Semaglutide 2.4 mg (Wegovy) Reduces Cardiovascular Risk in Overweight/Obesity with CVD

A. Michael Lincoff, MD

Credit: Matt Kohlmann, Cleveland Clinic

Results of the SELECT study confirm the cardiovascular benefit of semaglutide 2.4 mg (Wegovy) in people with overweight or obesity and preexisting cardiovascular disease.¹

Presented at the American Heart Association Scientific Sessions 2023, results of the study provide further insight into a 20% relative risk reduction in cardiovascular events revealed in Novo Nordisk’s announcement of topline results in August 2023, with full results suggesting use was associated with a trend toward benefit for reducing cardiovascular death, a composite heart failure endpoint, and all-cause mortality.^1,2

“Our results indicate the magnitude of cardiovascular risk reduction with semaglutide among people without type 1 or type 2 diabetes is the same as what we have seen in people with type 2 diabetes,” explained A. Michael Lincoff, MD, vice chairman for research of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine and an interventional cardiologist in the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute at the Cleveland Clinic.³ “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.”

Few, if any, agents have simultaneously captured the attention of the medical community and general public in the same manner as semaglutide has in 2023. After semaglutide 2.4 mg scored for chronic weight management in adults with obesity or overweight with at least one weight-related condition in June 2021, many looked forward to the results of the SELECT trial, which had been launched by Novo Nordisk in 2018, to confirm whether or not the effects might confer cardiovascular benefits.^1,4

Billed as the largest and longest trial of semaglutide in adults without type 1 or type 2 diabetes, SELECT was a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial of patients aged 45 years of age or older who had preexisting cardiovascular disease and a BMI of 27 kg/m2 or greater without a history of diabetes. The primary endpoint of interest for the trial was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis.^1,3

A total of 17,604 patients were enrolled, with 8803 randomized to semaglutide and 8801 randomized to placebo. The mean duration of exposure to the assigned interventions was 34.2 (SD, 13.7) months and the mean duration of follow-up was 39.8 (SD, 9.4) years. Per trial protocol, semaglutide was delivered once weekly and started in a 0.24 mg dose, titrated to the target dose of 2.4 mg after 16 weeks.¹

The overall study cohort had a mean age of 61.6 (Standard Deviation [SD], 8.9) years and 72.3% were male. Investigators noted the cohort had a mean baseline BMI of 33.3 (SD, 5.0) and 71.5% met the BMI criterion for obesity. Analysis of baseline medication use found 90.1% were taking lipid-lowering medications, 86.2% were taking platelet-aggregation inhibitors, 70.2% were taking beta-blockers, 45.0% were taking ACE inhibitors, and 29.5% were taking ARBs.¹

Analysis of outcome events suggested a primary outcome event was observed in 6.5% of the semaglutide group and 8.0% of the placebo group (HR, 0.80; 95% Confidence interval [CI], 0.72 to 0.90; P <.001). Further analysis indicated the mean change in body weight observed in the trial was –9.39% with semaglutide and –0.88% with placebo (estimated treatment difference, –8.51 percentage points; 95% CI, –8.75 to –8.27).¹

Analysis of secondary endpoints pointed to nonsignificant trends towards benefit for the following outcomes:¹

• Cardiovascular death: HR, 0.85; 95% CI, 0.71 to 1.01; P=.07
• Heart failure hospitalization or urgent medical visit: HR, 0.82; 95% CI, 0.71 to 0.96
• All-cause mortality: HR, 0.81; 95% CI, 0.71 to 0.93
• HbA1c of 6.5% or greater: HR, 0.27; 95% CI, 0.24 to 0.31

The trial’s safety analysis revealed adverse gastrointestinal events occurred among 10% of the semaglutide group and 2.0% of the semaglutide group (P <.001). Overall, serious adverse events were observed among 33.4% of the semaglutide group and 36.4% among the placebo group (P <.001). However, investigators also pointed out adverse events leading to permanent discontinuation of assigned intervention occurred among 16.6% of the semaglutide group and 8.2% of the placebo group (P <.001).¹

In an editorial published in the New England Journal of Medicine, Amit Khera, MD, of the University of Texas Southwestern Medical Center, and Tiffany M. Powell‑Wiley, MD, of the National Institutes of Health, applauded the results of the trial and efforts of investigators—noting the results signal the start of new age in cardiometabolic disease management.⁵

“We are in a new era of treating obesity and cardiometabolic risk with a growing armamentarium of options. The SELECT trial provides evidence of improved cardiovascular disease outcomes with GLP-1 receptor agonists in the absence of diabetes,” wrote the pair.⁵ “For patients with atherosclerotic cardiovascular disease and overweight or obesity, GLP-1 receptor agonist therapy with semaglutide joins the list of established therapies that form the basis of our pharmacologic strategies for reducing the risk of cardiovascular disease.”

References:

1. Lincoff AM, Brown-Frandsen K, Calhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. New England Journal of Medicine. 2023; DOI: 10.1056/NEJMoa2307563
2. Campbell P. Select trial shows semaglutide 2.4 mg could reduce cardiovascular risk. HCP Live. August 8, 2023. Accessed November 11, 2023. https://www.hcplive.com/view/select-trial-shows-semaglutide-2-4-mg-could-reduce-cardiovascular-risk.
3. AHA Newsroom. Major CVD event risk cut by 20% in adults without diabetes, with overweight or obesity. American Heart Association. Accessed November 11, 2023.https://newsroom.heart.org/news/major-cvd-event-risk-cut-by-20-in-adults-without-diabetes-with-overweight-or-obesity.
4. Campbell P. Semaglutide (Wegovy) approved for chronic weight management in patients with obesity or overweight. HCP Live. June 4, 2021. Accessed August 24, 2023. https://www.hcplive.com/view/semaglutide-approved-for-chronic-weight-management-in-patients-with-obesity-or-overweight.
5. Kehra AM, Powell-Wiley TM. SELECTing Treatments for Cardiovascular Disease — Obesity in the Spotlight. New England Journal of Medicine. 2023; DOI: 10.1056/NEJMe2312646