Semaglutide and cardiovascular outcome in overweight or obesity without diabetes – The SELECT trial

Presented at the AHA Scientific Sessions 2023 by: Michael Lincoff, MD - Cleveland, OH, USA

Introduction and methods

Background

GLP-1RAs have shown to reduce the risk of MACE in patients with T2D. However, it is unknown whether GLP-1RA reduce the risk of CV events in individuals with overweight or obesity without diabetes.

Aim of the study

The SELECT trial aimed to investigate whether semaglutide 2.4 mg subcutaneous injection once weekly reduces the incidence of CV outcomes among patients with pre-existing CVD and overweight or obesity, but who do not have diabetes.

Methods

SELECT was a randomized, double-blind, placebo-controlled superiority trial which was conducted at 804 sites in 41 countries. A total of 17,604 patients were randomized in a 1:1 ratio to receive subcutaneous semaglutide 2.4 mg once weekly or matching placebo. Inclusion criterial were age ≥ 45 years, BMI ≥ 27 kg/m² and established CVD (defined as prior MI, stroke or symptomatic PAD). Patients with a history of diabetes, HbA1c ≥ 6.5%, or treatment with glucose-lowering agent were excluded. Patients could also not be enrolled if they had severe heart failure, cardiac event or stroke within the prior 60 days or if they had a history of pancreatitis, severe psychiatric disorder, end stage kidney disease, or malignancy. The mean follow-up was 39.8 months.

Outcomes

The primary endpoint was defined as CV death, nonfatal MI or nonfatal stroke. Three confirmatory secondary endpoints were analyzed in a hierarchical fashion. The first was CV death, the second a heart failure composite endpoint (defined as CV death or hospitalization or an urgent medical visit for heart failure), and the third was any death.

Main results

CV outcomes

• Semaglutide reduced the primary endpoint by 20% compared to placebo (HR 0.80, 95%CI 0.72-0.90, P<0.001).
• The first confirmatory secondary endpoint of CV death did not reach statistical significance (HR 0.85, 95%CI 0.71-1.01, P=0.07). The HR for the heart failure composite endpoint was 0.82 (95%CI 0.71-0.96) and 0.81 for the endpoint of any death (95%CI 0.71-0.93).

Metabolic outcomes

• A lower rate of patients on semaglutide progressed to diabetes compared to patients on placebo (3.5% vs. 12.0%, HR 0.27, 95%CI 0.24-0.31).
• From randomization to week 104, Semaglutide reduced body weight (difference between groups: -8.5%), waist circumference (difference: -6.5 cm), SBD (difference: -3.3 mm Hg), hsCRP (difference: -37.8%) and triglycerides (difference: -15.6%).

Safety outcomes

• Serious adverse events occurred more often in the placebo group (36.4%), compared to the semaglutide group (33.4%, P<0.001).
• There were more adverse events leading to drug discontinuation in the semaglutide group (16.6%) compared to the placebo group (8.2%, P<0.001). This difference was driven by differences in gastrointestinal side effects (10.0% vs 2.0%, P<0.001). There was also a slightly higher risk of gallbladder-related events (2.8% vs 2.3%, P=0.04).
• Serious adverse events related to gastrointestinal disease or pancreatitis or other adverse events of special interest did not occur more frequently with semaglutide compared to placebo.

Conclusion

The results of the SELECT trial showed that once weekly subcutaneous semaglutide 2.4 mg reduced the risk of the primary outcome of CV death, MI, or stroke by 20% in patients with pre-existing CVD and overweight or obesity, but who do not have diabetes.

- Our reporting is based on the information provided at the AHA Scientific Session 2023-

The results of this study were simultaneously published in N. Engl. J. Med. Watch a video with Michael Lincoff about the SELECT trial