SELECT establishes cardiovascular benefit in obesity without diabetes
In 17,604 adults with overweight or obesity and heart disease but no diabetes, weekly semaglutide 2.4 mg cut heart attacks, strokes and cardiovascular deaths from 8.0% to 6.5% over about 40 months [1].
Results from the SELECT trial, presented November 11, 2023 at the American Heart Association Scientific Sessions and published the same day in the New England Journal of Medicine, showed that once-weekly semaglutide 2.4 mg (the dose sold as Wegovy) reduced major adverse cardiovascular events by 20% in people with overweight or obesity and existing heart disease who did not have diabetes [1][2][3].
The trial enrolled 17,604 patients 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 a previous heart attack, stroke, or symptomatic peripheral artery disease. People with a diabetes diagnosis or an A1c of 6.5% or higher at screening were excluded [1]. Half received semaglutide, escalated from 0.24 mg weekly to a target of 2.4 mg over 16 weeks, and half received placebo [1]. Novo Nordisk funded the trial [1].
What the numbers showed
The primary endpoint — cardiovascular death, nonfatal heart attack, or nonfatal stroke, whichever came first — occurred in 569 of 8,803 semaglutide patients (6.5%) and 701 of 8,801 placebo patients (8.0%), a hazard ratio of 0.80 (95% CI 0.72 to 0.90; P<0.001) [1]. Mean follow-up was 39.8 months and mean exposure to the study drug was 34.2 months [1].
Among the individual components, nonfatal heart attack fell from 3.7% to 2.7% (HR 0.72) [2]. Cardiovascular death was 2.5% with semaglutide versus 3.0% with placebo, which did not reach statistical significance (HR 0.85, P=0.07) [2]. Because the trial tested secondary endpoints in a fixed order requiring significance at each step, that result meant the later endpoints could not be formally confirmed [1]. Their raw numbers still favored semaglutide: all-cause death 4.3% versus 5.2% (HR 0.81), and the heart failure composite 3.4% versus 4.1% (HR 0.82) [2].
The population was sicker and heavier than a typical weight-loss trial: mean age about 62, 28% female, mean BMI 33.3, with 76% having had a prior heart attack and 88% on statins [2]. Two-thirds (66%) had prediabetes at baseline [2]. Progression to an A1c of 6.5% or higher occurred in 3.5% of the semaglutide group versus 12.0% on placebo [2].
Weight loss was more modest than in dedicated obesity trials: a mean 9.4% reduction at 104 weeks versus 0.9% with placebo [2]. Systolic blood pressure fell 3.8 mm Hg versus 0.5 mm Hg [2]. Only 77% of the semaglutide group reached the full 2.4 mg target dose [2].
On safety, adverse events leading to permanent discontinuation happened in 16.6% of semaglutide patients versus 8.2% on placebo (P<0.001), driven largely by gastrointestinal problems, reported in 10.0% versus 2.0% [1][2]. Serious adverse events overall were less common with semaglutide, 33.4% versus 36.4% (P<0.001) [2]. Acute pancreatitis (0.2% vs 0.3%), acute kidney failure (1.9% vs 2.3%) and malignant tumors (4.8% vs 4.7%) did not differ significantly [2].
Why it matters for patients
Before SELECT, no trial of a weight-loss drug or lifestyle program had clearly shown fewer heart attacks and strokes, which is one reason obesity treatment was often framed as cosmetic rather than cardiovascular care [1]. SELECT put a hard outcome number on it in a group without diabetes, and the benefit appeared on top of standard treatment, including statins in 88% of participants [2].
The trial also shows the trade-off in plain terms: roughly twice as many people stopped semaglutide because of side effects, mostly stomach-related [1][2]. And the findings apply to a specific group — adults 45 and older with a BMI of 27 or more who already have established cardiovascular disease. Whether the same benefit extends to people without prior heart disease was not tested here [1].
Why the drug helped is not settled. Weight loss averaged 9.4%, but blood pressure, blood sugar and inflammation-related pathways may all contribute; the mechanisms are described as multifactorial and not fully understood [2].
What happens next
On March 8, 2024, the FDA approved Wegovy to reduce the risk of major adverse cardiovascular events in adults with established cardiovascular disease and either obesity or overweight [3]. A later prespecified analysis published in The Lancet in 2024 examined SELECT participants with heart failure [2].
Sources
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