Semaglutide 2.4 mg cut cardiovascular events 20% in adults with obesity and heart disease, SELECT trial finds

Weekly semaglutide 2.4 mg reduced the combined risk of cardiovascular death, nonfatal heart attack or nonfatal stroke by 20% in adults who had overweight or obesity and existing heart disease but no diabetes ^[1][2]. The results of the SELECT trial were presented Nov. 11, 2023, at the American Heart Association Scientific Sessions in Philadelphia and published in the New England Journal of Medicine ^[1][2].

A primary endpoint event — whichever of cardiovascular death, nonfatal heart attack or nonfatal stroke came first — occurred in 569 of 8,803 people taking semaglutide (6.5%) and in 701 of 8,801 people taking placebo (8.0%). The hazard ratio was 0.80, with a 95% confidence interval of 0.72 to 0.90 (P<0.001) ^[1]. Mean follow-up was 39.8 months, and mean exposure to the study drug or placebo was 34.2 months ^[1].

The 2.4 mg dose studied is the dose sold as Wegovy ^[3].

How the trial was run

SELECT enrolled 17,604 people at 804 sites in 41 countries between October 2018 and March 2021 ^[1]. Participants were 45 or older, had a body-mass index of 27 or higher, and had established cardiovascular disease — a prior heart attack, a prior stroke, or symptomatic peripheral artery disease. People with a history of diabetes were excluded ^[1][2].

Patients were assigned at random, one-to-one, to once-weekly subcutaneous semaglutide or placebo. The semaglutide dose started at 0.24 mg and was raised every four weeks toward a 2.4 mg target ^[1]. The average participant was 61.6 years old, 28% were women, and the average BMI was 33.3. Seventy-six percent had had a heart attack, 23% a stroke, and 9% had symptomatic peripheral artery disease. Sixty-six percent had prediabetes, and 88% were taking a statin. In the semaglutide group, 77% reached the 2.4 mg target dose ^[1][2].

Other outcomes and side effects

Semaglutide compared with placebo ^[2]:

• Death from any cause: 4.3% versus 5.2% (hazard ratio 0.81, 95% CI 0.71 to 0.93).
• Nonfatal heart attack: 2.7% versus 3.7% (hazard ratio 0.72, 95% CI 0.61 to 0.85).
• A heart failure composite, meaning cardiovascular death or hospitalization or an urgent visit for heart failure: 3.4% versus 4.1% (hazard ratio 0.82, 95% CI 0.71 to 0.96).
• Cardiovascular death on its own: 2.5% versus 3.0% (hazard ratio 0.85, 95% CI 0.71 to 1.01; P=0.07), which did not reach statistical significance.

At 104 weeks, average body weight fell 9.4% with semaglutide and 0.9% with placebo. Systolic blood pressure fell 3.8 mm Hg versus 0.5 mm Hg, and new HbA1c readings of 6.5% or higher occurred in 3.5% versus 12.0% ^[2].

Adverse events leading to permanent discontinuation of the trial drug occurred in 1,461 people taking semaglutide (16.6%) and 718 taking placebo (8.2%; P<0.001) ^[1]. Gastrointestinal complications were reported in 10.0% versus 2.0% ^[2]. Serious adverse events overall were 33.4% versus 36.4%; acute pancreatitis 0.2% versus 0.3%; and malignant neoplasms 4.8% versus 4.7% ^[2]. The American College of Cardiology summary states that the cardiovascular benefit of this drug class is not fully understood and is likely to have more than one cause ^[2].

Why it matters for patients

The people studied had already had a heart attack, a stroke or peripheral artery disease. In that group, roughly one in 16 people on placebo had a cardiovascular death, heart attack or stroke over about 40 months, compared with about one in 15 on semaglutide ^[1]. Prior trials of lifestyle and drug treatments for overweight or obesity had not shown a clear reduction in cardiovascular events, according to the researchers ^[1][2][3].

Some limits are worth noting. SELECT did not test whether semaglutide prevents a first heart attack or stroke in people without existing cardiovascular disease, and that question has not been answered by this trial. People with diabetes were excluded, so the results do not speak directly to that group. The trial studied semaglutide 2.4 mg specifically; other GLP-1 drugs, other semaglutide doses and other obesity medications were not part of this comparison. Whether the benefit comes from weight loss alone, from effects on blood pressure, blood sugar or other pathways, or from a combination, has not been settled ^[2].

Side effects were common enough that about one in six participants on semaglutide stopped the drug permanently, most often because of gastrointestinal symptoms ^[1][2].

What happens next

On March 8, 2024, the FDA approved Wegovy for cardiovascular risk reduction in adults with established cardiovascular disease and either obesity or overweight ^[3]. Wegovy had first been approved in June 2021 for weight management ^[3]. A prespecified analysis of SELECT focused on participants with heart failure was later published in The Lancet ^[2].