The SELECT Trial: A Brief Summary

Podcast Transcript

Announcer:

Welcome to Cleveland Clinic Cardiac Consult, brought to you by the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute at Cleveland Clinic.

Michael Lincoff, MD:

Hello. I'm Michael Lincoff, the Vice Chair for Research in the Department of Cardiovascular Medicine at the Cleveland Clinic. And today we're going to talk about the SELECT Trial, which I had the privilege of recently presenting at the American Heart Association meeting. The background for this is that more than half of the world's population is expected to have overweight or obesity by 2035 and overweight and obesity is clearly associated with an increased risk of cardiovascular complications. Yet there's been no lifestyle or drug intervention for overweight or obesity that's been shown to reduce cardiovascular complications. GLP-1 receptor agonists do reduce the risk of major adverse cardiac events in patients with type 2 diabetes. Although these agents reduce weight, it's unknown whether they can reduce the risk of cardiovascular events among patients who do not have diabetes. So, the SELECT Trial was a large-scale randomized placebo-controlled trial designed to evaluate whether or not semaglutide, a potent GLP-1 receptor agonists would reduce the risk of cardiovascular events among patients with preexisting cardiovascular disease, overweight and obesity, but who did not have diabetes.

This is a large-scale multicenter trial conducted in 41 countries throughout the world. The trial included patients who were 45 years or older, had a body mass index of 27 kilograms per meter squared or greater, and had established cardiovascular disease defined as either having a prior myocardial infarction, a prior stroke, or symptomatic peripheral artery disease. Patients could not be enrolled if they had a history of type one or type two diabetes or a hemoglobin A1C of greater than 6.5 percent at enrollment or treatment with a glucose lowering drug. They were randomized in a one-to-one ratio to receive placebo or semaglutide with dose escalation to the weight loss dose of 2.4 milligrams once weekly subcutaneously. Importantly, these drugs were administered in addition to the standards of care for cardiovascular disease. So, most patients were on statins and antiplatelet agents, and baseline characteristics were well controlled in the treatment groups.

The patients, approximately 27 percent were women, about 71 percent met body mass index criteria for obesity, that is over 30, and about 67 percent met hemoglobin A1C criteria for pre-diabetes. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. And this occurred in 8 percent of patients in the placebo group over an average of 40 months follow-up as compared to 6.5 percent of patients in the semaglutide group. So, this represented a 0.8 hazard ratio or a 20 percent relative risk reduction, highly significant, with a P value of less than 0.001 for superiority of semaglutide. The magnitude of this treatment effect was concordant across all of the subgroups of patients that were tested, including men or women, baseline age, baseline body mass index and whether or not they had pre-diabetes at baseline.

Secondary endpoints included a cardiovascular mortality endpoint in which the hazard ratio was 0.85 did not reach statistical significance, a heart failure composite of cardiovascular death or hospitalization or urgent visit for heart failure for which the hazard ratio was 0.82 and the upper limit of the confidence interval was 0.96. And then death from any cause for which the hazard ratio was 0.81, representing a 19 percent reduction with a hazard ratio of 0.93. The other endpoints, cardiovascular endpoints were concordant. We saw the largest reduction in myocardial infarction for which the hazard ratio was 0.72, a 28 percent risk reduction. Body weight was decreased as expected by 9.4 percent in the semaglutide group as was waist circumference. Systolic blood pressure was reduced by 3.3 millimeters of mercury, a high sensitivity CRP, the inflammatory marker by 38 percent, triglycerides by 15.6 percent. The risk of progression to diabetes was one quarter with a hazard ratio of 0.27, and among patients who did not have pre-diabetes at baseline, the risk of progressing to pre-diabetes was a hazard ratio of 0.33, so nearly 70 percent reduction.

Importantly, serious adverse events were not increased with semaglutide were actually less frequent because of lower rates of cardiovascular disorders and infection. There was an increased risk of study drug discontinuation due to adverse events in the semaglutide group, 16 percent versus 8 percent due mostly to non-serious gastrointestinal events. There was no increase in acute pancreatitis or other major adverse events of special interest. So, in summary then, among patients who have preexisting cardiovascular disease and overweight or obesity but do not have diabetes. Once weekly semaglutide at a dose of 2.4 milligrams reduce the risk of cardiovascular death, myocardial infarction or stroke by 20 percent. The benefit occurred early, was seen very early after initiation, and was concordant across subgroups and cardiovascular endpoints.

There were no unexpected safety findings or greater risks of serious adverse events with semaglutide. The mechanisms of benefit remained speculative may relate to those of the physiologic benefits from reduction of metabolically dysfunctional body fat, but also direct effects of semaglutide other than weight loss. Semaglutide 2.4 milligrams is thus the first weight management therapy proven in a rigorous, randomized controlled trial to reduce the risk of cardiovascular events, and it establishes overweight and obesity as a modifiable risk factor for cardiovascular disease. Thank you very much.

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