SELECT and the GLP-1 heart trials, with the numbers

A drug that lowers weight or blood sugar does not automatically prevent heart attacks. Several diabetes drugs improved the lab number and did nothing for the heart. So regulators ask for cardiovascular outcome trials: thousands of people, years of follow-up, and a count of hard events. The usual primary end point is MACE, a composite of cardiovascular death, non-fatal heart attack and non-fatal stroke.

The GLP-1 drugs now have four large outcome trials behind them. This page goes through what each one found, who was in it, and what it does and does not tell someone who is not a trial participant.

The trials at a glance

HR is the hazard ratio. 0.80 means the rate of first events was 20 percent lower in the drug group over the trial. All four trials were double-blind and randomised, and all four were funded by the drug's maker.

SELECT: the first in people without diabetes

SELECT is the trial that matters most for people taking semaglutide for weight. It enrolled adults aged 45 or older with established cardiovascular disease and a BMI of 27 or more, and excluded anyone with diabetes. 8,803 were assigned to semaglutide 2.4 mg, the Wegovy dose, and 8,801 to placebo, on top of usual care.

Over a mean follow-up of 39.8 months, a first MACE event occurred in 569 people on semaglutide (6.5 percent) and 701 on placebo (8.0 percent). That is a hazard ratio of 0.80, a 20 percent relative reduction. In absolute terms it is 1.5 percentage points over a little more than three years. Rough arithmetic on those crude rates: about 67 people treated for that period to prevent one event.

The cost was tolerability. Adverse events led to permanent discontinuation of the drug in 16.6 percent of the semaglutide group and 8.2 percent of the placebo group, mostly gastrointestinal. The side effects page has the breakdown.

A secondary analysis of the same trial, published in Nature Medicine in 2024, looked at the kidneys. That result is on the kidney page.

The FDA label change, March 2024

On 8 March 2024 the FDA approved Wegovy to reduce the risk of cardiovascular death, heart attack and stroke in adults with established cardiovascular disease and either obesity or overweight, used with a reduced-calorie diet and more physical activity. The agency described it as the first weight-loss medication approved for that purpose. The indication is specific: it covers people who already have heart disease, which is who SELECT enrolled. It does not say that semaglutide prevents a first heart attack in someone with no heart disease, because that was not tested.

SUSTAIN-6 and LEADER: the diabetes trials

Before SELECT, the evidence came from people with type 2 diabetes. SUSTAIN-6 assigned 3,297 people at high cardiovascular risk to semaglutide 0.5 mg or 1 mg (the Ozempic doses) or placebo for 104 weeks. 83 percent had established cardiovascular disease, chronic kidney disease or both. MACE occurred in 6.6 percent on semaglutide and 8.9 percent on placebo, hazard ratio 0.74. Non-fatal stroke was lower (HR 0.61). Cardiovascular death was similar between groups.

SUSTAIN-6 was designed as a safety trial, to show the drug was not worse than placebo, so the efficacy result is less certain than a trial built to prove benefit. It also found one signal worth knowing: diabetic retinopathy complications were more frequent on semaglutide (HR 1.76, 95% CI 1.11 to 2.78). The usual explanation is a rapid fall in blood sugar in people with existing eye disease. It is why the labels mention retinopathy.

LEADER tested daily liraglutide in 9,340 people with type 2 diabetes and high cardiovascular risk, over a median of 3.8 years. MACE fell from 14.9 to 13.0 percent (HR 0.87). Cardiovascular death fell from 6.0 to 4.7 percent (HR 0.78) and death from any cause from 9.6 to 8.2 percent (HR 0.85).

SURPASS-CVOT: tirzepatide against an active drug

Tirzepatide's outcome trial did not use placebo. Because GLP-1 drugs already had proven benefit in diabetes, it compared tirzepatide (up to 15 mg) with dulaglutide 1.5 mg, itself a GLP-1 drug with a cardiovascular indication. 13,299 people with type 2 diabetes and atherosclerotic heart disease were randomised. The primary event rate was 12.2 percent on tirzepatide and 13.1 percent on dulaglutide, hazard ratio 0.92 with a 95.3 percent confidence interval of 0.83 to 1.01.

That meets the trial's noninferiority test (the upper limit was below 1.05) but not its superiority test (the upper limit had to be below 1.00). The fair reading: tirzepatide is at least as protective as an established GLP-1 drug, and not proven to be more so. Critics have noted that the dulaglutide dose was 1.5 mg rather than the higher 4.5 mg available. On 28 August 2026 the FDA expanded the Mounjaro label to reduce MACE risk in adults with type 2 diabetes at high cardiovascular risk, based on this trial.

There is no placebo-controlled cardiovascular outcome result for tirzepatide in people without diabetes to set beside SELECT yet. A 2026 Nature Medicine study of US insurance records, which is observational and shows association rather than cause, found no clear difference between tirzepatide and semaglutide on heart attack, stroke or death (HR 1.06, 95% CI 0.95 to 1.18).

What these trials do not answer

• Weight loss or something else? It is often suggested that the drugs act on inflammation, blood pressure and blood vessels as well as weight. The trial was not built to separate those effects.
• People with no heart disease. None of these trials tested primary prevention in people without diabetes or established cardiovascular disease.
• Compounded versions. All four trials used the branded products. The compounded versions were not studied.
• Stopping. The benefit was measured on treatment. What happens to risk after stopping was not measured.

What to watch on your own numbers

The trials measured hard events, but the routes in are things that show up in ordinary checks: blood pressure, LDL cholesterol, HbA1c, triglycerides, waist and weight. The GLP-1 blood work page and how to read a lab report cover which markers to bring to a review. The clinical trials overview links the weight trials, and the heart failure page covers a different heart question.

If you are on a GLP-1 for heart risk, the useful log is boring: the weekly dose, weight, resting heart rate and blood pressure readings, and each lipid panel when it comes back. The free GLP-1 tracker keeps the dose, the weight, side effects and, on Premium, lab results on one timeline, so the numbers your prescriber asks about are in one place rather than spread across portals and notes. It is free to download.