Do GLP-1 Receptor Agonists Improve Cardiovascular Health Independent of Weight Loss?

Hackensack University Medical Center physician perspective on the SELECT trial

The SELECT trial, published in The New England Journal of Medicine on November 11, reported that the GLP-1 receptor agonist semaglutide reduces risk of cardiovascular events in patients with obesity–but that’s not the question we ought to be asking, suggests Nathaniel Lebowitz, M.D., cardiologist, Hackensack University Medical Center, and assistant clinical professor of Cardiology at Hackensack Meridian School of Medicine. He offers the following perspective on the published results:

Because of the media attention this trial has received, physicians are fielding questions from patients about whether they should be on semaglutide (brand names Ozempic, indicated for type II diabetes, and Wegovy, indicated for weight loss in non-diabetic patients with a BMI>30, or >27 with additional risk factors).

Semaglutide is a GLP-1 receptor agonist, a drug class shown through several trials to effectively promote weight loss, improve glycemic control and several metabolic metrics. The mechanism of action is not completely clear but has been implicated in a host of areas relating to appetite, inflammation and metabolism. Theories with varying degrees of evidence exist relating to pleiotropic effects beyond weight loss and glucose metabolism.

The interest of cardiologists is drawn by the indication for cardiovascular protection in patients with Type 2 diabetes mellitus. Over the years, cardiovascular protection trials have prompted editorials and even guideline recommendations to choose, whenever possible, diabetic drugs with evidence of CV benefit and to avoid sulfonylureas in patients with established ASCVD. Drugs with CV protection data include pioglitazone, metformin, semaglutide and others. The CV protection indication for semaglutide stems from a meta-analysis published in 2021 (Lancet Diabetes Endocrinol 2021 Oct;9(10):653-662).

This meta-analysis of GLP-1 receptor agonist trials reported a 14% MACE reduction in diabetics compared to placebo. However, there has been no single large-scale trial looking at CV endpoints in non-diabetics. The study design was double-blind, placebo controlled with multiple centers.

17,604 patients were enrolled, aged >45 (mean age 61.6±8.9 years) with a BMI >27 (mean BMI 33.3±5.0) and established cardiovascular disease. Participants were randomized in a 1:1 ratio to receive either placebo or semaglutide (2.4 mg every 7 days as the maximal dose, with a 16-week titration period starting at 0.24 mg) for a mean duration of 34.2±13.7 months.

The primary endpoint was a composite of non-fatal MI, stroke and CV death (MACE). The primary endpoint occurred in 6.5% in the semaglutide group (569 of 8,803 patients) and 8.0% in the placebo group (701 of 8,801 patients), a relative risk reduction of 20% (HR 0.80; 95% CI: 0.72-0.90; P<0.001).>

A secondary endpoint of heart failure plus all-cause mortality achieved an RRR of 18% (HR 0.82; 95% CI: 0.71-0.96) and 19% (0.81; 95% CI: 0.71-0.93), respectively. Secondary efficacy endpoints for heart failure and all-cause mortality likewise favored the semaglutide group, with hazard ratios of 0.82 (95% CI: 0.71-0.96) and 0.81 (95% CI: 0.71-0.93), respectively. An additional secondary endpoint for death from cardiovascular causes followed a similar trend but did not achieve statistical significance between groups (2.5% of patients on semaglutide versus 3.0% on placebo; HR: 0.85; 95% CI: 0.71-1.01; P=0.07).

By itself, CV death trended to favor semaglutide but did not reach statistical significance. As we would expect, the semaglutide group lost a significant amount of body weight, approximately 10% of body weight at 104 weeks post randomization compared to less than 1% in the placebo group. Interestingly, as this was a “real-world” study, weight loss was less than that in the original phase 3 clinical trials, mirroring what we see in clinical practice. Also, like real-world practice, 16.6% of patients had to discontinue the drug due to (mostly GI) side effects compared to 8.2% of placebo group patients (p< />

Based on this study, we can say with certainty that treatment with semaglutide reduced CV risk in non-diabetics at high risk of CVD who are overweight or obese. It's true that a 20% RRR places the drug in a rarefied group with statins and PCSK9 Inhibitors for CV risk reduction.

The real question, however, is whether that risk reduction can be attributed to the drug or whether the same effects could be achieved with weight loss from other means, such as calorie restriction, exercise, bariatric surgery, etc. Weight loss with these non-drug interventions clearly reduces CV risk, with improvements in a host of obesity-related pathologic states, including hypertension, hyperlipidemia and sleep apnea to name but a few.

Studies with bariatric surgery for morbid obesity have shown as high as a 60% RRR of CVD, admittedly with greater percent of body weight lost. The authors make a weak attempt to address this question by noting that the curves diverge early, but a close reading reveals that most of the weight loss also occurs quite early in the trial. The authors have not addressed this most critical question, because we would have expected a positive result due to weight loss.

What we still don’t know is whether there would be additional benefit beyond that achieved with weight loss alone. Further considerations that might have pragmatic implications in clinical practice include loss of muscle mass that I observe in addition to loss of fat mass. As sarcopenia occurs at ages as early as the 50s, ultimately leading to frailty with debility related states in the elderly, if other weight loss modalities that include calorie restriction with exercise could achieve similar CV outcomes, then that would certainly be preferable.

This is all speculation as a study that answers the central question really needs to be done. Namely, a weight loss intervention study with non-drug weight loss modalities compared to a similar degree of weight loss with semaglutide. It’s a critical question because if semaglutide can significantly reduce CV risk beyond that achieved with weight loss alone, then it would be a dramatic finding that might even lead to an indication for the treatment of CVD.

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