What the SELECT Trial Found About Semaglutide and Heart Attack Risk

SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity) was a large, double-blind, placebo-controlled trial published in the New England Journal of Medicine in 2023 by Lincoff and colleagues. It was designed to answer a simple question: does a weight-loss drug lower the chance of heart attack and stroke?

The trial enrolled 17,604 adults aged 45 or older at 804 sites in 41 countries. Everyone had a body mass index (BMI) of 27 or higher and established cardiovascular disease, meaning a prior heart attack, stroke or symptomatic peripheral artery disease. People with diabetes were excluded, which made SELECT the first large outcomes trial of an obesity drug in people without diabetes.

Participants were randomly assigned to weekly semaglutide 2.4 mg (the Wegovy dose) or placebo, on top of standard care such as statins and blood pressure medicine. They were followed for a mean of 39.8 months.

Semaglutide reduced the risk of major cardiovascular events by 20%. The primary outcome was MACE (major adverse cardiovascular events), a combination of cardiovascular death, non-fatal heart attack and non-fatal stroke. It occurred in 6.5% of the semaglutide group versus 8.0% of the placebo group, a hazard ratio of 0.80 (95% confidence interval 0.72 to 0.90).

A hazard ratio compares the rate of events over time: 0.80 means about 20% fewer events in the treatment group. In absolute terms, that is about 1.5 percentage points over roughly three and a half years, or about 1 event prevented for every 67 people treated.

Both parts of the heart story moved in the right direction. Non-fatal heart attacks and cardiovascular deaths were lower with semaglutide, and non-fatal stroke was numerically lower but the difference was not large enough to stand alone as statistically significant. The trial also reported lower all-cause mortality in a secondary analysis, though hierarchical testing limits how strongly that finding can be claimed.

Probably not entirely. Participants on semaglutide lost about 9% of their body weight on average by two years, compared with under 1% on placebo. Yet later analyses suggested the cardiovascular benefit did not track closely with how much weight a person lost, and it was seen across baseline BMI categories, including people with a lower BMI.

That points to other mechanisms. GLP-1 medications lower blood pressure modestly, improve blood sugar and cholesterol, and reduce C-reactive protein (CRP), a blood marker of inflammation. Inflammation drives plaque buildup and rupture in arteries, so an anti-inflammatory effect could explain part of the benefit. Some laboratory work also suggests direct effects on blood vessels and plaque.

This matters because it reframes semaglutide as more than a scale-moving drug. For someone with heart disease, the medication can be considered a cardiovascular treatment, not a cosmetic choice.

The kidney story is similar: see [what the FLOW trial found for kidney health](/blog/glp1s-and-kidney-health-what-the-flow-trial-found).

Side effects were mostly gastrointestinal. More people stopped semaglutide because of adverse events than stopped placebo: about 16.6% versus 8.2% permanently discontinued the treatment. Nausea, diarrhea, vomiting and constipation were the most common reasons. Serious adverse events overall were actually fewer in the semaglutide group (about 33.4% vs 36.4%), driven by fewer cardiac and other events.

There was a higher rate of gallbladder-related problems (gallstones and gallbladder inflammation) with semaglutide, consistent with earlier trials. Rapid weight loss itself raises gallstone risk. Pancreatitis was not more frequent in this trial, and there was no signal for a new thyroid cancer problem, though the trial was not designed to settle that question; see [what the data shows on GLP-1s and thyroid cancer](/blog/glp1-thyroid-cancer-risk-what-the-data-shows).

Because trials only include people who tolerate the drug through a run-in and follow-up, real-world discontinuation may be higher. Slow dose escalation and practical side-effect strategies are important for staying on treatment.

SELECT included about 27% women, so the evidence is less complete for women than for men. Subgroup analyses generally showed a similar direction of benefit across sex, but the confidence intervals are wider and the trial was not powered to prove sex-specific effects.

This matters because a woman's cardiovascular risk changes around menopause. Estrogen helps keep blood vessels flexible and helps regulate cholesterol. After menopause, LDL cholesterol (the "bad" kind) tends to rise, blood pressure creeps up, and belly fat increases. Heart disease is the leading cause of death in women, yet women are still under-represented in cardiovascular trials.

Read more about the hormone connection in [cholesterol in menopause](/blog/cholesterol-in-menopause-why-ldl-rises-and-what-to-do) and the often-missed [peripheral artery disease risk in menopause](/blog/peripheral-artery-disease-in-menopause-the-overlooked-risk). SELECT does not answer whether combining a GLP-1 with menopausal hormone therapy adds heart benefit; that question is still open.

If you are perimenopausal or postmenopausal, treat the trial as encouraging data, then talk to your clinician about your personal risk using tools that account for family history, blood pressure, cholesterol and smoking.

Not directly. Everyone in SELECT already had established cardiovascular disease, so it is a secondary prevention trial, meaning it tested prevention of another event in people who already had one. The results cannot be assumed to apply to someone with a healthy heart taking semaglutide only for weight loss.

That said, obesity is itself a risk factor for heart disease, and semaglutide improves several risk factors at once: weight, waist size, blood pressure, blood sugar and cholesterol. Other studies show improvement in those markers in people without established disease. But better markers do not automatically mean fewer heart attacks, and trials in lower-risk people would be needed to know.

For context, the FDA expanded semaglutide's (Wegovy) labeling in 2024 to include reducing the risk of major cardiovascular events in adults with established cardiovascular disease and either obesity or overweight. Insurance coverage for that use may be easier than for weight loss alone; see your plan and your prescriber. Sleep apnea is another condition with its own trial evidence, covered in [SURMOUNT-OSA](/blog/glp1-sleep-apnea-surmount-osa-trial).

Start with your own numbers: blood pressure, LDL cholesterol, blood sugar or A1C, family history, and any prior heart or vascular events. Ask whether you fit the SELECT profile, meaning established cardiovascular disease with a BMI over 27, and whether your insurer treats cardiovascular risk reduction as a covered indication.

Also ask how a GLP-1 fits with your existing heart medicines. Statins, blood pressure drugs and aspirin should not be stopped when starting a GLP-1. Weight loss may lower your blood pressure enough that doses of antihypertensive drugs need adjusting, so home readings are useful.

Finally, keep lifestyle basics in the plan. Protein and strength training protect muscle while you lose weight, and regular walking supports heart health regardless of medication. A GLP-1 is one tool, not a substitute for the rest.