, he said, is coming up with a treatment for people with elevated HDL triglyceride. “That’s where we don’t have as much data because this test hasn’t been used. I’m pretty sure that statins are going to work fine for these people, because they lower LDL cholesterol and they also lower triglycerides, and some of the data have shown already that they reduce the LDL remnant,” Dr. Ballantyne said.

The Danish study provides enough of a basis for pursuing future studies to better understand the effect of statins on LDL triglyceride levels, Dr. Ballantyne added.

The study received funding from the Novo Nordisk Foundation and the Danish Heart Foundation, along with institutional support. Dr. Nordestgaard has no relevant disclosures. Dr. Ballantyne disclosed receiving research support from Denka.

High levels of triglyceride molecules in LDL cholesterol are “robustly” linked with an increased risk of atherosclerotic cardiovascular disease, according to a study that used two different methods in two separate cohorts from a large European population study plus a meta-analysis to verify the results.

“There have been some studies in the past, as you can see from our meta-analysis, that found a similar association, but I don’t think most people are convinced that there is really this relationship, and certainly I was not convinced,” lead investigator Børge G. Nordestgaard, MD, DMSc, professor at the University of Copenhagen, said in an interview.

The study enrolled 68,290 patients from the Copenhagen General Population study; 38,081 were assigned to direct automated assay to measure their LDL triglycerides and 30,208 had nuclear magnetic resonance (NMR) spectroscopy. Median follow-up was 3 and 9.2 years for the respective cohorts.

LDL triglycerides carry higher ASCVD risk

In the automated assay group, each 0.1-mmol/L (9 mg/dL)–higher direct LDL triglycerides carried a 22%-38% higher risk for the following outcomes: ASCVD (hazard ratio, 1.26; 95% confidence interval, 1.17-1.35); ischemic heart disease (HR, 1.27; 95% CI, 1.16-1.39); myocardial infarction (HR, 1.28; 95% CI, 1.11-1.48); ischemic stroke (HR, 1.22; 95% CI, 1.08-1.38); and peripheral artery disease (HR, 1.38; 95% CI, 1.21-1.58).

In the group that had NMR spectroscopy to measure LDL triglycerides, risks were similar, ranging from HRs of 1.13 (95% CI, 1.05-1.23) for ischemic stroke to 1.41 (95% CI, 1.31-1.52) for myocardial infarction. The investigators noted that apolipoprotein B levels didn’t entirely explain these results.

The meta-analysis included 18 studies that evaluated varying cardiovascular disease outcomes. It compared random-effects risk ratios for the highest quartile vs. the lowest quartile of LDL triglycerides. They were 1.50 (95% CI, 1.35-1.66) for ASCVD (four studies, 71,526 individuals, 8,576 events); 1.62 (95% CI, 1.37-1.93) for ischemic heart disease (six studies, 107,538 individuals, 9,734 events); 1.30 (95% CI, 1.13-1.49) for ischemic stroke (four studies, 78,026 individuals, 4,273 events); and 1.53 (95% CI, 1.29-1.81) for peripheral artery disease (four studies, 107,511 individuals, 1,848 events). The study was published online in the Journal of the American College of Cardiology.

Results confirm hypothesis the study sought to disprove

The purpose of the study was to actually disprove the hypothesis that the study ended up confirming, Dr. Nordestgaard said. “When we started this study, my idea was that we wanted to show that LDL triglyceride was not related to these diseases, because that didn’t make sense to me,” he said. “I’m so used to the thinking that the cholesterol content of these particles drive atherosclerosis and therefore atherosclerotic cardiovascular disease.”

He noted that LDL can carry both cholesterol and triglycerides, and that larger remnant lipoproteins can carry a substantial amount of triglycerides and a lesser amount of cholesterol. “Those remnants actually transfer into LDL, so they somewhat bring the triglycerides molecules into LDL,” Dr. Nordestgaard said.

The direct automated assay test used in the study to measure LDL triglycerides is not approved for use in the United States by the Food and Drug Administration, according to Denka, the manufacturer of the test.

The use of the Copenhagen General Population Study cohorts is a strength of the study because it has 100% follow-up with all patients, Dr. Nordestgaard said. The meta-analysis is another strength. “So we can show real clearly, not only in our two prospective studies, but also added to the former ones in the literature: All say exactly the same thing: High LDL triglycerides carry a high risk for ASCVD and its components.”

A limitation Dr. Nordestgaard acknowledged: The study doesn’t explain the causal relationship between high LDL triglycerides and ASCVD. But the study provides “very sound evidence that there’s a relationship,” he added. The study population was also a White, Danish population that lacked ethnic and racial diversity.

Next step is finding a treatment

The Danish study essentially confirms what the Atherosclerosis Risk in Community Study (ARIC) found with regard to LDL triglycerides, said Christie M. Ballantyne, MD, chief of cardiology at Baylor College of Medicine in Houston, and an ARIC investigator. 

This study is the “first step” to coming up with a test to identify risk, he said. “These data are pretty convincing, when you throw in the data in this study plus all the meta-analyses data, that LDL triglycerides, when they’re elevated, identify individuals at increased risk for an atherosclerotic cardiovascular event.”

The next step, he said, is coming up with a treatment for people with elevated HDL triglyceride. “That’s where we don’t have as much data because this test hasn’t been used. I’m pretty sure that statins are going to work fine for these people, because they lower LDL cholesterol and they also lower triglycerides, and some of the data have shown already that they reduce the LDL remnant,” Dr. Ballantyne said.

The Danish study provides enough of a basis for pursuing future studies to better understand the effect of statins on LDL triglyceride levels, Dr. Ballantyne added.

The study received funding from the Novo Nordisk Foundation and the Danish Heart Foundation, along with institutional support. Dr. Nordestgaard has no relevant disclosures. Dr. Ballantyne disclosed receiving research support from Denka.

High levels of triglyceride molecules in LDL cholesterol are “robustly” linked with an increased risk of atherosclerotic cardiovascular disease, according to a study that used two different methods in two separate cohorts from a large European population study plus a meta-analysis to verify the results.

“There have been some studies in the past, as you can see from our meta-analysis, that found a similar association, but I don’t think most people are convinced that there is really this relationship, and certainly I was not convinced,” lead investigator Børge G. Nordestgaard, MD, DMSc, professor at the University of Copenhagen, said in an interview.

The study enrolled 68,290 patients from the Copenhagen General Population study; 38,081 were assigned to direct automated assay to measure their LDL triglycerides and 30,208 had nuclear magnetic resonance (NMR) spectroscopy. Median follow-up was 3 and 9.2 years for the respective cohorts.

LDL triglycerides carry higher ASCVD risk

In the automated assay group, each 0.1-mmol/L (9 mg/dL)–higher direct LDL triglycerides carried a 22%-38% higher risk for the following outcomes: ASCVD (hazard ratio, 1.26; 95% confidence interval, 1.17-1.35); ischemic heart disease (HR, 1.27; 95% CI, 1.16-1.39); myocardial infarction (HR, 1.28; 95% CI, 1.11-1.48); ischemic stroke (HR, 1.22; 95% CI, 1.08-1.38); and peripheral artery disease (HR, 1.38; 95% CI, 1.21-1.58).

In the group that had NMR spectroscopy to measure LDL triglycerides, risks were similar, ranging from HRs of 1.13 (95% CI, 1.05-1.23) for ischemic stroke to 1.41 (95% CI, 1.31-1.52) for myocardial infarction. The investigators noted that apolipoprotein B levels didn’t entirely explain these results.

The meta-analysis included 18 studies that evaluated varying cardiovascular disease outcomes. It compared random-effects risk ratios for the highest quartile vs. the lowest quartile of LDL triglycerides. They were 1.50 (95% CI, 1.35-1.66) for ASCVD (four studies, 71,526 individuals, 8,576 events); 1.62 (95% CI, 1.37-1.93) for ischemic heart disease (six studies, 107,538 individuals, 9,734 events); 1.30 (95% CI, 1.13-1.49) for ischemic stroke (four studies, 78,026 individuals, 4,273 events); and 1.53 (95% CI, 1.29-1.81) for peripheral artery disease (four studies, 107,511 individuals, 1,848 events). The study was published online in the Journal of the American College of Cardiology.

Results confirm hypothesis the study sought to disprove

The purpose of the study was to actually disprove the hypothesis that the study ended up confirming, Dr. Nordestgaard said. “When we started this study, my idea was that we wanted to show that LDL triglyceride was not related to these diseases, because that didn’t make sense to me,” he said. “I’m so used to the thinking that the cholesterol content of these particles drive atherosclerosis and therefore atherosclerotic cardiovascular disease.”

He noted that LDL can carry both cholesterol and triglycerides, and that larger remnant lipoproteins can carry a substantial amount of triglycerides and a lesser amount of cholesterol. “Those remnants actually transfer into LDL, so they somewhat bring the triglycerides molecules into LDL,” Dr. Nordestgaard said.

The direct automated assay test used in the study to measure LDL triglycerides is not approved for use in the United States by the Food and Drug Administration, according to Denka, the manufacturer of the test.

The use of the Copenhagen General Population Study cohorts is a strength of the study because it has 100% follow-up with all patients, Dr. Nordestgaard said. The meta-analysis is another strength. “So we can show real clearly, not only in our two prospective studies, but also added to the former ones in the literature: All say exactly the same thing: High LDL triglycerides carry a high risk for ASCVD and its components.”

A limitation Dr. Nordestgaard acknowledged: The study doesn’t explain the causal relationship between high LDL triglycerides and ASCVD. But the study provides “very sound evidence that there’s a relationship,” he added. The study population was also a White, Danish population that lacked ethnic and racial diversity.

Next step is finding a treatment

The Danish study essentially confirms what the Atherosclerosis Risk in Community Study (ARIC) found with regard to LDL triglycerides, said Christie M. Ballantyne, MD, chief of cardiology at Baylor College of Medicine in Houston, and an ARIC investigator. 

This study is the “first step” to coming up with a test to identify risk, he said. “These data are pretty convincing, when you throw in the data in this study plus all the meta-analyses data, that LDL triglycerides, when they’re elevated, identify individuals at increased risk for an atherosclerotic cardiovascular event.”

The next step, he said, is coming up with a treatment for people with elevated HDL triglyceride. “That’s where we don’t have as much data because this test hasn’t been used. I’m pretty sure that statins are going to work fine for these people, because they lower LDL cholesterol and they also lower triglycerides, and some of the data have shown already that they reduce the LDL remnant,” Dr. Ballantyne said.

The Danish study provides enough of a basis for pursuing future studies to better understand the effect of statins on LDL triglyceride levels, Dr. Ballantyne added.

The study received funding from the Novo Nordisk Foundation and the Danish Heart Foundation, along with institutional support. Dr. Nordestgaard has no relevant disclosures. Dr. Ballantyne disclosed receiving research support from Denka.

Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.

The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.

“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.

“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”

Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”

Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
 

Evaluating hard outcomes

The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.

As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.

The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).

Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).

For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.

The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
 

An ‘obvious disconnect’

Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.

They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.

Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.

At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.

“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.

Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”

Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
 

The ‘full picture’

Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”

In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.

Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.

When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.

“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.

“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.

Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.

“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”

Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.

Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
 

Open access

Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.

“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.

“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”

Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”

Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”

The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.

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

Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.

The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.

“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.

“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”

Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”

Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
 

Evaluating hard outcomes

The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.

As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.

The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).

Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).

For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.

The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
 

An ‘obvious disconnect’

Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.

They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.

Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.

At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.

“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.

Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”

Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
 

The ‘full picture’

Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”

In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.

Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.

When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.

“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.

“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.

Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.

“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”

Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.

Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
 

Open access

Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.

“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.

“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”

Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”

Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”

The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.

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

Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.

The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.

“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.

“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”

Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”

Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
 

Evaluating hard outcomes

The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.

As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.

The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).

Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).

For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.

The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
 

An ‘obvious disconnect’

Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.

They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.

Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.

At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.

“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.

Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”

Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
 

The ‘full picture’

Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”

In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.

Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.

When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.

“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.

“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.

Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.

“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”

Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.

Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
 

Open access

Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.

“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.

“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”

Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”

Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”

The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.

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

The Food and Drug Administration has approved semaglutide 2.4 mg (Wegovy), a once-weekly subcutaneous injection, for the additional indication of treating obesity in adolescents aged 12 years and older.

This is defined as those with an initial body mass index at or above the 95th percentile for age and sex (based on CDC growth charts). Semaglutide must be administered along with lifestyle intervention of a reduced calorie meal plan and increased physical activity.

Olivier Le Moal/Getty Images

When Wegovy was approved for use in adults with obesity in June 2021, it was labeled a “game changer.”

The new approval is based on the results of the STEP TEENS phase 3 trial of once-weekly 2.4 mg of semaglutide in adolescents 12- to <18 years old with obesity, the drug’s manufacturer, Novo Nordisk, announced in a press release.

In STEP TEENS, reported at Obesity Week 2022 in November, and simultaneously published in the New England Journal of Medicine, adolescents with obesity treated with semaglutide for 68 weeks had a 16.1% reduction in BMI compared with a 0.6% increase in BMI in those receiving placebo. Both groups also received lifestyle intervention. Mean weight loss was 15.3 kg (33.7 pounds) among teens on semaglutide, while those on placebo gained 2.4 kg (5.3 pounds).

At the time, Claudia K. Fox, MD, MPH, codirector of the Center for Pediatric Obesity Medicine at the University of Minnesota – who was not involved with the research – told this news organization the results were “mind-blowing ... we are getting close to bariatric surgery results” in these adolescent patients with obesity.

Semaglutide is a GLP-1 agonist, as is a related agent, also from Novo Nordisk, liraglutide (Saxenda), a daily subcutaneous injection, which was approved for use in adolescents aged 12 and older in December 2020. Wegovy is the first weekly subcutaneous injection approved for use in adolescents.

Other agents approved for obesity in those older than 12 in the United States include the combination phentermine and topiramate extended-release capsules (Qsymia) in June 2022, and orlistat (Alli). Phentermine is approved for those aged 16 and older.  

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

The Food and Drug Administration has approved semaglutide 2.4 mg (Wegovy), a once-weekly subcutaneous injection, for the additional indication of treating obesity in adolescents aged 12 years and older.

This is defined as those with an initial body mass index at or above the 95th percentile for age and sex (based on CDC growth charts). Semaglutide must be administered along with lifestyle intervention of a reduced calorie meal plan and increased physical activity.

Olivier Le Moal/Getty Images

When Wegovy was approved for use in adults with obesity in June 2021, it was labeled a “game changer.”

The new approval is based on the results of the STEP TEENS phase 3 trial of once-weekly 2.4 mg of semaglutide in adolescents 12- to <18 years old with obesity, the drug’s manufacturer, Novo Nordisk, announced in a press release.

In STEP TEENS, reported at Obesity Week 2022 in November, and simultaneously published in the New England Journal of Medicine, adolescents with obesity treated with semaglutide for 68 weeks had a 16.1% reduction in BMI compared with a 0.6% increase in BMI in those receiving placebo. Both groups also received lifestyle intervention. Mean weight loss was 15.3 kg (33.7 pounds) among teens on semaglutide, while those on placebo gained 2.4 kg (5.3 pounds).

At the time, Claudia K. Fox, MD, MPH, codirector of the Center for Pediatric Obesity Medicine at the University of Minnesota – who was not involved with the research – told this news organization the results were “mind-blowing ... we are getting close to bariatric surgery results” in these adolescent patients with obesity.

Semaglutide is a GLP-1 agonist, as is a related agent, also from Novo Nordisk, liraglutide (Saxenda), a daily subcutaneous injection, which was approved for use in adolescents aged 12 and older in December 2020. Wegovy is the first weekly subcutaneous injection approved for use in adolescents.

Other agents approved for obesity in those older than 12 in the United States include the combination phentermine and topiramate extended-release capsules (Qsymia) in June 2022, and orlistat (Alli). Phentermine is approved for those aged 16 and older.  

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

The Food and Drug Administration has approved semaglutide 2.4 mg (Wegovy), a once-weekly subcutaneous injection, for the additional indication of treating obesity in adolescents aged 12 years and older.

This is defined as those with an initial body mass index at or above the 95th percentile for age and sex (based on CDC growth charts). Semaglutide must be administered along with lifestyle intervention of a reduced calorie meal plan and increased physical activity.

Olivier Le Moal/Getty Images

When Wegovy was approved for use in adults with obesity in June 2021, it was labeled a “game changer.”

The new approval is based on the results of the STEP TEENS phase 3 trial of once-weekly 2.4 mg of semaglutide in adolescents 12- to <18 years old with obesity, the drug’s manufacturer, Novo Nordisk, announced in a press release.

In STEP TEENS, reported at Obesity Week 2022 in November, and simultaneously published in the New England Journal of Medicine, adolescents with obesity treated with semaglutide for 68 weeks had a 16.1% reduction in BMI compared with a 0.6% increase in BMI in those receiving placebo. Both groups also received lifestyle intervention. Mean weight loss was 15.3 kg (33.7 pounds) among teens on semaglutide, while those on placebo gained 2.4 kg (5.3 pounds).

At the time, Claudia K. Fox, MD, MPH, codirector of the Center for Pediatric Obesity Medicine at the University of Minnesota – who was not involved with the research – told this news organization the results were “mind-blowing ... we are getting close to bariatric surgery results” in these adolescent patients with obesity.

Semaglutide is a GLP-1 agonist, as is a related agent, also from Novo Nordisk, liraglutide (Saxenda), a daily subcutaneous injection, which was approved for use in adolescents aged 12 and older in December 2020. Wegovy is the first weekly subcutaneous injection approved for use in adolescents.

Other agents approved for obesity in those older than 12 in the United States include the combination phentermine and topiramate extended-release capsules (Qsymia) in June 2022, and orlistat (Alli). Phentermine is approved for those aged 16 and older.  

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

Leading cardiology societies have issued a “call for action” on a global scale to reinvent randomized clinical trials fit for the 21st century.

“Randomized trials are an essential tool for reliably assessing the effects of treatments, but they have become too costly and too burdensome,” first author Louise Bowman, University of Oxford, England, told this news organization. “We urgently need to modernize our approach to clinical trials in order to continue to improve patient care.”

The joint opinion is from the European Society of Cardiology, the American Heart Association, the American College of Cardiology, and the World Heart Federation. It was simultaneously published online in the European Heart Journal, Circulation, Journal of the American College of Cardiology, and Global Heart.

The authors note that the availability of large-scale “real-world” data is increasingly being touted as a way to bypass the challenges of conducting randomized trials. Yet, observational analyses of real-world data “are not a suitable alternative to randomization,” Prof. Bowman said.

Cardiology has historically led the way in transforming clinical practice with groundbreaking “mega-trials,” such as the International Study of Infarct Survival (ISIS), Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto (GISSI), and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO).

But over the past 25 years, there has been a huge increase in the rules and related bureaucracy governing clinical trials, which hinders the ability to conduct trials swiftly and affordably, the authors point out.

The COVID-19 pandemic has shown that important clinical trials can be performed quickly and efficiently in busy hospitals, they note.

“The RECOVERY trial in COVID-19 has been an excellent example of this, with results that are estimated to have saved around 1 million lives worldwide within just 1 year,” Prof. Bowman told this news organization.

A Good Clinical Trials Collaborative made up of key stakeholders recently developed new guidelines designed to promote better, more efficient randomized controlled trials.

“If widely adopted and used alongside valuable 21st century electronic health records, we could transform the clinical trials landscape and do many more high-quality trials very cost-effectively,” Prof. Bowman said.

“Widespread adoption and implementation of the revised guidelines will require collaboration with a wide range of national and international organizations, including patient, professional, academic, and industry groups, funders and government organizations, and ethics, health policy, and regulatory bodies,” Prof. Bowman acknowledged.

“This is work that the Good Clinical Trials Collaborative is leading. It is hoped that this endorsement by the joint cardiovascular societies will increase awareness and provide valuable support to his important work,” she added.

No commercial funding was received. The authors have disclosed no relevant financial relationships.

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

Leading cardiology societies have issued a “call for action” on a global scale to reinvent randomized clinical trials fit for the 21st century.

“Randomized trials are an essential tool for reliably assessing the effects of treatments, but they have become too costly and too burdensome,” first author Louise Bowman, University of Oxford, England, told this news organization. “We urgently need to modernize our approach to clinical trials in order to continue to improve patient care.”

The joint opinion is from the European Society of Cardiology, the American Heart Association, the American College of Cardiology, and the World Heart Federation. It was simultaneously published online in the European Heart Journal, Circulation, Journal of the American College of Cardiology, and Global Heart.

The authors note that the availability of large-scale “real-world” data is increasingly being touted as a way to bypass the challenges of conducting randomized trials. Yet, observational analyses of real-world data “are not a suitable alternative to randomization,” Prof. Bowman said.

Cardiology has historically led the way in transforming clinical practice with groundbreaking “mega-trials,” such as the International Study of Infarct Survival (ISIS), Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto (GISSI), and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO).

But over the past 25 years, there has been a huge increase in the rules and related bureaucracy governing clinical trials, which hinders the ability to conduct trials swiftly and affordably, the authors point out.

The COVID-19 pandemic has shown that important clinical trials can be performed quickly and efficiently in busy hospitals, they note.

“The RECOVERY trial in COVID-19 has been an excellent example of this, with results that are estimated to have saved around 1 million lives worldwide within just 1 year,” Prof. Bowman told this news organization.

A Good Clinical Trials Collaborative made up of key stakeholders recently developed new guidelines designed to promote better, more efficient randomized controlled trials.

“If widely adopted and used alongside valuable 21st century electronic health records, we could transform the clinical trials landscape and do many more high-quality trials very cost-effectively,” Prof. Bowman said.

“Widespread adoption and implementation of the revised guidelines will require collaboration with a wide range of national and international organizations, including patient, professional, academic, and industry groups, funders and government organizations, and ethics, health policy, and regulatory bodies,” Prof. Bowman acknowledged.

“This is work that the Good Clinical Trials Collaborative is leading. It is hoped that this endorsement by the joint cardiovascular societies will increase awareness and provide valuable support to his important work,” she added.

No commercial funding was received. The authors have disclosed no relevant financial relationships.

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

Leading cardiology societies have issued a “call for action” on a global scale to reinvent randomized clinical trials fit for the 21st century.

“Randomized trials are an essential tool for reliably assessing the effects of treatments, but they have become too costly and too burdensome,” first author Louise Bowman, University of Oxford, England, told this news organization. “We urgently need to modernize our approach to clinical trials in order to continue to improve patient care.”

The joint opinion is from the European Society of Cardiology, the American Heart Association, the American College of Cardiology, and the World Heart Federation. It was simultaneously published online in the European Heart Journal, Circulation, Journal of the American College of Cardiology, and Global Heart.

The authors note that the availability of large-scale “real-world” data is increasingly being touted as a way to bypass the challenges of conducting randomized trials. Yet, observational analyses of real-world data “are not a suitable alternative to randomization,” Prof. Bowman said.

Cardiology has historically led the way in transforming clinical practice with groundbreaking “mega-trials,” such as the International Study of Infarct Survival (ISIS), Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto (GISSI), and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO).

But over the past 25 years, there has been a huge increase in the rules and related bureaucracy governing clinical trials, which hinders the ability to conduct trials swiftly and affordably, the authors point out.

The COVID-19 pandemic has shown that important clinical trials can be performed quickly and efficiently in busy hospitals, they note.

“The RECOVERY trial in COVID-19 has been an excellent example of this, with results that are estimated to have saved around 1 million lives worldwide within just 1 year,” Prof. Bowman told this news organization.

A Good Clinical Trials Collaborative made up of key stakeholders recently developed new guidelines designed to promote better, more efficient randomized controlled trials.

“If widely adopted and used alongside valuable 21st century electronic health records, we could transform the clinical trials landscape and do many more high-quality trials very cost-effectively,” Prof. Bowman said.

“Widespread adoption and implementation of the revised guidelines will require collaboration with a wide range of national and international organizations, including patient, professional, academic, and industry groups, funders and government organizations, and ethics, health policy, and regulatory bodies,” Prof. Bowman acknowledged.

“This is work that the Good Clinical Trials Collaborative is leading. It is hoped that this endorsement by the joint cardiovascular societies will increase awareness and provide valuable support to his important work,” she added.

No commercial funding was received. The authors have disclosed no relevant financial relationships.

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

High levels of lipoprotein(a) increase the risk for incident cardiovascular disease (CVD) for hypertensive individuals but not for those without hypertension, a new MESA analysis suggests.

There are ways to test for statistical interaction, “in this case, multiplicative interaction between Lp(a) and hypertension, which suggests that Lp(a) is actually modifying the effect between blood pressure and cardiovascular disease. It’s not simply additive,” senior author Michael D. Shapiro, DO, Wake Forest University, Winston-Salem, N.C., told this news organization.

“So that’s new and I don’t think anybody’s looked at that before.”

Although Lp(a) is recognized as an independent cause of atherosclerotic CVD (ASCVD), the significance of Lp(a) in hypertension has been “virtually untapped,” he noted. A recent prospective study reported that elevated CVD risk was present only in individuals with Lp(a) ≥ 30 mg/dL and hypertension but it included only Chinese participants with stable coronary artery disease.

The current analysis, published online in the journal Hypertension, included 6,674 participants in the ongoing Multi-Ethnic Study of Atherosclerosis (MESA), all free of baseline ASCVD, who were recruited from six communities in the United States and had measured baseline Lp(a), blood pressure, and CVD events data over follow-up from 2000 to 2018.

Participants were stratified into four groups based on the presence or absence of hypertension (defined as 140/90 mm Hg or higher or the use of antihypertensive drugs) and an Lp(a) threshold of 50 mg/dL, as recommended by the American College of Cardiology/American Heart Association cholesterol guideline for consideration as an ASCVD risk-enhancing factor.

Slightly more than half of participants were female (52.8%), 38.6% were White, 27.5% were African American, 22.1% were Hispanic, and 11.9% were Chinese American.

According to the researchers, 809 participants had a CVD event over an average follow-up of 13.9 years, including 7.7% of group 1 with Lp(a) < 50 mg/dL and no hypertension, 8.0% of group 2 with Lp(a) ≥ 50 mg/dL and no hypertension, 16.2% of group 3 with Lp(a) < 50 mg/dL and hypertension, and 18.8% of group 4 with Lp(a) ≥ 50 mg/dL and hypertension.

When compared with group 1 in a fully adjusted Cox proportional model, participants with elevated Lp(a) and no hypertension (group 2) did not have an increased risk of CVD events (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.79-1.50).

CVD risk, however, was significantly higher in group 3 with normal Lp(a) and hypertension (HR, 1.66; 95% CI, 1.39-1.98) and group 4 with elevated Lp(a) and hypertension (HR, 2.07, 95% CI, 1.63-2.62).

Among all participants with hypertension (groups 3 and 4), Lp(a) was associated with a significant increase in CVD risk (HR, 1.24, 95% CI, 1.01-1.53).

“What I think is interesting here is that in the absence of hypertension, we didn’t really see an increased risk despite having an elevated Lp(a),” said Dr. Shapiro. “What it may indicate is that really for Lp(a) to be associated with risk, there may already need to be some kind of arterial damage that allows the Lp(a) to have its atherogenic impact.

“In other words, in individuals who have totally normal arterial walls, potentially, maybe that is protective enough against Lp(a) that in the absence of any other injurious factor, maybe it’s not an issue,” he said. “That’s a big hypothesis-generating [statement], but hypertension is certainly one of those risk factors that’s known to cause endothelial injury and endothelial dysfunction.”

Dr. Shapiro pointed out that when first measured in MESA, Lp(a) was measured in 4,600 participants who were not on statins, which is important because statins can increase Lp(a) levels.

“When you look just at those participants, those 4,600, you actually do see a relationship between Lp(a) and cardiovascular disease,” he said. “When you look at the whole population, including the 17% who are baseline populations, even when you adjust for statin therapy, we fail to see that, at least in the long-term follow up.”

Nevertheless, he cautioned that hypertension is just one of many traditional cardiovascular risk factors that could affect the relationship between Lp(a) and CVD risk. “I don’t want to suggest that we believe there’s something specifically magical about hypertension and Lp(a). If we chose, say, diabetes or smoking or another traditional risk factor, we may or may not have seen kind of similar results.”

When the investigators stratified the analyses by sex and race/ethnicity, they found that Lp(a) was not associated with CVD risk, regardless of hypertension status. In Black participants, however, greater CVD risk was seen when both elevated Lp(a) and hypertension were present (HR, 2.07, 95% CI, 1.34-3.21; P = .001).

Asked whether the results support one-time universal screening for Lp(a), which is almost exclusively genetically determined, Dr. Shapiro said he supports screening but that this was a secondary analysis and its numbers were modest. He added that median Lp(a) level is higher in African Americans than any other racial/ethnic group but the “most recent data has clarified that, per any absolute level of Lp(a), it appears to confer the same absolute risk in any racial or ethnic group.”

The authors acknowledge that differential loss to follow-up could have resulted in selection bias in the study and that there were relatively few CVD events in group 2, which may have limited the ability to detect differences in groups without hypertension, particularly in the subgroup analyses. Other limitations are the potential for residual confounding and participants may have developed hypertension during follow-up, resulting in misclassification bias.

Further research is needed to better understand the mechanistic link between Lp(a), hypertension, and CVD, Dr. Shapiro said. Further insights also should be provided by the ongoing phase 3 Lp(a) HORIZON trial evaluating the effect of Lp(a) lowering with the investigational antisense drug, pelacarsen, on cardiovascular events in 8,324 patients with established CVD and elevated Lp(a). The study is expected to be completed in May 2025.

The study was supported by contracts from the National Heart, Lung, and Blood Institute and by grants from the National Center for Advanced Translational Sciences. Dr. Shapiro reports participating in scientific advisory boards with Amgen, Novartis, and Novo Nordisk, and consulting for Regeneron.

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

High levels of lipoprotein(a) increase the risk for incident cardiovascular disease (CVD) for hypertensive individuals but not for those without hypertension, a new MESA analysis suggests.

There are ways to test for statistical interaction, “in this case, multiplicative interaction between Lp(a) and hypertension, which suggests that Lp(a) is actually modifying the effect between blood pressure and cardiovascular disease. It’s not simply additive,” senior author Michael D. Shapiro, DO, Wake Forest University, Winston-Salem, N.C., told this news organization.

“So that’s new and I don’t think anybody’s looked at that before.”

Although Lp(a) is recognized as an independent cause of atherosclerotic CVD (ASCVD), the significance of Lp(a) in hypertension has been “virtually untapped,” he noted. A recent prospective study reported that elevated CVD risk was present only in individuals with Lp(a) ≥ 30 mg/dL and hypertension but it included only Chinese participants with stable coronary artery disease.

The current analysis, published online in the journal Hypertension, included 6,674 participants in the ongoing Multi-Ethnic Study of Atherosclerosis (MESA), all free of baseline ASCVD, who were recruited from six communities in the United States and had measured baseline Lp(a), blood pressure, and CVD events data over follow-up from 2000 to 2018.

Participants were stratified into four groups based on the presence or absence of hypertension (defined as 140/90 mm Hg or higher or the use of antihypertensive drugs) and an Lp(a) threshold of 50 mg/dL, as recommended by the American College of Cardiology/American Heart Association cholesterol guideline for consideration as an ASCVD risk-enhancing factor.

Slightly more than half of participants were female (52.8%), 38.6% were White, 27.5% were African American, 22.1% were Hispanic, and 11.9% were Chinese American.

According to the researchers, 809 participants had a CVD event over an average follow-up of 13.9 years, including 7.7% of group 1 with Lp(a) < 50 mg/dL and no hypertension, 8.0% of group 2 with Lp(a) ≥ 50 mg/dL and no hypertension, 16.2% of group 3 with Lp(a) < 50 mg/dL and hypertension, and 18.8% of group 4 with Lp(a) ≥ 50 mg/dL and hypertension.

When compared with group 1 in a fully adjusted Cox proportional model, participants with elevated Lp(a) and no hypertension (group 2) did not have an increased risk of CVD events (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.79-1.50).

CVD risk, however, was significantly higher in group 3 with normal Lp(a) and hypertension (HR, 1.66; 95% CI, 1.39-1.98) and group 4 with elevated Lp(a) and hypertension (HR, 2.07, 95% CI, 1.63-2.62).

Among all participants with hypertension (groups 3 and 4), Lp(a) was associated with a significant increase in CVD risk (HR, 1.24, 95% CI, 1.01-1.53).

“What I think is interesting here is that in the absence of hypertension, we didn’t really see an increased risk despite having an elevated Lp(a),” said Dr. Shapiro. “What it may indicate is that really for Lp(a) to be associated with risk, there may already need to be some kind of arterial damage that allows the Lp(a) to have its atherogenic impact.

“In other words, in individuals who have totally normal arterial walls, potentially, maybe that is protective enough against Lp(a) that in the absence of any other injurious factor, maybe it’s not an issue,” he said. “That’s a big hypothesis-generating [statement], but hypertension is certainly one of those risk factors that’s known to cause endothelial injury and endothelial dysfunction.”

Dr. Shapiro pointed out that when first measured in MESA, Lp(a) was measured in 4,600 participants who were not on statins, which is important because statins can increase Lp(a) levels.

“When you look just at those participants, those 4,600, you actually do see a relationship between Lp(a) and cardiovascular disease,” he said. “When you look at the whole population, including the 17% who are baseline populations, even when you adjust for statin therapy, we fail to see that, at least in the long-term follow up.”

Nevertheless, he cautioned that hypertension is just one of many traditional cardiovascular risk factors that could affect the relationship between Lp(a) and CVD risk. “I don’t want to suggest that we believe there’s something specifically magical about hypertension and Lp(a). If we chose, say, diabetes or smoking or another traditional risk factor, we may or may not have seen kind of similar results.”

When the investigators stratified the analyses by sex and race/ethnicity, they found that Lp(a) was not associated with CVD risk, regardless of hypertension status. In Black participants, however, greater CVD risk was seen when both elevated Lp(a) and hypertension were present (HR, 2.07, 95% CI, 1.34-3.21; P = .001).

Asked whether the results support one-time universal screening for Lp(a), which is almost exclusively genetically determined, Dr. Shapiro said he supports screening but that this was a secondary analysis and its numbers were modest. He added that median Lp(a) level is higher in African Americans than any other racial/ethnic group but the “most recent data has clarified that, per any absolute level of Lp(a), it appears to confer the same absolute risk in any racial or ethnic group.”

The authors acknowledge that differential loss to follow-up could have resulted in selection bias in the study and that there were relatively few CVD events in group 2, which may have limited the ability to detect differences in groups without hypertension, particularly in the subgroup analyses. Other limitations are the potential for residual confounding and participants may have developed hypertension during follow-up, resulting in misclassification bias.

Further research is needed to better understand the mechanistic link between Lp(a), hypertension, and CVD, Dr. Shapiro said. Further insights also should be provided by the ongoing phase 3 Lp(a) HORIZON trial evaluating the effect of Lp(a) lowering with the investigational antisense drug, pelacarsen, on cardiovascular events in 8,324 patients with established CVD and elevated Lp(a). The study is expected to be completed in May 2025.

The study was supported by contracts from the National Heart, Lung, and Blood Institute and by grants from the National Center for Advanced Translational Sciences. Dr. Shapiro reports participating in scientific advisory boards with Amgen, Novartis, and Novo Nordisk, and consulting for Regeneron.

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

High levels of lipoprotein(a) increase the risk for incident cardiovascular disease (CVD) for hypertensive individuals but not for those without hypertension, a new MESA analysis suggests.

There are ways to test for statistical interaction, “in this case, multiplicative interaction between Lp(a) and hypertension, which suggests that Lp(a) is actually modifying the effect between blood pressure and cardiovascular disease. It’s not simply additive,” senior author Michael D. Shapiro, DO, Wake Forest University, Winston-Salem, N.C., told this news organization.

“So that’s new and I don’t think anybody’s looked at that before.”

Although Lp(a) is recognized as an independent cause of atherosclerotic CVD (ASCVD), the significance of Lp(a) in hypertension has been “virtually untapped,” he noted. A recent prospective study reported that elevated CVD risk was present only in individuals with Lp(a) ≥ 30 mg/dL and hypertension but it included only Chinese participants with stable coronary artery disease.

The current analysis, published online in the journal Hypertension, included 6,674 participants in the ongoing Multi-Ethnic Study of Atherosclerosis (MESA), all free of baseline ASCVD, who were recruited from six communities in the United States and had measured baseline Lp(a), blood pressure, and CVD events data over follow-up from 2000 to 2018.

Participants were stratified into four groups based on the presence or absence of hypertension (defined as 140/90 mm Hg or higher or the use of antihypertensive drugs) and an Lp(a) threshold of 50 mg/dL, as recommended by the American College of Cardiology/American Heart Association cholesterol guideline for consideration as an ASCVD risk-enhancing factor.

Slightly more than half of participants were female (52.8%), 38.6% were White, 27.5% were African American, 22.1% were Hispanic, and 11.9% were Chinese American.

According to the researchers, 809 participants had a CVD event over an average follow-up of 13.9 years, including 7.7% of group 1 with Lp(a) < 50 mg/dL and no hypertension, 8.0% of group 2 with Lp(a) ≥ 50 mg/dL and no hypertension, 16.2% of group 3 with Lp(a) < 50 mg/dL and hypertension, and 18.8% of group 4 with Lp(a) ≥ 50 mg/dL and hypertension.

When compared with group 1 in a fully adjusted Cox proportional model, participants with elevated Lp(a) and no hypertension (group 2) did not have an increased risk of CVD events (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.79-1.50).

CVD risk, however, was significantly higher in group 3 with normal Lp(a) and hypertension (HR, 1.66; 95% CI, 1.39-1.98) and group 4 with elevated Lp(a) and hypertension (HR, 2.07, 95% CI, 1.63-2.62).

Among all participants with hypertension (groups 3 and 4), Lp(a) was associated with a significant increase in CVD risk (HR, 1.24, 95% CI, 1.01-1.53).

“What I think is interesting here is that in the absence of hypertension, we didn’t really see an increased risk despite having an elevated Lp(a),” said Dr. Shapiro. “What it may indicate is that really for Lp(a) to be associated with risk, there may already need to be some kind of arterial damage that allows the Lp(a) to have its atherogenic impact.

“In other words, in individuals who have totally normal arterial walls, potentially, maybe that is protective enough against Lp(a) that in the absence of any other injurious factor, maybe it’s not an issue,” he said. “That’s a big hypothesis-generating [statement], but hypertension is certainly one of those risk factors that’s known to cause endothelial injury and endothelial dysfunction.”

Dr. Shapiro pointed out that when first measured in MESA, Lp(a) was measured in 4,600 participants who were not on statins, which is important because statins can increase Lp(a) levels.

“When you look just at those participants, those 4,600, you actually do see a relationship between Lp(a) and cardiovascular disease,” he said. “When you look at the whole population, including the 17% who are baseline populations, even when you adjust for statin therapy, we fail to see that, at least in the long-term follow up.”

Nevertheless, he cautioned that hypertension is just one of many traditional cardiovascular risk factors that could affect the relationship between Lp(a) and CVD risk. “I don’t want to suggest that we believe there’s something specifically magical about hypertension and Lp(a). If we chose, say, diabetes or smoking or another traditional risk factor, we may or may not have seen kind of similar results.”

When the investigators stratified the analyses by sex and race/ethnicity, they found that Lp(a) was not associated with CVD risk, regardless of hypertension status. In Black participants, however, greater CVD risk was seen when both elevated Lp(a) and hypertension were present (HR, 2.07, 95% CI, 1.34-3.21; P = .001).

Asked whether the results support one-time universal screening for Lp(a), which is almost exclusively genetically determined, Dr. Shapiro said he supports screening but that this was a secondary analysis and its numbers were modest. He added that median Lp(a) level is higher in African Americans than any other racial/ethnic group but the “most recent data has clarified that, per any absolute level of Lp(a), it appears to confer the same absolute risk in any racial or ethnic group.”

The authors acknowledge that differential loss to follow-up could have resulted in selection bias in the study and that there were relatively few CVD events in group 2, which may have limited the ability to detect differences in groups without hypertension, particularly in the subgroup analyses. Other limitations are the potential for residual confounding and participants may have developed hypertension during follow-up, resulting in misclassification bias.

Further research is needed to better understand the mechanistic link between Lp(a), hypertension, and CVD, Dr. Shapiro said. Further insights also should be provided by the ongoing phase 3 Lp(a) HORIZON trial evaluating the effect of Lp(a) lowering with the investigational antisense drug, pelacarsen, on cardiovascular events in 8,324 patients with established CVD and elevated Lp(a). The study is expected to be completed in May 2025.

The study was supported by contracts from the National Heart, Lung, and Blood Institute and by grants from the National Center for Advanced Translational Sciences. Dr. Shapiro reports participating in scientific advisory boards with Amgen, Novartis, and Novo Nordisk, and consulting for Regeneron.

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

“I could relate to many, many, many of the experiences and emotions that Charlie, which is Brendan Fraser’s character, was portraying,” Patricia Nece recalls after watching a preview copy of the new film “The Whale.”

A24

Much of the movie “rang true and hit home for me as things that I, too, had experienced,” Ms. Nece, the board of directors’ chair of the Obesity Action Coalition (OAC) and a person living with obesity, shares with this news organization.

In theaters as of December 9, The Whale chronicles the experience of a 600-lb, middle-aged man named Charlie. Throughout the film, Charlie seeks to rebuild his relationship with his estranged teenage daughter. Charlie had left his daughter and family to pursue a relationship with a man, who eventually died. As he navigates the pain surrounding his partner’s death and his lack of community, Charlie turns to food for comfort.

When the movie premiered at the Venice Film Festival, Mr. Fraser received a 6-minute standing ovation. However, activists criticized the movie for casting Fraser over an actor with obesity as well as its depiction of people with obesity.

Representatives from the National Association to Advance Fat Acceptance contend that casting an actor without obesity only contributes to ongoing bias against people of size. “Medical weight stigma and other socio-political determinants of health for people of all sizes cause far more harm to fat people than body fat does. Bias endangers fat people’s health. Anti-obesity organizations, such as those consulted with for this movie, contribute to stigma rather than reducing it as they claim,” NAAFA wrote in a statement to this news organization.

And they added that though the fat suit used in the movie may be superior to previous ones, it is still not an accurate depiction: “The creators of The Whale consider its CGI-generated fat suit to be superior to tactile fat suits, but we don’t. The issue with fat suits in Hollywood is not that they aren’t realistic enough. The issue is that they are used rather than using performers who actually live in bodies like the ones being depicted. If there is a 600-pound character in a movie, there should be a 600-pound human in that role. Rather than concentrate on the hype around the fake fat body created for The Whale, we want to see Hollywood create more opportunities for fat people across the size spectrum, both in front of the camera and behind the scenes.”
 

Prosthetics vs. reality?

Ms. Nece says she understands the controversy surrounding the use of fat suits but believes that it was not done in poor taste.

“OAC got involved with the movie after Brendan was already chosen for the part, and we never would have gotten involved with it had the prosthetics or fat suit been used to ridicule or make fun of people with obesity, which is usually the case,” she explains.

“But we knew from the start that that was never the intent of anyone involved with The Whale. And I think that’s shown by the fact that Brendan and Darren Aronofsky, the director, reached out to people who live with obesity on a daily basis to find out and learn more about it and to educate themselves about it,” Ms. Nece continues.

In a Daily Mail article, Mr. Fraser credited his son Griffin, who is autistic and obese, with helping him understand the struggles that people with obesity face.

Rachel Goldman, PhD, a clinical psychologist in private practice in New York and a professor in the psychology department at New York University, notes that there are other considerations that played into casting. “I know there was some pushback in terms of could, a say 600-lb individual, even be able to go to be on set every day and do this kind of work, and the answer is we don’t know.”

“I’m sure Darren chose Brendan for many reasons above and beyond just his body. I think that’s very important to keep in mind that just as much as representation is very important, I think it is also about finding the right person for the right role,” adds Dr. Goldman, who served as a consultant to the film.
 

Fat suits, extreme weight gains all to play a role

About 42% of adults in the United States have obesity, according to the 2017-2020 National Health and Nutrition Examination Survey, but that reality is not reflected in films or television.

A study of 1018 major television characters found that 24% of men and 14% of women had either overweight or obesity – far below the national average. And when characters with obesity are portrayed, actors often wear prosthetics, like Gwyneth Paltrow in Shallow Hal or Eddie Murphy in the Nutty Professor.

But unlike Mr. Fraser, some actors gain weight quickly instead.

This practice is unhealthy, says Jaime Almandoz, MD, an associate professor at the University of Texas Southwestern Medical Center, Dallas, and a nonsurgical weight management expert. In interviews, actors have shared how they increased calorie intake by drinking two milkshakes per day, going to fast food places regularly, or, in Mark Walhberg’s case, consuming 7,000 calories per day to gain 30 pounds for his role as boxer-turned-priest in the movie Father Stu.

This method provides their bodies with excess calories they are unable to burn off. “Then the amount of sugar and fat that streams into the blood as a result creates problems both directly and indirectly as your body tries to store it. It basically ends up using overflow warehouses for fat storage, like the liver for example, so we can create a condition called fatty liver, or in the muscle and other places, and this excess sugar and fat in the bloodstream cause several factors that are both insulin resistance causing,” Dr. Almandoz explains.

Though gaining weight helps the actor understand the character’s life experience, it may also be risky.

“To have an actor deliberately put his own health at risk and gain a certain amount of weight and whatever that might entail, one – that’s not necessarily the safest thing for that actor – but two, it’s also important to highlight the authentic experience of someone who has dealt with this chronic disease as well,” says Disha Narang, MD, a quadruple-board certified endocrinologist, obesity medicine, and culinary medicine specialist at Northwestern Medicine Lake Forest Hospital, Chicago.

These extreme fluctuations in weight may create problems. “It is typically not something we recommend because there could be metabolic damages as well as health concerns when patients are trying to gain weight quickly, just as we don’t want patients to lose weight quickly,” says Kurt Hong, MD, PhD, board-certified in internal medicine and clinical nutrition at the University of Southern California, Los Angeles.

Dr. Hong notes that it may be difficult for individuals to experience sudden weight gain because the body works hard to maintain a state of homeostasis.

“Similarly, to someone trying to gain weight you overeat, initially your body will try to again, maybe enhance its metabolic efficiency to hold the body stable,” Dr. Hong adds.

Dietary choices that may contribute to insulin resistance or promote high blood sugar can contribute to inflammation and a number of other adverse health outcomes, notes Dr. Almandoz. “The things that actors need to do in order to gain this magnitude of weight and they want to do it in the most time-effective manner is often not helpful for our bodies, it can be very problematic, the same thing goes for weight loss when actors need to lose significant amounts of weight for roles,” says Dr. Almandoz.

And Dr. Hong explained that for patients trying to lose weight, they may cut calories, but the body will try to compensate by slowing down the metabolism to keep their weight the same.
 

‘Your own worst bully’

In “The Whale,” Charlie appears to suffer from internalized weight bias, which is common to many people living with obesity, Ms. Nece says.

“Internalized weight bias is when the person of size takes all that negativity and turns it on themselves. The easiest way to describe that is to tell you that I became my own worst bully because I started believing all the negative things people said to me about my weight,” Ms. Nece adds.

Her hope is that the film will bring attention to the harm that this bias creates, especially when it derives from other people. “There’s no telling whether it will, but what Charlie experiences in bias and stigma from others clearly happens. It’s realistic. Those of us in large bodies have experienced what he is experiencing, so some people have said the movie is fat-phobic, but I see it as I can relate to those experiences because I have them too, so they are very realistic.”

Ms. Nece notes that it is important for clinicians to understand that obesity is a multifaceted and sensitive topic. “For those medical professionals who do not already know that obesity is complex, I hope the film will begin to open their eyes to the many different facets involved in obesity and their patients with obesity, I hope it will help them empathize and show compassion to their patients with obesity,” she concludes.

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

“I could relate to many, many, many of the experiences and emotions that Charlie, which is Brendan Fraser’s character, was portraying,” Patricia Nece recalls after watching a preview copy of the new film “The Whale.”

A24

Much of the movie “rang true and hit home for me as things that I, too, had experienced,” Ms. Nece, the board of directors’ chair of the Obesity Action Coalition (OAC) and a person living with obesity, shares with this news organization.

In theaters as of December 9, The Whale chronicles the experience of a 600-lb, middle-aged man named Charlie. Throughout the film, Charlie seeks to rebuild his relationship with his estranged teenage daughter. Charlie had left his daughter and family to pursue a relationship with a man, who eventually died. As he navigates the pain surrounding his partner’s death and his lack of community, Charlie turns to food for comfort.

When the movie premiered at the Venice Film Festival, Mr. Fraser received a 6-minute standing ovation. However, activists criticized the movie for casting Fraser over an actor with obesity as well as its depiction of people with obesity.

Representatives from the National Association to Advance Fat Acceptance contend that casting an actor without obesity only contributes to ongoing bias against people of size. “Medical weight stigma and other socio-political determinants of health for people of all sizes cause far more harm to fat people than body fat does. Bias endangers fat people’s health. Anti-obesity organizations, such as those consulted with for this movie, contribute to stigma rather than reducing it as they claim,” NAAFA wrote in a statement to this news organization.

And they added that though the fat suit used in the movie may be superior to previous ones, it is still not an accurate depiction: “The creators of The Whale consider its CGI-generated fat suit to be superior to tactile fat suits, but we don’t. The issue with fat suits in Hollywood is not that they aren’t realistic enough. The issue is that they are used rather than using performers who actually live in bodies like the ones being depicted. If there is a 600-pound character in a movie, there should be a 600-pound human in that role. Rather than concentrate on the hype around the fake fat body created for The Whale, we want to see Hollywood create more opportunities for fat people across the size spectrum, both in front of the camera and behind the scenes.”
 

Prosthetics vs. reality?

Ms. Nece says she understands the controversy surrounding the use of fat suits but believes that it was not done in poor taste.

“OAC got involved with the movie after Brendan was already chosen for the part, and we never would have gotten involved with it had the prosthetics or fat suit been used to ridicule or make fun of people with obesity, which is usually the case,” she explains.

“But we knew from the start that that was never the intent of anyone involved with The Whale. And I think that’s shown by the fact that Brendan and Darren Aronofsky, the director, reached out to people who live with obesity on a daily basis to find out and learn more about it and to educate themselves about it,” Ms. Nece continues.

In a Daily Mail article, Mr. Fraser credited his son Griffin, who is autistic and obese, with helping him understand the struggles that people with obesity face.

Rachel Goldman, PhD, a clinical psychologist in private practice in New York and a professor in the psychology department at New York University, notes that there are other considerations that played into casting. “I know there was some pushback in terms of could, a say 600-lb individual, even be able to go to be on set every day and do this kind of work, and the answer is we don’t know.”

“I’m sure Darren chose Brendan for many reasons above and beyond just his body. I think that’s very important to keep in mind that just as much as representation is very important, I think it is also about finding the right person for the right role,” adds Dr. Goldman, who served as a consultant to the film.
 

Fat suits, extreme weight gains all to play a role

About 42% of adults in the United States have obesity, according to the 2017-2020 National Health and Nutrition Examination Survey, but that reality is not reflected in films or television.

A study of 1018 major television characters found that 24% of men and 14% of women had either overweight or obesity – far below the national average. And when characters with obesity are portrayed, actors often wear prosthetics, like Gwyneth Paltrow in Shallow Hal or Eddie Murphy in the Nutty Professor.

But unlike Mr. Fraser, some actors gain weight quickly instead.

This practice is unhealthy, says Jaime Almandoz, MD, an associate professor at the University of Texas Southwestern Medical Center, Dallas, and a nonsurgical weight management expert. In interviews, actors have shared how they increased calorie intake by drinking two milkshakes per day, going to fast food places regularly, or, in Mark Walhberg’s case, consuming 7,000 calories per day to gain 30 pounds for his role as boxer-turned-priest in the movie Father Stu.

This method provides their bodies with excess calories they are unable to burn off. “Then the amount of sugar and fat that streams into the blood as a result creates problems both directly and indirectly as your body tries to store it. It basically ends up using overflow warehouses for fat storage, like the liver for example, so we can create a condition called fatty liver, or in the muscle and other places, and this excess sugar and fat in the bloodstream cause several factors that are both insulin resistance causing,” Dr. Almandoz explains.

Though gaining weight helps the actor understand the character’s life experience, it may also be risky.

“To have an actor deliberately put his own health at risk and gain a certain amount of weight and whatever that might entail, one – that’s not necessarily the safest thing for that actor – but two, it’s also important to highlight the authentic experience of someone who has dealt with this chronic disease as well,” says Disha Narang, MD, a quadruple-board certified endocrinologist, obesity medicine, and culinary medicine specialist at Northwestern Medicine Lake Forest Hospital, Chicago.

These extreme fluctuations in weight may create problems. “It is typically not something we recommend because there could be metabolic damages as well as health concerns when patients are trying to gain weight quickly, just as we don’t want patients to lose weight quickly,” says Kurt Hong, MD, PhD, board-certified in internal medicine and clinical nutrition at the University of Southern California, Los Angeles.

Dr. Hong notes that it may be difficult for individuals to experience sudden weight gain because the body works hard to maintain a state of homeostasis.

“Similarly, to someone trying to gain weight you overeat, initially your body will try to again, maybe enhance its metabolic efficiency to hold the body stable,” Dr. Hong adds.

Dietary choices that may contribute to insulin resistance or promote high blood sugar can contribute to inflammation and a number of other adverse health outcomes, notes Dr. Almandoz. “The things that actors need to do in order to gain this magnitude of weight and they want to do it in the most time-effective manner is often not helpful for our bodies, it can be very problematic, the same thing goes for weight loss when actors need to lose significant amounts of weight for roles,” says Dr. Almandoz.

And Dr. Hong explained that for patients trying to lose weight, they may cut calories, but the body will try to compensate by slowing down the metabolism to keep their weight the same.
 

‘Your own worst bully’

In “The Whale,” Charlie appears to suffer from internalized weight bias, which is common to many people living with obesity, Ms. Nece says.

“Internalized weight bias is when the person of size takes all that negativity and turns it on themselves. The easiest way to describe that is to tell you that I became my own worst bully because I started believing all the negative things people said to me about my weight,” Ms. Nece adds.

Her hope is that the film will bring attention to the harm that this bias creates, especially when it derives from other people. “There’s no telling whether it will, but what Charlie experiences in bias and stigma from others clearly happens. It’s realistic. Those of us in large bodies have experienced what he is experiencing, so some people have said the movie is fat-phobic, but I see it as I can relate to those experiences because I have them too, so they are very realistic.”

Ms. Nece notes that it is important for clinicians to understand that obesity is a multifaceted and sensitive topic. “For those medical professionals who do not already know that obesity is complex, I hope the film will begin to open their eyes to the many different facets involved in obesity and their patients with obesity, I hope it will help them empathize and show compassion to their patients with obesity,” she concludes.

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

“I could relate to many, many, many of the experiences and emotions that Charlie, which is Brendan Fraser’s character, was portraying,” Patricia Nece recalls after watching a preview copy of the new film “The Whale.”

A24

Much of the movie “rang true and hit home for me as things that I, too, had experienced,” Ms. Nece, the board of directors’ chair of the Obesity Action Coalition (OAC) and a person living with obesity, shares with this news organization.

In theaters as of December 9, The Whale chronicles the experience of a 600-lb, middle-aged man named Charlie. Throughout the film, Charlie seeks to rebuild his relationship with his estranged teenage daughter. Charlie had left his daughter and family to pursue a relationship with a man, who eventually died. As he navigates the pain surrounding his partner’s death and his lack of community, Charlie turns to food for comfort.

When the movie premiered at the Venice Film Festival, Mr. Fraser received a 6-minute standing ovation. However, activists criticized the movie for casting Fraser over an actor with obesity as well as its depiction of people with obesity.

Representatives from the National Association to Advance Fat Acceptance contend that casting an actor without obesity only contributes to ongoing bias against people of size. “Medical weight stigma and other socio-political determinants of health for people of all sizes cause far more harm to fat people than body fat does. Bias endangers fat people’s health. Anti-obesity organizations, such as those consulted with for this movie, contribute to stigma rather than reducing it as they claim,” NAAFA wrote in a statement to this news organization.

And they added that though the fat suit used in the movie may be superior to previous ones, it is still not an accurate depiction: “The creators of The Whale consider its CGI-generated fat suit to be superior to tactile fat suits, but we don’t. The issue with fat suits in Hollywood is not that they aren’t realistic enough. The issue is that they are used rather than using performers who actually live in bodies like the ones being depicted. If there is a 600-pound character in a movie, there should be a 600-pound human in that role. Rather than concentrate on the hype around the fake fat body created for The Whale, we want to see Hollywood create more opportunities for fat people across the size spectrum, both in front of the camera and behind the scenes.”
 

Prosthetics vs. reality?

Ms. Nece says she understands the controversy surrounding the use of fat suits but believes that it was not done in poor taste.

“OAC got involved with the movie after Brendan was already chosen for the part, and we never would have gotten involved with it had the prosthetics or fat suit been used to ridicule or make fun of people with obesity, which is usually the case,” she explains.

“But we knew from the start that that was never the intent of anyone involved with The Whale. And I think that’s shown by the fact that Brendan and Darren Aronofsky, the director, reached out to people who live with obesity on a daily basis to find out and learn more about it and to educate themselves about it,” Ms. Nece continues.

In a Daily Mail article, Mr. Fraser credited his son Griffin, who is autistic and obese, with helping him understand the struggles that people with obesity face.

Rachel Goldman, PhD, a clinical psychologist in private practice in New York and a professor in the psychology department at New York University, notes that there are other considerations that played into casting. “I know there was some pushback in terms of could, a say 600-lb individual, even be able to go to be on set every day and do this kind of work, and the answer is we don’t know.”

“I’m sure Darren chose Brendan for many reasons above and beyond just his body. I think that’s very important to keep in mind that just as much as representation is very important, I think it is also about finding the right person for the right role,” adds Dr. Goldman, who served as a consultant to the film.
 

Fat suits, extreme weight gains all to play a role

About 42% of adults in the United States have obesity, according to the 2017-2020 National Health and Nutrition Examination Survey, but that reality is not reflected in films or television.

A study of 1018 major television characters found that 24% of men and 14% of women had either overweight or obesity – far below the national average. And when characters with obesity are portrayed, actors often wear prosthetics, like Gwyneth Paltrow in Shallow Hal or Eddie Murphy in the Nutty Professor.

But unlike Mr. Fraser, some actors gain weight quickly instead.

This practice is unhealthy, says Jaime Almandoz, MD, an associate professor at the University of Texas Southwestern Medical Center, Dallas, and a nonsurgical weight management expert. In interviews, actors have shared how they increased calorie intake by drinking two milkshakes per day, going to fast food places regularly, or, in Mark Walhberg’s case, consuming 7,000 calories per day to gain 30 pounds for his role as boxer-turned-priest in the movie Father Stu.

This method provides their bodies with excess calories they are unable to burn off. “Then the amount of sugar and fat that streams into the blood as a result creates problems both directly and indirectly as your body tries to store it. It basically ends up using overflow warehouses for fat storage, like the liver for example, so we can create a condition called fatty liver, or in the muscle and other places, and this excess sugar and fat in the bloodstream cause several factors that are both insulin resistance causing,” Dr. Almandoz explains.

Though gaining weight helps the actor understand the character’s life experience, it may also be risky.

“To have an actor deliberately put his own health at risk and gain a certain amount of weight and whatever that might entail, one – that’s not necessarily the safest thing for that actor – but two, it’s also important to highlight the authentic experience of someone who has dealt with this chronic disease as well,” says Disha Narang, MD, a quadruple-board certified endocrinologist, obesity medicine, and culinary medicine specialist at Northwestern Medicine Lake Forest Hospital, Chicago.

These extreme fluctuations in weight may create problems. “It is typically not something we recommend because there could be metabolic damages as well as health concerns when patients are trying to gain weight quickly, just as we don’t want patients to lose weight quickly,” says Kurt Hong, MD, PhD, board-certified in internal medicine and clinical nutrition at the University of Southern California, Los Angeles.

Dr. Hong notes that it may be difficult for individuals to experience sudden weight gain because the body works hard to maintain a state of homeostasis.

“Similarly, to someone trying to gain weight you overeat, initially your body will try to again, maybe enhance its metabolic efficiency to hold the body stable,” Dr. Hong adds.

Dietary choices that may contribute to insulin resistance or promote high blood sugar can contribute to inflammation and a number of other adverse health outcomes, notes Dr. Almandoz. “The things that actors need to do in order to gain this magnitude of weight and they want to do it in the most time-effective manner is often not helpful for our bodies, it can be very problematic, the same thing goes for weight loss when actors need to lose significant amounts of weight for roles,” says Dr. Almandoz.

And Dr. Hong explained that for patients trying to lose weight, they may cut calories, but the body will try to compensate by slowing down the metabolism to keep their weight the same.
 

‘Your own worst bully’

In “The Whale,” Charlie appears to suffer from internalized weight bias, which is common to many people living with obesity, Ms. Nece says.

“Internalized weight bias is when the person of size takes all that negativity and turns it on themselves. The easiest way to describe that is to tell you that I became my own worst bully because I started believing all the negative things people said to me about my weight,” Ms. Nece adds.

Her hope is that the film will bring attention to the harm that this bias creates, especially when it derives from other people. “There’s no telling whether it will, but what Charlie experiences in bias and stigma from others clearly happens. It’s realistic. Those of us in large bodies have experienced what he is experiencing, so some people have said the movie is fat-phobic, but I see it as I can relate to those experiences because I have them too, so they are very realistic.”

Ms. Nece notes that it is important for clinicians to understand that obesity is a multifaceted and sensitive topic. “For those medical professionals who do not already know that obesity is complex, I hope the film will begin to open their eyes to the many different facets involved in obesity and their patients with obesity, I hope it will help them empathize and show compassion to their patients with obesity,” she concludes.

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

A new strategy for the management of atherosclerotic plaque as a source of major adverse cardiac events is needed with the focus shifting from the flow-limiting coronary artery luminal lesions to the overall atherosclerotic burden, be it obstructive or nonobstructive, according to a review article.

The article, by Peter H. Stone, MD, and Peter Libby, MD, Brigham and Women’s Hospital, Boston, and William E. Boden, MD, Boston University School of Medicine, was published online in JAMA Cardiology.  

The review explored new data from vascular biology, atherosclerosis imaging, natural history outcome studies, and large-scale clinical trials that support what the authors refer to as “The Plaque Hypothesis” – the idea that major adverse cardiac events such as myocardial infarction and cardiac death are triggered by destabilization of vulnerable plaque, which may be obstructive or nonobstructive.

“We need to consider embracing a new management strategy that directs our diagnostic and management focus to evaluate the entire length of the atheromatous coronary artery and broaden the target of our therapeutic intervention to include all regions of the plaque (both flow-limiting and non–flow-limiting), even those that are distant from the presumed ischemia-producing obstruction,” the authors concluded.

Dr. Stone explained to this news organization that, for several decades, the medical community has focused on plaques causing severe obstruction of coronary arteries as being responsible for major adverse cardiac events. This approach – known as the Ischemia Hypothesis – has been the accepted strategy for many years, with all guidelines advising the identification of the stenoses that cause the most obstruction for treatment with stenting.

However, the authors pointed out that a number of studies have now suggested that, while these severe obstructive stenoses cause angina, they do not seem to be responsible for the hard events of MI, acute coronary syndrome (ACS), and cardiac death. 

Several studies including the COURAGE trial and BARI-2D, and the recent ISCHEMIA trial have all failed to show a reduction in these hard endpoints by intervening on these severe obstructive lesions, Dr. Stone noted. 

“We present evidence for a new approach – that it is the composition and vascular biology of the atherosclerotic plaques that cause MI, ACS, and cardiac death, rather than simply how obstructive they are,” he said.  

Dr. Stone pointed out that plaque seen on a coronary angiogram looks at only the lumen of the artery, but plaque is primarily based in the wall of the artery, and if that plaque is inflamed it can easily be the culprit responsible for adverse events even without encroaching into the lumen.

“Our paper describes many factors which can cause plaques to destabilize and cause an ACS. These include anatomical, biochemical, and biomechanical features that together cause plaque rupture or erosion and precipitate a clinical event. It is not sufficient to just look for obstructive plaques on a coronary angiogram,” he said. “We are barking up the wrong tree. We need to look for inflamed plaque in the whole wall of the coronary arteries.”

The authors described different factors that identify a plaque at high risk of destabilization. These include a large area of vulnerable plaque, a thin-cap atheroma, a severe inflamed core, macrocalcifications, a large plaque burden, and a physical profile that would encourage a thrombus to become trapped.  

“Atherosclerotic plaques are very heterogeneous and complex structures and it is not just the mountain peaks but also the lower foothills that can precipitate a flow-limiting obstruction,” Dr. Stone noted. 

“The slope of the mountain is probably very important in the ability for a thrombus to form. If the slope is gradual there isn’t a problem. But if the slope is jagged with sharp edges this can cause a thrombus to become trapped. We need to look at the entirety of plaque and all its risk features to identify the culprit areas that could cause MI or cardiac death. These are typically not the obstructive plaques we have all been fixated on for many years,” he added. 

“We need to focus on plaque heterogeneity. Once plaque is old and just made up of scar tissue which is not inflamed it does not cause much [of] a problem – we can probably just leave it alone. Some of these obstructive plaques may cause some angina but many do not cause major cardiac events unless they have other high-risk features,” he said. 

“Cardiac events are still caused by obstruction of blood flow but that can be an abrupt process where a thrombus attaches itself to an area of destabilized plaque. These areas of plaque were not necessarily obstructing to start with. We believe that this is the explanation behind the observation that 50% of all people who have an MI (half of which are fatal) do not have symptoms beforehand,” Dr. Stone commented. 

Because these areas of destabilized plaque do not cause symptoms, he believes that vast populations of people with established cardiovascular risk factors should undergo screening. “At the moment we wait for people to experience chest pain or to have an MI – that is far too little too late.” 

To identify these areas of high-risk plaques, imaging techniques looking inside the artery wall are needed such as intravascular ultrasound. However, this is an invasive procedure, and the noninvasive coronary CT angiography also gives a good picture, so it is probably the best way to begin as a wider screening modality, with more invasive screening methods then used in those found to be at risk, Dr. Stone suggested.  

Plaques that are identified as likely to destabilize can be treated with percutaneous coronary intervention and stenting.  

While systemic therapies are useful, those currently available are not sufficient, Dr. Stone noted. For example, there are still high levels of major cardiac events in patients treated with the PCSK9 inhibitors, which bring about very large reductions in LDL cholesterol. “These therapies are beneficial, but they are not enough on their own. So, these areas of unstable plaque would need to be treated with stenting or something similar. We believe that the intervention of stenting is good but at present it is targeted at the wrong areas,” he stated.  

“Clearly what we’ve been doing – stenting only obstructive lesions – does not reduce hard clinical events. Imaging methods have improved so much in recent years that we can now identify high-risk areas of plaque. This whole field of studying the vulnerable plaque has been ongoing for many years, but it is only recently that imaging methods have become good enough to identify plaques at risk. This field is now coming of age,” he added.

The next steps are to start identifying these plaques in larger populations, more accurately characterizing those at the highest risk, and then performing randomized trials of preemptive intervention in those believed to be at highest risk, and follow up for clinical events, Dr. Stone explained.  

Advances in detecting unstable plaque may also permit early evaluation of novel therapeutics and gauge the intensity of lifestyle and disease-modifying pharmacotherapy, the authors suggested.

This work was supported in part by the National Heart, Lung, and Blood Institute, the American Heart Association, the RRM Charitable Fund, the Simard Fund, and the Schaubert Family. Dr. Libby is an unpaid consultant to or involved in clinical trials with Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, MedImmune, Merck, Norvo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron; and is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Elucid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, MedImmune, Moderna, Novartis, PlaqueTec, TenSixteen Bio, Soley Thereapeutics, and XBiotech.

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

A new strategy for the management of atherosclerotic plaque as a source of major adverse cardiac events is needed with the focus shifting from the flow-limiting coronary artery luminal lesions to the overall atherosclerotic burden, be it obstructive or nonobstructive, according to a review article.

The article, by Peter H. Stone, MD, and Peter Libby, MD, Brigham and Women’s Hospital, Boston, and William E. Boden, MD, Boston University School of Medicine, was published online in JAMA Cardiology.  

The review explored new data from vascular biology, atherosclerosis imaging, natural history outcome studies, and large-scale clinical trials that support what the authors refer to as “The Plaque Hypothesis” – the idea that major adverse cardiac events such as myocardial infarction and cardiac death are triggered by destabilization of vulnerable plaque, which may be obstructive or nonobstructive.

“We need to consider embracing a new management strategy that directs our diagnostic and management focus to evaluate the entire length of the atheromatous coronary artery and broaden the target of our therapeutic intervention to include all regions of the plaque (both flow-limiting and non–flow-limiting), even those that are distant from the presumed ischemia-producing obstruction,” the authors concluded.

Dr. Stone explained to this news organization that, for several decades, the medical community has focused on plaques causing severe obstruction of coronary arteries as being responsible for major adverse cardiac events. This approach – known as the Ischemia Hypothesis – has been the accepted strategy for many years, with all guidelines advising the identification of the stenoses that cause the most obstruction for treatment with stenting.

However, the authors pointed out that a number of studies have now suggested that, while these severe obstructive stenoses cause angina, they do not seem to be responsible for the hard events of MI, acute coronary syndrome (ACS), and cardiac death. 

Several studies including the COURAGE trial and BARI-2D, and the recent ISCHEMIA trial have all failed to show a reduction in these hard endpoints by intervening on these severe obstructive lesions, Dr. Stone noted. 

“We present evidence for a new approach – that it is the composition and vascular biology of the atherosclerotic plaques that cause MI, ACS, and cardiac death, rather than simply how obstructive they are,” he said.  

Dr. Stone pointed out that plaque seen on a coronary angiogram looks at only the lumen of the artery, but plaque is primarily based in the wall of the artery, and if that plaque is inflamed it can easily be the culprit responsible for adverse events even without encroaching into the lumen.

“Our paper describes many factors which can cause plaques to destabilize and cause an ACS. These include anatomical, biochemical, and biomechanical features that together cause plaque rupture or erosion and precipitate a clinical event. It is not sufficient to just look for obstructive plaques on a coronary angiogram,” he said. “We are barking up the wrong tree. We need to look for inflamed plaque in the whole wall of the coronary arteries.”

The authors described different factors that identify a plaque at high risk of destabilization. These include a large area of vulnerable plaque, a thin-cap atheroma, a severe inflamed core, macrocalcifications, a large plaque burden, and a physical profile that would encourage a thrombus to become trapped.  

“Atherosclerotic plaques are very heterogeneous and complex structures and it is not just the mountain peaks but also the lower foothills that can precipitate a flow-limiting obstruction,” Dr. Stone noted. 

“The slope of the mountain is probably very important in the ability for a thrombus to form. If the slope is gradual there isn’t a problem. But if the slope is jagged with sharp edges this can cause a thrombus to become trapped. We need to look at the entirety of plaque and all its risk features to identify the culprit areas that could cause MI or cardiac death. These are typically not the obstructive plaques we have all been fixated on for many years,” he added. 

“We need to focus on plaque heterogeneity. Once plaque is old and just made up of scar tissue which is not inflamed it does not cause much [of] a problem – we can probably just leave it alone. Some of these obstructive plaques may cause some angina but many do not cause major cardiac events unless they have other high-risk features,” he said. 

“Cardiac events are still caused by obstruction of blood flow but that can be an abrupt process where a thrombus attaches itself to an area of destabilized plaque. These areas of plaque were not necessarily obstructing to start with. We believe that this is the explanation behind the observation that 50% of all people who have an MI (half of which are fatal) do not have symptoms beforehand,” Dr. Stone commented. 

Because these areas of destabilized plaque do not cause symptoms, he believes that vast populations of people with established cardiovascular risk factors should undergo screening. “At the moment we wait for people to experience chest pain or to have an MI – that is far too little too late.” 

To identify these areas of high-risk plaques, imaging techniques looking inside the artery wall are needed such as intravascular ultrasound. However, this is an invasive procedure, and the noninvasive coronary CT angiography also gives a good picture, so it is probably the best way to begin as a wider screening modality, with more invasive screening methods then used in those found to be at risk, Dr. Stone suggested.  

Plaques that are identified as likely to destabilize can be treated with percutaneous coronary intervention and stenting.  

While systemic therapies are useful, those currently available are not sufficient, Dr. Stone noted. For example, there are still high levels of major cardiac events in patients treated with the PCSK9 inhibitors, which bring about very large reductions in LDL cholesterol. “These therapies are beneficial, but they are not enough on their own. So, these areas of unstable plaque would need to be treated with stenting or something similar. We believe that the intervention of stenting is good but at present it is targeted at the wrong areas,” he stated.  

“Clearly what we’ve been doing – stenting only obstructive lesions – does not reduce hard clinical events. Imaging methods have improved so much in recent years that we can now identify high-risk areas of plaque. This whole field of studying the vulnerable plaque has been ongoing for many years, but it is only recently that imaging methods have become good enough to identify plaques at risk. This field is now coming of age,” he added.

The next steps are to start identifying these plaques in larger populations, more accurately characterizing those at the highest risk, and then performing randomized trials of preemptive intervention in those believed to be at highest risk, and follow up for clinical events, Dr. Stone explained.  

Advances in detecting unstable plaque may also permit early evaluation of novel therapeutics and gauge the intensity of lifestyle and disease-modifying pharmacotherapy, the authors suggested.

This work was supported in part by the National Heart, Lung, and Blood Institute, the American Heart Association, the RRM Charitable Fund, the Simard Fund, and the Schaubert Family. Dr. Libby is an unpaid consultant to or involved in clinical trials with Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, MedImmune, Merck, Norvo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron; and is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Elucid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, MedImmune, Moderna, Novartis, PlaqueTec, TenSixteen Bio, Soley Thereapeutics, and XBiotech.

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

A new strategy for the management of atherosclerotic plaque as a source of major adverse cardiac events is needed with the focus shifting from the flow-limiting coronary artery luminal lesions to the overall atherosclerotic burden, be it obstructive or nonobstructive, according to a review article.

The article, by Peter H. Stone, MD, and Peter Libby, MD, Brigham and Women’s Hospital, Boston, and William E. Boden, MD, Boston University School of Medicine, was published online in JAMA Cardiology.  

The review explored new data from vascular biology, atherosclerosis imaging, natural history outcome studies, and large-scale clinical trials that support what the authors refer to as “The Plaque Hypothesis” – the idea that major adverse cardiac events such as myocardial infarction and cardiac death are triggered by destabilization of vulnerable plaque, which may be obstructive or nonobstructive.

“We need to consider embracing a new management strategy that directs our diagnostic and management focus to evaluate the entire length of the atheromatous coronary artery and broaden the target of our therapeutic intervention to include all regions of the plaque (both flow-limiting and non–flow-limiting), even those that are distant from the presumed ischemia-producing obstruction,” the authors concluded.

Dr. Stone explained to this news organization that, for several decades, the medical community has focused on plaques causing severe obstruction of coronary arteries as being responsible for major adverse cardiac events. This approach – known as the Ischemia Hypothesis – has been the accepted strategy for many years, with all guidelines advising the identification of the stenoses that cause the most obstruction for treatment with stenting.

However, the authors pointed out that a number of studies have now suggested that, while these severe obstructive stenoses cause angina, they do not seem to be responsible for the hard events of MI, acute coronary syndrome (ACS), and cardiac death. 

Several studies including the COURAGE trial and BARI-2D, and the recent ISCHEMIA trial have all failed to show a reduction in these hard endpoints by intervening on these severe obstructive lesions, Dr. Stone noted. 

“We present evidence for a new approach – that it is the composition and vascular biology of the atherosclerotic plaques that cause MI, ACS, and cardiac death, rather than simply how obstructive they are,” he said.  

Dr. Stone pointed out that plaque seen on a coronary angiogram looks at only the lumen of the artery, but plaque is primarily based in the wall of the artery, and if that plaque is inflamed it can easily be the culprit responsible for adverse events even without encroaching into the lumen.

“Our paper describes many factors which can cause plaques to destabilize and cause an ACS. These include anatomical, biochemical, and biomechanical features that together cause plaque rupture or erosion and precipitate a clinical event. It is not sufficient to just look for obstructive plaques on a coronary angiogram,” he said. “We are barking up the wrong tree. We need to look for inflamed plaque in the whole wall of the coronary arteries.”

The authors described different factors that identify a plaque at high risk of destabilization. These include a large area of vulnerable plaque, a thin-cap atheroma, a severe inflamed core, macrocalcifications, a large plaque burden, and a physical profile that would encourage a thrombus to become trapped.  

“Atherosclerotic plaques are very heterogeneous and complex structures and it is not just the mountain peaks but also the lower foothills that can precipitate a flow-limiting obstruction,” Dr. Stone noted. 

“The slope of the mountain is probably very important in the ability for a thrombus to form. If the slope is gradual there isn’t a problem. But if the slope is jagged with sharp edges this can cause a thrombus to become trapped. We need to look at the entirety of plaque and all its risk features to identify the culprit areas that could cause MI or cardiac death. These are typically not the obstructive plaques we have all been fixated on for many years,” he added. 

“We need to focus on plaque heterogeneity. Once plaque is old and just made up of scar tissue which is not inflamed it does not cause much [of] a problem – we can probably just leave it alone. Some of these obstructive plaques may cause some angina but many do not cause major cardiac events unless they have other high-risk features,” he said. 

“Cardiac events are still caused by obstruction of blood flow but that can be an abrupt process where a thrombus attaches itself to an area of destabilized plaque. These areas of plaque were not necessarily obstructing to start with. We believe that this is the explanation behind the observation that 50% of all people who have an MI (half of which are fatal) do not have symptoms beforehand,” Dr. Stone commented. 

Because these areas of destabilized plaque do not cause symptoms, he believes that vast populations of people with established cardiovascular risk factors should undergo screening. “At the moment we wait for people to experience chest pain or to have an MI – that is far too little too late.” 

To identify these areas of high-risk plaques, imaging techniques looking inside the artery wall are needed such as intravascular ultrasound. However, this is an invasive procedure, and the noninvasive coronary CT angiography also gives a good picture, so it is probably the best way to begin as a wider screening modality, with more invasive screening methods then used in those found to be at risk, Dr. Stone suggested.  

Plaques that are identified as likely to destabilize can be treated with percutaneous coronary intervention and stenting.  

While systemic therapies are useful, those currently available are not sufficient, Dr. Stone noted. For example, there are still high levels of major cardiac events in patients treated with the PCSK9 inhibitors, which bring about very large reductions in LDL cholesterol. “These therapies are beneficial, but they are not enough on their own. So, these areas of unstable plaque would need to be treated with stenting or something similar. We believe that the intervention of stenting is good but at present it is targeted at the wrong areas,” he stated.  

“Clearly what we’ve been doing – stenting only obstructive lesions – does not reduce hard clinical events. Imaging methods have improved so much in recent years that we can now identify high-risk areas of plaque. This whole field of studying the vulnerable plaque has been ongoing for many years, but it is only recently that imaging methods have become good enough to identify plaques at risk. This field is now coming of age,” he added.

The next steps are to start identifying these plaques in larger populations, more accurately characterizing those at the highest risk, and then performing randomized trials of preemptive intervention in those believed to be at highest risk, and follow up for clinical events, Dr. Stone explained.  

Advances in detecting unstable plaque may also permit early evaluation of novel therapeutics and gauge the intensity of lifestyle and disease-modifying pharmacotherapy, the authors suggested.

This work was supported in part by the National Heart, Lung, and Blood Institute, the American Heart Association, the RRM Charitable Fund, the Simard Fund, and the Schaubert Family. Dr. Libby is an unpaid consultant to or involved in clinical trials with Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, MedImmune, Merck, Norvo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron; and is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Elucid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, MedImmune, Moderna, Novartis, PlaqueTec, TenSixteen Bio, Soley Thereapeutics, and XBiotech.

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

Age-related changes in general and cardiovascular health likely require modifications in how acute coronary syndrome (ACS) is diagnosed and managed in adults aged 75 and older, the American Heart Association says in a new scientific statement.

The statement outlines a framework to integrate geriatric risks into the management of ACS, including the diagnostic approach, pharmacotherapy, revascularization strategies, prevention of adverse events, and transition care planning.

The 31-page statement was published online in the AHA journal Circulation (2022 Dec 12. doi: 10.1161/CIR.0000000000001112). It updates a 2007 AHA statement on treatment of ACS in the elderly.
 

Complex patient group

Adults aged 75 and older make up roughly 30%-40% of all hospitalized patients with ACS and the majority of ACS-related deaths occur in this group, the writing group notes.

“Older patients have more pronounced anatomical changes and more severe functional impairment, and they are more likely to have additional health conditions,” writing group chair Abdulla A. Damluji, MD, PhD, director of the Inova Center of Outcomes Research in Fairfax, Va., notes in a news release.

“These include frailty, other chronic disorders (treated with multiple medications), physical dysfunction, cognitive decline and/or urinary incontinence – and these are not regularly studied in the context of ACS,” Dr. Damluji explained.

The writing group notes that the presence of one or more geriatric syndromes may substantially affect ACS clinical presentation, clinical course and prognosis, therapeutic decision-making, and response to treatment.

“It is therefore fundamental that clinicians caring for older patients with ACS be alert to the presence of geriatric syndromes and be able to integrate them into the care plan when appropriate,” they say.

They recommend a holistic, individualized, and patient-centered approach to ACS care in the elderly, taking into consideration coexisting and overlapping health issues.
 

Considerations for clinical care

The AHA statement offers several “considerations for clinical practice” with regard to ACS diagnosis and management in elderly adults. They include:

• ACS presentations without chest pain, such as shortness of breath, syncope, or sudden confusion, are more common in older adults.
• Many older adults have persistent elevations in cardiac troponin levels from myocardial fibrosis and kidney disease that diminish the positive predictive value of high-sensitivity cardiac troponin (hs-cTn) assays for identifying acute and chronic myocardial injury. For this reason, evaluating patterns of rise and fall is essential.
• Age-related changes in metabolism, weight, and muscle mass may require different choices in anticoagulant medications to lower bleeding risk.
• Clopidogrel (Plavix) is the preferred P2Y12 inhibitor because of a significantly lower bleeding profile than ticagrelor (Brilinta) or prasugrel (Effient). For patients with ST-segment myocardial infarction (STEMI) or complex anatomy, the use of ticagrelor is “reasonable.”
• Poor kidney function can increase the risk for contrast-induced acute kidney injury.
• Although the risks are greater, percutaneous coronary intervention or bypass surgery are beneficial in select older adults with ACS.
• Post-MI care should include cardiac rehabilitation tailored to address each patient’s circumstances and personal goals of care.
• For patients with cognitive difficulties and limited mobility, consider simplified medication plans with fewer doses per day and 90-day supplies to prevent the need for frequent refills.
• Patient care plans should be individualized, with input from a multidisciplinary team that may include cardiologists, surgeons, geriatricians, primary care clinicians, nutritionists, social workers, and family members.
• Determine a priori goals of care in older patients to help avoid an unwanted or futile intervention.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Cardiovascular Diseases in Older Populations Committee of the Council on Clinical Cardiology; the Council on Cardiovascular and Stroke Nursing; the Council on Cardiovascular Radiology and Intervention; and the Council on Lifestyle and Cardiometabolic Health.

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

Age-related changes in general and cardiovascular health likely require modifications in how acute coronary syndrome (ACS) is diagnosed and managed in adults aged 75 and older, the American Heart Association says in a new scientific statement.

The statement outlines a framework to integrate geriatric risks into the management of ACS, including the diagnostic approach, pharmacotherapy, revascularization strategies, prevention of adverse events, and transition care planning.

The 31-page statement was published online in the AHA journal Circulation (2022 Dec 12. doi: 10.1161/CIR.0000000000001112). It updates a 2007 AHA statement on treatment of ACS in the elderly.
 

Complex patient group

Adults aged 75 and older make up roughly 30%-40% of all hospitalized patients with ACS and the majority of ACS-related deaths occur in this group, the writing group notes.

“Older patients have more pronounced anatomical changes and more severe functional impairment, and they are more likely to have additional health conditions,” writing group chair Abdulla A. Damluji, MD, PhD, director of the Inova Center of Outcomes Research in Fairfax, Va., notes in a news release.

“These include frailty, other chronic disorders (treated with multiple medications), physical dysfunction, cognitive decline and/or urinary incontinence – and these are not regularly studied in the context of ACS,” Dr. Damluji explained.

The writing group notes that the presence of one or more geriatric syndromes may substantially affect ACS clinical presentation, clinical course and prognosis, therapeutic decision-making, and response to treatment.

“It is therefore fundamental that clinicians caring for older patients with ACS be alert to the presence of geriatric syndromes and be able to integrate them into the care plan when appropriate,” they say.

They recommend a holistic, individualized, and patient-centered approach to ACS care in the elderly, taking into consideration coexisting and overlapping health issues.
 

Considerations for clinical care

The AHA statement offers several “considerations for clinical practice” with regard to ACS diagnosis and management in elderly adults. They include:

• ACS presentations without chest pain, such as shortness of breath, syncope, or sudden confusion, are more common in older adults.
• Many older adults have persistent elevations in cardiac troponin levels from myocardial fibrosis and kidney disease that diminish the positive predictive value of high-sensitivity cardiac troponin (hs-cTn) assays for identifying acute and chronic myocardial injury. For this reason, evaluating patterns of rise and fall is essential.
• Age-related changes in metabolism, weight, and muscle mass may require different choices in anticoagulant medications to lower bleeding risk.
• Clopidogrel (Plavix) is the preferred P2Y12 inhibitor because of a significantly lower bleeding profile than ticagrelor (Brilinta) or prasugrel (Effient). For patients with ST-segment myocardial infarction (STEMI) or complex anatomy, the use of ticagrelor is “reasonable.”
• Poor kidney function can increase the risk for contrast-induced acute kidney injury.
• Although the risks are greater, percutaneous coronary intervention or bypass surgery are beneficial in select older adults with ACS.
• Post-MI care should include cardiac rehabilitation tailored to address each patient’s circumstances and personal goals of care.
• For patients with cognitive difficulties and limited mobility, consider simplified medication plans with fewer doses per day and 90-day supplies to prevent the need for frequent refills.
• Patient care plans should be individualized, with input from a multidisciplinary team that may include cardiologists, surgeons, geriatricians, primary care clinicians, nutritionists, social workers, and family members.
• Determine a priori goals of care in older patients to help avoid an unwanted or futile intervention.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Cardiovascular Diseases in Older Populations Committee of the Council on Clinical Cardiology; the Council on Cardiovascular and Stroke Nursing; the Council on Cardiovascular Radiology and Intervention; and the Council on Lifestyle and Cardiometabolic Health.

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

Age-related changes in general and cardiovascular health likely require modifications in how acute coronary syndrome (ACS) is diagnosed and managed in adults aged 75 and older, the American Heart Association says in a new scientific statement.

The statement outlines a framework to integrate geriatric risks into the management of ACS, including the diagnostic approach, pharmacotherapy, revascularization strategies, prevention of adverse events, and transition care planning.

The 31-page statement was published online in the AHA journal Circulation (2022 Dec 12. doi: 10.1161/CIR.0000000000001112). It updates a 2007 AHA statement on treatment of ACS in the elderly.
 

Complex patient group

Adults aged 75 and older make up roughly 30%-40% of all hospitalized patients with ACS and the majority of ACS-related deaths occur in this group, the writing group notes.

“Older patients have more pronounced anatomical changes and more severe functional impairment, and they are more likely to have additional health conditions,” writing group chair Abdulla A. Damluji, MD, PhD, director of the Inova Center of Outcomes Research in Fairfax, Va., notes in a news release.

“These include frailty, other chronic disorders (treated with multiple medications), physical dysfunction, cognitive decline and/or urinary incontinence – and these are not regularly studied in the context of ACS,” Dr. Damluji explained.

The writing group notes that the presence of one or more geriatric syndromes may substantially affect ACS clinical presentation, clinical course and prognosis, therapeutic decision-making, and response to treatment.

“It is therefore fundamental that clinicians caring for older patients with ACS be alert to the presence of geriatric syndromes and be able to integrate them into the care plan when appropriate,” they say.

They recommend a holistic, individualized, and patient-centered approach to ACS care in the elderly, taking into consideration coexisting and overlapping health issues.
 

Considerations for clinical care

The AHA statement offers several “considerations for clinical practice” with regard to ACS diagnosis and management in elderly adults. They include:

• ACS presentations without chest pain, such as shortness of breath, syncope, or sudden confusion, are more common in older adults.
• Many older adults have persistent elevations in cardiac troponin levels from myocardial fibrosis and kidney disease that diminish the positive predictive value of high-sensitivity cardiac troponin (hs-cTn) assays for identifying acute and chronic myocardial injury. For this reason, evaluating patterns of rise and fall is essential.
• Age-related changes in metabolism, weight, and muscle mass may require different choices in anticoagulant medications to lower bleeding risk.
• Clopidogrel (Plavix) is the preferred P2Y12 inhibitor because of a significantly lower bleeding profile than ticagrelor (Brilinta) or prasugrel (Effient). For patients with ST-segment myocardial infarction (STEMI) or complex anatomy, the use of ticagrelor is “reasonable.”
• Poor kidney function can increase the risk for contrast-induced acute kidney injury.
• Although the risks are greater, percutaneous coronary intervention or bypass surgery are beneficial in select older adults with ACS.
• Post-MI care should include cardiac rehabilitation tailored to address each patient’s circumstances and personal goals of care.
• For patients with cognitive difficulties and limited mobility, consider simplified medication plans with fewer doses per day and 90-day supplies to prevent the need for frequent refills.
• Patient care plans should be individualized, with input from a multidisciplinary team that may include cardiologists, surgeons, geriatricians, primary care clinicians, nutritionists, social workers, and family members.
• Determine a priori goals of care in older patients to help avoid an unwanted or futile intervention.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Cardiovascular Diseases in Older Populations Committee of the Council on Clinical Cardiology; the Council on Cardiovascular and Stroke Nursing; the Council on Cardiovascular Radiology and Intervention; and the Council on Lifestyle and Cardiometabolic Health.

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

Metabolic syndrome is associated with a significantly increased risk for gout in young men, but the risk can be mitigated by improvement in individual components of the syndrome, based on data from a pair of population-based studies totaling more than 4 million individuals.

Gout remains the most common type of inflammatory arthritis in men, and the rate has been rising among younger adults, Yeonghee Eun, MD, PhD, of Sungkyunkwan University, Seoul, South Korea, and colleagues wrote. An increasing body of evidence suggests a link between gout and metabolic syndrome (MetS), but large studies have been lacking, especially in younger adults.

In a study published in Frontiers in Medicine, the researchers reviewed data from 3,569,104 men aged 20-39 years who underwent a health checkup between 2009 and 2012 in South Korea, based on the Korean National Health Insurance Service. The primary outcome of incident gout was identified using claims data. The mean age of the participants was 31.5 years.

Over a mean follow-up of 7.4 years, the incidence of gout was 3.36 per 1,000 person-years. The risk of developing gout was more than twice as high among individuals who met MetS criteria than in those who did not (adjusted hazard ratio, 2.44).

MetS was defined as the presence of at least two of the following components: hypertriglyceridemia, abdominal obesity, reduced HDL cholesterol, elevated blood pressure, and elevated fasting glucose.

Overall, individuals with all five MetS components had a fivefold increase in gout risk, compared with people who did not have MetS (aHR, 5.24). In an analysis of each component of MetS, hypertriglyceridemia and abdominal obesity showed the strongest association with gout (aHRs of 2.08 and 2.33, respectively).

The impact of MetS on risk of incident gout was greater in younger participants, which suggests that the management of MetS in young people should be emphasized, the researchers said.

In a further analysis of body mass index subgroups, MetS had the greatest impact on gout risk for individuals who were underweight (aHR, 3.82). “In particular, in the underweight group, the risk of gout increased 10-fold when abdominal obesity was present,” the researchers said.

The study was limited by several factors including potential selection bias and potential overestimation of gout incidence because of the use of diagnostic codes, the researchers noted. Other limitations included lack of control for nutritional or dietary risk factors and the inability to include cases that occurred after the study period.

However, findings were strengthened by the large number of participants with MetS who were underweight or normal weight, the researchers wrote. More research on the mechanism of action is needed, but the data suggest that MetS is a key risk factor in the development of gout in young men.

In a second study, published in Arthritis & Rheumatology, Dr. Eun and colleagues examined associations between MetS changes and incident gout in young men. Although previous studies have shown that changes in MetS status can alter the risk of cardiovascular events, atrial fibrillation, end-stage renal disease, and all-cause mortality, the impact of these changes on gout has not been well studied, they said. The researchers used the same study cohort, the National Health Insurance Service database in South Korea. They reviewed data from 1,293,166 individuals aged 20-39 years. Of these, 18,473 were diagnosed with gout for an incidence rate 3.36/1,000 person-years. The researchers compared gout incidence for men who met criteria for MetS at three health checkups and those without MetS.

Overall, patients with MetS at all three checkups had a nearly fourfold higher risk of gout than those who never had MetS, with an adjusted hazard ratio of 3.82, the researchers wrote. The development of MetS over the study period more than doubled the risk of gout, but recovery from MetS reduced incident gout risk by approximately 50% (aHR, 0.52).

In findings similar to the Frontiers in Medicine study, the greatest associations with gout were noted for changes in elevated triglycerides and changes in abdominal obesity; aHRs for development and recovery for elevated triglycerides were 1.74 and 0.56, respectively, and for abdominal obesity, 1.94 and 0.69, respectively.

More research is needed to explore the mechanism by which both abdominal obesity and elevated triglycerides drive the development of gout, the researchers wrote in their discussion.

Also similar to the Frontiers study, the associations among changes in MetS and incident gout were greater for the youngest participants (in their 20s) and in the underweight or normal weight BMI groups.

Limitations of the second study included possible selection bias because of the study population of workplace employees who participated in regular health checks and the lack of data on women or on men aged 40 years and older, the researchers noted. Other limitations included possible misclassification of MetS because of varying health checkup results and drug claims, and lack of data on serum urate, which prevented assessment of hyperuricemia as a cause of gout.

However, the results were strengthened by the large sample size and suggest that MetS is a modifiable risk factor for gout, the researchers concluded.

Neither of the studies received outside funding. The researchers had no financial conflicts to disclose.

Metabolic syndrome is associated with a significantly increased risk for gout in young men, but the risk can be mitigated by improvement in individual components of the syndrome, based on data from a pair of population-based studies totaling more than 4 million individuals.

Gout remains the most common type of inflammatory arthritis in men, and the rate has been rising among younger adults, Yeonghee Eun, MD, PhD, of Sungkyunkwan University, Seoul, South Korea, and colleagues wrote. An increasing body of evidence suggests a link between gout and metabolic syndrome (MetS), but large studies have been lacking, especially in younger adults.

In a study published in Frontiers in Medicine, the researchers reviewed data from 3,569,104 men aged 20-39 years who underwent a health checkup between 2009 and 2012 in South Korea, based on the Korean National Health Insurance Service. The primary outcome of incident gout was identified using claims data. The mean age of the participants was 31.5 years.

Over a mean follow-up of 7.4 years, the incidence of gout was 3.36 per 1,000 person-years. The risk of developing gout was more than twice as high among individuals who met MetS criteria than in those who did not (adjusted hazard ratio, 2.44).

MetS was defined as the presence of at least two of the following components: hypertriglyceridemia, abdominal obesity, reduced HDL cholesterol, elevated blood pressure, and elevated fasting glucose.

Overall, individuals with all five MetS components had a fivefold increase in gout risk, compared with people who did not have MetS (aHR, 5.24). In an analysis of each component of MetS, hypertriglyceridemia and abdominal obesity showed the strongest association with gout (aHRs of 2.08 and 2.33, respectively).

The impact of MetS on risk of incident gout was greater in younger participants, which suggests that the management of MetS in young people should be emphasized, the researchers said.

In a further analysis of body mass index subgroups, MetS had the greatest impact on gout risk for individuals who were underweight (aHR, 3.82). “In particular, in the underweight group, the risk of gout increased 10-fold when abdominal obesity was present,” the researchers said.

The study was limited by several factors including potential selection bias and potential overestimation of gout incidence because of the use of diagnostic codes, the researchers noted. Other limitations included lack of control for nutritional or dietary risk factors and the inability to include cases that occurred after the study period.

However, findings were strengthened by the large number of participants with MetS who were underweight or normal weight, the researchers wrote. More research on the mechanism of action is needed, but the data suggest that MetS is a key risk factor in the development of gout in young men.

In a second study, published in Arthritis & Rheumatology, Dr. Eun and colleagues examined associations between MetS changes and incident gout in young men. Although previous studies have shown that changes in MetS status can alter the risk of cardiovascular events, atrial fibrillation, end-stage renal disease, and all-cause mortality, the impact of these changes on gout has not been well studied, they said. The researchers used the same study cohort, the National Health Insurance Service database in South Korea. They reviewed data from 1,293,166 individuals aged 20-39 years. Of these, 18,473 were diagnosed with gout for an incidence rate 3.36/1,000 person-years. The researchers compared gout incidence for men who met criteria for MetS at three health checkups and those without MetS.

Overall, patients with MetS at all three checkups had a nearly fourfold higher risk of gout than those who never had MetS, with an adjusted hazard ratio of 3.82, the researchers wrote. The development of MetS over the study period more than doubled the risk of gout, but recovery from MetS reduced incident gout risk by approximately 50% (aHR, 0.52).

In findings similar to the Frontiers in Medicine study, the greatest associations with gout were noted for changes in elevated triglycerides and changes in abdominal obesity; aHRs for development and recovery for elevated triglycerides were 1.74 and 0.56, respectively, and for abdominal obesity, 1.94 and 0.69, respectively.

More research is needed to explore the mechanism by which both abdominal obesity and elevated triglycerides drive the development of gout, the researchers wrote in their discussion.

Also similar to the Frontiers study, the associations among changes in MetS and incident gout were greater for the youngest participants (in their 20s) and in the underweight or normal weight BMI groups.

Limitations of the second study included possible selection bias because of the study population of workplace employees who participated in regular health checks and the lack of data on women or on men aged 40 years and older, the researchers noted. Other limitations included possible misclassification of MetS because of varying health checkup results and drug claims, and lack of data on serum urate, which prevented assessment of hyperuricemia as a cause of gout.

However, the results were strengthened by the large sample size and suggest that MetS is a modifiable risk factor for gout, the researchers concluded.

Neither of the studies received outside funding. The researchers had no financial conflicts to disclose.

Metabolic syndrome is associated with a significantly increased risk for gout in young men, but the risk can be mitigated by improvement in individual components of the syndrome, based on data from a pair of population-based studies totaling more than 4 million individuals.

Gout remains the most common type of inflammatory arthritis in men, and the rate has been rising among younger adults, Yeonghee Eun, MD, PhD, of Sungkyunkwan University, Seoul, South Korea, and colleagues wrote. An increasing body of evidence suggests a link between gout and metabolic syndrome (MetS), but large studies have been lacking, especially in younger adults.

In a study published in Frontiers in Medicine, the researchers reviewed data from 3,569,104 men aged 20-39 years who underwent a health checkup between 2009 and 2012 in South Korea, based on the Korean National Health Insurance Service. The primary outcome of incident gout was identified using claims data. The mean age of the participants was 31.5 years.

Over a mean follow-up of 7.4 years, the incidence of gout was 3.36 per 1,000 person-years. The risk of developing gout was more than twice as high among individuals who met MetS criteria than in those who did not (adjusted hazard ratio, 2.44).

MetS was defined as the presence of at least two of the following components: hypertriglyceridemia, abdominal obesity, reduced HDL cholesterol, elevated blood pressure, and elevated fasting glucose.

Overall, individuals with all five MetS components had a fivefold increase in gout risk, compared with people who did not have MetS (aHR, 5.24). In an analysis of each component of MetS, hypertriglyceridemia and abdominal obesity showed the strongest association with gout (aHRs of 2.08 and 2.33, respectively).

The impact of MetS on risk of incident gout was greater in younger participants, which suggests that the management of MetS in young people should be emphasized, the researchers said.

In a further analysis of body mass index subgroups, MetS had the greatest impact on gout risk for individuals who were underweight (aHR, 3.82). “In particular, in the underweight group, the risk of gout increased 10-fold when abdominal obesity was present,” the researchers said.

The study was limited by several factors including potential selection bias and potential overestimation of gout incidence because of the use of diagnostic codes, the researchers noted. Other limitations included lack of control for nutritional or dietary risk factors and the inability to include cases that occurred after the study period.

However, findings were strengthened by the large number of participants with MetS who were underweight or normal weight, the researchers wrote. More research on the mechanism of action is needed, but the data suggest that MetS is a key risk factor in the development of gout in young men.

In a second study, published in Arthritis & Rheumatology, Dr. Eun and colleagues examined associations between MetS changes and incident gout in young men. Although previous studies have shown that changes in MetS status can alter the risk of cardiovascular events, atrial fibrillation, end-stage renal disease, and all-cause mortality, the impact of these changes on gout has not been well studied, they said. The researchers used the same study cohort, the National Health Insurance Service database in South Korea. They reviewed data from 1,293,166 individuals aged 20-39 years. Of these, 18,473 were diagnosed with gout for an incidence rate 3.36/1,000 person-years. The researchers compared gout incidence for men who met criteria for MetS at three health checkups and those without MetS.

Overall, patients with MetS at all three checkups had a nearly fourfold higher risk of gout than those who never had MetS, with an adjusted hazard ratio of 3.82, the researchers wrote. The development of MetS over the study period more than doubled the risk of gout, but recovery from MetS reduced incident gout risk by approximately 50% (aHR, 0.52).

In findings similar to the Frontiers in Medicine study, the greatest associations with gout were noted for changes in elevated triglycerides and changes in abdominal obesity; aHRs for development and recovery for elevated triglycerides were 1.74 and 0.56, respectively, and for abdominal obesity, 1.94 and 0.69, respectively.

More research is needed to explore the mechanism by which both abdominal obesity and elevated triglycerides drive the development of gout, the researchers wrote in their discussion.

Also similar to the Frontiers study, the associations among changes in MetS and incident gout were greater for the youngest participants (in their 20s) and in the underweight or normal weight BMI groups.

Limitations of the second study included possible selection bias because of the study population of workplace employees who participated in regular health checks and the lack of data on women or on men aged 40 years and older, the researchers noted. Other limitations included possible misclassification of MetS because of varying health checkup results and drug claims, and lack of data on serum urate, which prevented assessment of hyperuricemia as a cause of gout.

However, the results were strengthened by the large sample size and suggest that MetS is a modifiable risk factor for gout, the researchers concluded.

Neither of the studies received outside funding. The researchers had no financial conflicts to disclose.

New more aggressive targets for blood pressure and lipids are among the changes to the annual American Diabetes Association (ADA) Standards of Care in Diabetes – 2023.

The document, long considered the gold standard for care of the more than 100 million Americans living with diabetes and prediabetes, was published as a supplement in Diabetes Care. The guidelines are also accessible to doctors via an app; last year’s standards were accessed more than 4 million times.

The standards now advise a blood pressure target for people with diabetes of less than 130/80 mm Hg, and low-density lipoprotein (LDL) cholesterol targets of below 70 mg/dL or no greater than 55 mg/dL, depending on the individual’s cardiovascular risk.

Courtesy Joslin Diabetes Center

“In this year’s version of the ADA Standards of Care – the longstanding guidelines for diabetes management globally – you’ll see information that really speaks to how we can more aggressively treat diabetes and reduce complications in a variety of different ways,” ADA Chief Scientific and Medical Officer Robert A. Gabbay, MD, PhD, said in an interview.

Other changes for 2023 include a new emphasis on weight loss as a goal of therapy for type 2 diabetes; guidance for screening and assessing peripheral arterial disease in an effort to prevent amputations; use of finerenone in people with diabetes and chronic kidney disease; use of approved point-of-care A1c tests; and guidance on screening for food insecurity, along with an elevated role for community health workers.

“The management of type 2 diabetes is not just about glucose,” Dr. Gabbay emphasized, noting that the ADA Standards have increasingly focused on cardiorenal risk as well as weight management. “We need to think about all those things, not just one. We have better tools now that have been helpful in being able to move forward with this.”
 

New targets in cardiovascular disease and risk management

As it has been for the past 6 years, the section on cardiovascular disease and risk management is also endorsed by the American College of Cardiology.

The new definition of hypertension in people with diabetes is ≥ 130 mm Hg systolic or ≥ 80 mm Hg diastolic blood pressure, repeated on two measurements at different times. Among individuals with established cardiovascular disease, hypertension can be diagnosed with one measurement of ≥ 180/110 mm Hg.

The goal of treatment is now less than 130/80 mm Hg if it can be reached safely.

In 2012, easing of the systolic target to 140 mm Hg by the ADA caused some controversy.

But, as Dr. Gabbay explained: “The evidence wasn’t there 10 years ago. We stuck to the evidence at that time, although there was a belief that lower was better. Over the past decade, a number of studies have made it quite clear that there is benefit to a lower target. That’s why we staked out the ground on this.”

The new Standards of Care also has new lipid targets. For people with diabetes aged 40-75 years at increased cardiovascular risk, including those with one or more atherosclerotic risk factors, high-intensity statin therapy is recommended to reduce LDL cholesterol by 50% or more from baseline and to a target of less than 70 mg/dL, in contrast to the previous target of 100 mg/dL.  

To achieve that goal, the document advises to consider adding ezetimibe or a PCSK9 inhibitor to maximally tolerated statin therapy.

For people with diabetes aged 40-75 who have established cardiovascular disease, treatment with high-intensity statin therapy is recommended with the target of a 50% or greater reduction from baseline and an LDL cholesterol level of 55 mg/dL or lower, in contrast to the previous 70 mg/dL.

“That is a lower goal than previously recommended, and based on strong evidence in the literature,” Dr. Gabbay noted.

Here, a stronger recommendation is made for ezetimibe or a PCSK9 inhibitor added to maximal statins.

And for people with diabetes older than 75 years, those already on statins should continue taking them. For those who aren’t, it may be reasonable to initiate moderate-intensity statin therapy after discussion of the benefits and risks.

Another new recommendation based on recent trial data is use of a sodium–glucose cotransporter 2 (SGLT2) inhibitor in people with diabetes and heart failure with preserved, as well as reduced, ejection fraction.
 

Kidney disease guidance updated: SGLT2 inhibitors, finerenone

Another recommendation calls for the addition of finerenone for people with type 2 diabetes who have chronic kidney disease (CKD) with albuminuria and have been treated with the maximum tolerated doses of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) to improve cardiovascular outcomes as well as reduce the risk of CKD progression.

The threshold for initiating an SGLT2 inhibitor for kidney protection has changed to an estimated glomerular filtration rate (eGFR) ≥ 20 mL/min/1.73 m² and urinary albumin ≥ 200 mg/g creatinine (previously ≥ 25 mL/min/1.73 m² and ≥ 300 mg/g, respectively). An SGLT2 inhibitor may also be beneficial in people with a urinary albumin of normal to ≥ 200 mg/g creatinine, but supporting data have not yet been published.

Referral to a nephrologist is advised for individuals with increasing urinary albumin levels or continued decreasing eGFR or eGFR < 30 mL/min/1.73 m².
 

Weight loss, point-of-care testing, food insecurity assessment 

Other changes for 2023 include fresh emphasis on supporting weight loss of up to 15% with the new twincretin tirzepatide (Mounjaro) – approved in the United States in May for type 2 diabetes – added as a glucose-lowering drug with weight loss potential.

A novel section was added with guidance for peripheral arterial disease screening.

And a new recommendation advises use of point-of-care A1c testing for diabetes screening and diagnosis using only tests approved by the Food and Drug Administration.

Also introduced for 2023 is guidance to use community health workers to support the management of diabetes and cardiovascular risk factors, particularly in underserved areas and health systems.

“Community health workers can be a link to help people navigate and engage with the health system for better outcomes,” said Dr. Gabbay.

He added that these professionals are among those who can also assist with screening for food insecurity, another new recommendation. “We talk about screening for food insecurity and tools to use. That shouldn’t be something only dietitians do.”

Dr. Gabbay said he’d like to see more clinicians partner with community health workers. “We’d like to see more of that ... They should be considered part of the health care team,” he said.

Dr. Gabbay has reported serving on advisory boards for Lark, Health Reveal, Sweetch, StartUp Health, Vida Health, and Onduo.

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

New more aggressive targets for blood pressure and lipids are among the changes to the annual American Diabetes Association (ADA) Standards of Care in Diabetes – 2023.

The document, long considered the gold standard for care of the more than 100 million Americans living with diabetes and prediabetes, was published as a supplement in Diabetes Care. The guidelines are also accessible to doctors via an app; last year’s standards were accessed more than 4 million times.

The standards now advise a blood pressure target for people with diabetes of less than 130/80 mm Hg, and low-density lipoprotein (LDL) cholesterol targets of below 70 mg/dL or no greater than 55 mg/dL, depending on the individual’s cardiovascular risk.

Courtesy Joslin Diabetes Center

“In this year’s version of the ADA Standards of Care – the longstanding guidelines for diabetes management globally – you’ll see information that really speaks to how we can more aggressively treat diabetes and reduce complications in a variety of different ways,” ADA Chief Scientific and Medical Officer Robert A. Gabbay, MD, PhD, said in an interview.

Other changes for 2023 include a new emphasis on weight loss as a goal of therapy for type 2 diabetes; guidance for screening and assessing peripheral arterial disease in an effort to prevent amputations; use of finerenone in people with diabetes and chronic kidney disease; use of approved point-of-care A1c tests; and guidance on screening for food insecurity, along with an elevated role for community health workers.

“The management of type 2 diabetes is not just about glucose,” Dr. Gabbay emphasized, noting that the ADA Standards have increasingly focused on cardiorenal risk as well as weight management. “We need to think about all those things, not just one. We have better tools now that have been helpful in being able to move forward with this.”
 

New targets in cardiovascular disease and risk management

As it has been for the past 6 years, the section on cardiovascular disease and risk management is also endorsed by the American College of Cardiology.

The new definition of hypertension in people with diabetes is ≥ 130 mm Hg systolic or ≥ 80 mm Hg diastolic blood pressure, repeated on two measurements at different times. Among individuals with established cardiovascular disease, hypertension can be diagnosed with one measurement of ≥ 180/110 mm Hg.

The goal of treatment is now less than 130/80 mm Hg if it can be reached safely.

In 2012, easing of the systolic target to 140 mm Hg by the ADA caused some controversy.

But, as Dr. Gabbay explained: “The evidence wasn’t there 10 years ago. We stuck to the evidence at that time, although there was a belief that lower was better. Over the past decade, a number of studies have made it quite clear that there is benefit to a lower target. That’s why we staked out the ground on this.”

The new Standards of Care also has new lipid targets. For people with diabetes aged 40-75 years at increased cardiovascular risk, including those with one or more atherosclerotic risk factors, high-intensity statin therapy is recommended to reduce LDL cholesterol by 50% or more from baseline and to a target of less than 70 mg/dL, in contrast to the previous target of 100 mg/dL.  

To achieve that goal, the document advises to consider adding ezetimibe or a PCSK9 inhibitor to maximally tolerated statin therapy.

For people with diabetes aged 40-75 who have established cardiovascular disease, treatment with high-intensity statin therapy is recommended with the target of a 50% or greater reduction from baseline and an LDL cholesterol level of 55 mg/dL or lower, in contrast to the previous 70 mg/dL.

“That is a lower goal than previously recommended, and based on strong evidence in the literature,” Dr. Gabbay noted.

Here, a stronger recommendation is made for ezetimibe or a PCSK9 inhibitor added to maximal statins.

And for people with diabetes older than 75 years, those already on statins should continue taking them. For those who aren’t, it may be reasonable to initiate moderate-intensity statin therapy after discussion of the benefits and risks.

Another new recommendation based on recent trial data is use of a sodium–glucose cotransporter 2 (SGLT2) inhibitor in people with diabetes and heart failure with preserved, as well as reduced, ejection fraction.
 

Kidney disease guidance updated: SGLT2 inhibitors, finerenone

Another recommendation calls for the addition of finerenone for people with type 2 diabetes who have chronic kidney disease (CKD) with albuminuria and have been treated with the maximum tolerated doses of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) to improve cardiovascular outcomes as well as reduce the risk of CKD progression.

The threshold for initiating an SGLT2 inhibitor for kidney protection has changed to an estimated glomerular filtration rate (eGFR) ≥ 20 mL/min/1.73 m² and urinary albumin ≥ 200 mg/g creatinine (previously ≥ 25 mL/min/1.73 m² and ≥ 300 mg/g, respectively). An SGLT2 inhibitor may also be beneficial in people with a urinary albumin of normal to ≥ 200 mg/g creatinine, but supporting data have not yet been published.

Referral to a nephrologist is advised for individuals with increasing urinary albumin levels or continued decreasing eGFR or eGFR < 30 mL/min/1.73 m².
 

Weight loss, point-of-care testing, food insecurity assessment 

Other changes for 2023 include fresh emphasis on supporting weight loss of up to 15% with the new twincretin tirzepatide (Mounjaro) – approved in the United States in May for type 2 diabetes – added as a glucose-lowering drug with weight loss potential.

A novel section was added with guidance for peripheral arterial disease screening.

And a new recommendation advises use of point-of-care A1c testing for diabetes screening and diagnosis using only tests approved by the Food and Drug Administration.

Also introduced for 2023 is guidance to use community health workers to support the management of diabetes and cardiovascular risk factors, particularly in underserved areas and health systems.

“Community health workers can be a link to help people navigate and engage with the health system for better outcomes,” said Dr. Gabbay.

He added that these professionals are among those who can also assist with screening for food insecurity, another new recommendation. “We talk about screening for food insecurity and tools to use. That shouldn’t be something only dietitians do.”

Dr. Gabbay said he’d like to see more clinicians partner with community health workers. “We’d like to see more of that ... They should be considered part of the health care team,” he said.

Dr. Gabbay has reported serving on advisory boards for Lark, Health Reveal, Sweetch, StartUp Health, Vida Health, and Onduo.

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

New more aggressive targets for blood pressure and lipids are among the changes to the annual American Diabetes Association (ADA) Standards of Care in Diabetes – 2023.

The document, long considered the gold standard for care of the more than 100 million Americans living with diabetes and prediabetes, was published as a supplement in Diabetes Care. The guidelines are also accessible to doctors via an app; last year’s standards were accessed more than 4 million times.

The standards now advise a blood pressure target for people with diabetes of less than 130/80 mm Hg, and low-density lipoprotein (LDL) cholesterol targets of below 70 mg/dL or no greater than 55 mg/dL, depending on the individual’s cardiovascular risk.

Courtesy Joslin Diabetes Center

“In this year’s version of the ADA Standards of Care – the longstanding guidelines for diabetes management globally – you’ll see information that really speaks to how we can more aggressively treat diabetes and reduce complications in a variety of different ways,” ADA Chief Scientific and Medical Officer Robert A. Gabbay, MD, PhD, said in an interview.

Other changes for 2023 include a new emphasis on weight loss as a goal of therapy for type 2 diabetes; guidance for screening and assessing peripheral arterial disease in an effort to prevent amputations; use of finerenone in people with diabetes and chronic kidney disease; use of approved point-of-care A1c tests; and guidance on screening for food insecurity, along with an elevated role for community health workers.

“The management of type 2 diabetes is not just about glucose,” Dr. Gabbay emphasized, noting that the ADA Standards have increasingly focused on cardiorenal risk as well as weight management. “We need to think about all those things, not just one. We have better tools now that have been helpful in being able to move forward with this.”
 

New targets in cardiovascular disease and risk management

As it has been for the past 6 years, the section on cardiovascular disease and risk management is also endorsed by the American College of Cardiology.

The new definition of hypertension in people with diabetes is ≥ 130 mm Hg systolic or ≥ 80 mm Hg diastolic blood pressure, repeated on two measurements at different times. Among individuals with established cardiovascular disease, hypertension can be diagnosed with one measurement of ≥ 180/110 mm Hg.

The goal of treatment is now less than 130/80 mm Hg if it can be reached safely.

In 2012, easing of the systolic target to 140 mm Hg by the ADA caused some controversy.

But, as Dr. Gabbay explained: “The evidence wasn’t there 10 years ago. We stuck to the evidence at that time, although there was a belief that lower was better. Over the past decade, a number of studies have made it quite clear that there is benefit to a lower target. That’s why we staked out the ground on this.”

The new Standards of Care also has new lipid targets. For people with diabetes aged 40-75 years at increased cardiovascular risk, including those with one or more atherosclerotic risk factors, high-intensity statin therapy is recommended to reduce LDL cholesterol by 50% or more from baseline and to a target of less than 70 mg/dL, in contrast to the previous target of 100 mg/dL.  

To achieve that goal, the document advises to consider adding ezetimibe or a PCSK9 inhibitor to maximally tolerated statin therapy.

For people with diabetes aged 40-75 who have established cardiovascular disease, treatment with high-intensity statin therapy is recommended with the target of a 50% or greater reduction from baseline and an LDL cholesterol level of 55 mg/dL or lower, in contrast to the previous 70 mg/dL.

“That is a lower goal than previously recommended, and based on strong evidence in the literature,” Dr. Gabbay noted.

Here, a stronger recommendation is made for ezetimibe or a PCSK9 inhibitor added to maximal statins.

And for people with diabetes older than 75 years, those already on statins should continue taking them. For those who aren’t, it may be reasonable to initiate moderate-intensity statin therapy after discussion of the benefits and risks.

Another new recommendation based on recent trial data is use of a sodium–glucose cotransporter 2 (SGLT2) inhibitor in people with diabetes and heart failure with preserved, as well as reduced, ejection fraction.
 

Kidney disease guidance updated: SGLT2 inhibitors, finerenone

Another recommendation calls for the addition of finerenone for people with type 2 diabetes who have chronic kidney disease (CKD) with albuminuria and have been treated with the maximum tolerated doses of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) to improve cardiovascular outcomes as well as reduce the risk of CKD progression.

The threshold for initiating an SGLT2 inhibitor for kidney protection has changed to an estimated glomerular filtration rate (eGFR) ≥ 20 mL/min/1.73 m² and urinary albumin ≥ 200 mg/g creatinine (previously ≥ 25 mL/min/1.73 m² and ≥ 300 mg/g, respectively). An SGLT2 inhibitor may also be beneficial in people with a urinary albumin of normal to ≥ 200 mg/g creatinine, but supporting data have not yet been published.

Referral to a nephrologist is advised for individuals with increasing urinary albumin levels or continued decreasing eGFR or eGFR < 30 mL/min/1.73 m².
 

Weight loss, point-of-care testing, food insecurity assessment 

Other changes for 2023 include fresh emphasis on supporting weight loss of up to 15% with the new twincretin tirzepatide (Mounjaro) – approved in the United States in May for type 2 diabetes – added as a glucose-lowering drug with weight loss potential.

A novel section was added with guidance for peripheral arterial disease screening.

And a new recommendation advises use of point-of-care A1c testing for diabetes screening and diagnosis using only tests approved by the Food and Drug Administration.

Also introduced for 2023 is guidance to use community health workers to support the management of diabetes and cardiovascular risk factors, particularly in underserved areas and health systems.

“Community health workers can be a link to help people navigate and engage with the health system for better outcomes,” said Dr. Gabbay.

He added that these professionals are among those who can also assist with screening for food insecurity, another new recommendation. “We talk about screening for food insecurity and tools to use. That shouldn’t be something only dietitians do.”

Dr. Gabbay said he’d like to see more clinicians partner with community health workers. “We’d like to see more of that ... They should be considered part of the health care team,” he said.

Dr. Gabbay has reported serving on advisory boards for Lark, Health Reveal, Sweetch, StartUp Health, Vida Health, and Onduo.

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