Semaglutide reduces CV risk in overweight/obese patients without T2D

Treatment with semaglutide reduced the risk of major adverse cardiovascular events (MACE) among overweight/obese patients with pre-existing cardiovascular (CV) disease but without type 2 diabetes (T2D), according to the SELECT trial presented at AHA 2023.

At a mean follow-up of 39.8 months, the primary composite endpoint of CV death, nonfatal myocardial infarction, or nonfatal stroke occurred in 6.5 percent of patients who received semaglutide compared with 8.0 percent of those who received placebo (hazard ratio [HR], 0.80; p<0.001). [AHA 2023, abstract LBS.01]

“Notably, the difference in rates between the two treatment groups began to emerge very early after the initiation of treatment … and was concordant across a variety of different subgroups that were tested and for the different CV endpoints,” said lead author Dr Michael Lincoff from Cleveland Clinic in Cleveland, Ohio, US.

“High body mass index (BMI) is estimated to have accounted for 4 million deaths in 2015, more than two-thirds of which were caused by CV disease and yet no lifestyle or pharmacologic weight management strategy has been shown to reduce the excess CV risk associated with overweight and obesity,” Lincoff said.

“For the first time, this trial demonstrated that treating CV disease in the setting of obesity without T2D decreases MACE by 20 percent,” said discussant Associate Professor Ania Jastreboff from Yale School of Medicine in New Haven, Connecticut, US.

“Therefore, semaglutide 2.4 mg is the first weight management therapy proven in a rigorous randomized controlled trial to reduce the risk of CV events, which establishes overweight and obesity as a modifiable risk factor for CV disease, and as a treatment, it could well be applied much more broadly to the expanding population of patients with overweight or obesity and CV disease,” Lincoff noted.

This multicentre, double-blind, placebo-controlled, event-driven superiority trial analysed 17,604 patients (mean age 61.6 years, 28 percent female) who were overweight/obese (body mass index of ≥27 kg/m²) and had pre-existing CV disease but without a history of diabetes. Participants were randomly assigned to receive either once-weekly subcutaneous semaglutide 2.4 mg (n=8,803) or placebo (n=8,801).

With regard to confirmatory secondary endpoints, treatment with semaglutide reduced the incidence of death from CV causes (2.5 percent vs 3.0 percent; HR, 0.85), heart failure (HF) composite endpoint (defined as death from CV causes or hospitalization or an urgent medical visit for HF, 3.4 percent vs 4.1 percent; HR, 0.82), and death from any cause (4.3 percent vs 5.2 percent; HR, 0.81) compared with placebo.

Semaglutide recipients also had a lower risk of developing diabetes (3.5 percent vs 12.0 percent; HR, 0.27) or prediabetes (21.3 percent vs 50.3 percent; HR, 0.33) than the placebo recipients.

There was also a greater decrease in body weight (9.4 percent vs 0.88 percent; estimated treatment difference [ETD], –8.51 percentage points) and waist circumference (7.6 vs 1.0 cm; ETD, –6.5 cm) in the semaglutide group vs the placebo group.

Greater reductions in systolic blood pressure, high sensitivity C-reactive protein, and triglycerides (ETD, 3.3 mg Hg, 37.8 percent, and 15.6 percent, respectively) were also observed with semaglutide over placebo.

In terms of safety, serious adverse events (AEs) occurred at a lower rate in the semaglutide group vs the placebo group (33.4 percent vs 36.4 percent; p<0.001). However, more AEs leading to treatment discontinuation was observed with semaglutide vs placebo (16.6 percent vs 8.2 percent). “This difference was driven almost entirely by differences in gastrointestinal side effects,” said Lincoff.

“Nonetheless, and importantly, serious AEs related to gastrointestinal disease or pancreatitis, or other AEs of special interest did not occur more frequently with semaglutide … There were no unexpected safety findings … with semaglutide in this largest and longest trial, with the most data for now, for this group of patients,” he added.

“The SELECT trial is a turning point. Treatment with semaglutide demonstrates clear secondary CV benefit in people with obesity without diabetes … The trial builds on existing literature demonstrating safety and CV benefit in people with diabetes and now expands it to people with obesity,” said Jastreboff.

“When treating CV disease, select treating obesity,” she added.