In a late-breaking abstract1 presented at the 2023 American Heart Association Scientific Sessions, researchers presented data demonstrating that semaglutide 2.4 mg (Wegovy) is associated with a statistically significant 20% risk reduction in major adverse cardiovascular events (MACE) in adults with established cardiovascular disease (CVD) and overweight or obesity without diabetes.2,3

Data were published simultaneously in the New England Journal of Medicine.4

Semaglutide, a long-acting glucagon-like peptide 1 (GLP-1) medication prescribed for individuals with type 2 diabetes, has made headlines both in and out of the health care industry following its June 2021 FDA approval for chronic weight management, adjunct to diet and exercise, for adults with overweight or obesity and at least 1 weight-related comorbidity.5,6 At the time of the drug’s approval, it was the first and only once-weekly GLP-1 receptor agonist approved for this patient population. In December 2022, the FDA approved the drug for the treatment of obesity in adolescents aged 12 years and older.7

“For the first time, we have evidence that semaglutide 2.4 mg improves cardiovascular outcomes in at-risk patients with BMI of 27 and above with established CVD, without diabetes,” said lead study author Michael Lincoff, MD, vice chair for research in the Department of Cardiovascular Medicine and an interventional cardiologist in the Sydell and Arnold Miller Family Heart, Vascular, and Thoracic Institute, both at the Cleveland Clinic. “The 3-point MACE risk reduction observed in SELECT suggests the potential for a new option in obesity treatment, addressing some of the leading causes of preventable death worldwide.

In the SELECT clinical trial (NCT03574597), researchers sought to demonstrate if semaglutide—previously shown to reduce MACE risk in individuals with type 2 diabetes—could also reduce that risk in adults with overweight and obesity in those without diabetes. This multicenter, randomized, double-blind, placebo-controlled, event-driven superiority trial enrolled 17,604 patients aged 45 years or older with pre-existing CVD and a body mass index (BMI) of 27 kg/m or higher who did not have diabetes. Participants were randomly assigned to receive either once-weekly subcutaneous semaglutide 2.4 mg (n=8803) or placebo (n=8801), as well as standard of care for cardiovascular disease, including any cholesterol, antiplatelet, or beta blocker therapies.

The primary cardiovascular efficacy endpoint was any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Changes in body weight, HbA1c, and other cardiovascular risk factors from randomization to week 104 were also measured.

Analyses of the 3 MACE components demonstrated that the risk of nonfatal myocardial infarction was reduced by 28%, cardiovascular death by 15%, and nonfatal stroke by 7% vs placebo (HR, 0.72, 0.85, and 0.93, respectively; the reduction in cardiovascular death risk was not statistically significant over the length of the trial). Beneficial effects were also consistently noted across other measured cardiovascular endpoints. Analysis of confirmatory secondary endpoints—including death from cardiovascular causes, a composite heart failure endpoint (death from cardiovascular disease, hospitalization, or urgent medical visit), and death from any cause—indicated that the risk of composite heart failure events and death from any cause were reduced by 18% and 19%, respectively, vs placebo (HRs, 0.82 and 0.81).

Participants in the semaglutide group also demonstrated an average reduction in body weight of 9.4%, vs 0.9% in the placebo group.

Although rates of serious adverse events were lower in the semaglutide group (6.5% vs 8% in placebo), the semaglutide group had a slightly higher rate of adverse events, such as gastrointestinal and gallbladder-related disorders, that led to permanent treatment discontinuation.

Some important study limitations were noted, including the focus of the study population on adults with preexisting CVD; the trial, therefore, did not evaluate the effects of semaglutide on the primary prevention of cardiovascular events in adults with overweight or obesity without CVD. Another limitation includes the lack of diversity in the study population, where only 27.7% of participants were women and 3.8% were Black, relative to the general population.

“It’s been estimated that within 10 years, over half of the world’s population will have overweight or obesity,” Lincoff said. “And while GLP-1 medications are frequently prescribed for patients with vascular disease and type 2 diabetes, there is a significant number of people who do not have type 1 or type 2 diabetes but do have vascular disease and overweight or obesity for whom these medications are often not available,” due to issues ranging from care access to insurance coverage, among other factors.

“Importantly, our results indicate the magnitude of cardiovascular risk reduction with semaglutide among people without [diabetes] is the same as what we have seen in people with type 2 diabetes,” Lincoff continued. “Our findings expand the opportunity to treat patients who have overweight or obesity and existing heart disease without type 1 or type 2 diabetes, and we have a chance to significantly reduce their risk of a secondary cardiovascular event, including death.”

Semaglutide manufacturer Novo Nordisk has filed for a label update in both the United States and the European Union to include an indication for MACE risk reduction in adults with a BMI greater than 27 kg/m2 and established cardiovascular disease. The FDA granted priority review for the addition of SELECT clinical trial data to the semaglutide label, and a decision is expected in 2024.

Disclosures: Lincoff is a paid consultant for Novo Nordisk. Multiple other study authors reported relationships with Novo Nordisk and other industry stakeholders. For the full list of disclosures, please see the full text of the study.

  1. Semaglutide and cardiovascular outcomes in patients with overweight or obesity who do not have diabetes. Presented at: American Heart Association 2023 Scientific Sessions; November 11-13, 2023; Philadelphia, PA. Abstract LBS.01.
  2. Major CVD event risk cut by 20% in adults without diabetes, with overweight or obesity. News release. American Heart Association. November 11, 2023. Accessed November 14, 2023.
  3. Novo Nordisk A/S: semaglutide 2.4 mg (Wegovy) cardiovascular outcomes data presented at American Heart Association Scientific Sessions and simultaneously published in New England Journal of Medicine. November 11, 2023. Accessed November 14, 2023.
  4. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al; for the SELECT Trial Investigators. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. Published online ahead of print November 11, 2023. doi:10.1056/NEJMoa2307563
  5. FDA approves new drug treatment for chronic weight management, first since 2014. News release. FDA. June 4, 2021. Accessed November 14, 2023.
  6. Wegovy (semaglutide 2.4 mg), the first and only once-weekly GLP-1 therapy for weight management, approved in the US. News release. Novo Nordisk. June 4, 2023. Accessed November 14, 2023.
  7. FDA approves once-weeklyl Wegovy injection for the treatment of obesity in teens aged 12 years and older. News release. Novo Nordisk. December 23, 2022. Accessed November 14, 2023.