GLP-1s and Heart Health: What the SELECT Trial Revealed

The SELECT trial (NEJM 2023) found that semaglutide 2.4mg reduced the risk of major adverse cardiovascular events (MACE) — a combined measure of heart attack, stroke, and death from cardiovascular causes — by 20% compared with placebo. This was a landmark result because it was the first time a GLP-1 medication prescribed for weight loss was proven to prevent heart events in people without diabetes.

SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) enrolled 17,604 adults aged 45 and older who had a body mass index of 27 or higher and established cardiovascular disease, but no history of diabetes. Participants were followed for an average of about 40 months. Everyone continued their standard heart medications; the only difference was semaglutide versus placebo.

The headline number — a 20% relative risk reduction — is clinically meaningful. For context, that is in the same ballpark as some widely used cardiac drugs. The result, published by Lincoff and colleagues, reshaped how doctors think about these medications: not just as weight-loss tools, but as cardiovascular medicine.

GLP-1 medications protect the heart through several overlapping mechanisms, and weight loss is only part of the story. One of the most striking findings in SELECT was that the cardiovascular benefit began to appear early — within the first months — before participants had lost most of their weight. That timing strongly suggests the drugs act on the cardiovascular system directly, not only by shrinking body fat.

Several mechanisms are at play. GLP-1 receptor agonists lower blood pressure, modestly improve cholesterol and triglyceride profiles, and reduce systemic inflammation — measured by markers like C-reactive protein — which is a key driver of atherosclerosis (the buildup of plaque in arteries). They also improve blood sugar control and reduce visceral fat, the metabolically active fat around the organs that raises heart risk.

Because menopause independently shifts cholesterol and raises blood pressure, these effects matter especially for midlife women. Our guides on [menopause and cholesterol](/blog/menopause-cholesterol-why-your-numbers-change) and [menopause and blood pressure](/blog/menopause-and-blood-pressure-why-it-rises-and-what-helps) explain how these risks stack up — and how a GLP-1 may counteract several at once.

The people most likely to benefit are those who match the SELECT population: adults 45 and older with overweight or obesity (BMI 27+) and existing cardiovascular disease, but not diabetes. For this group, the evidence is now strong enough that the FDA approved Wegovy in March 2024 specifically to reduce the risk of cardiovascular death, heart attack, and stroke — the first weight-loss drug to earn a heart-protection indication.

That said, SELECT does not prove the same 20% benefit in every group. It did not study people at low cardiovascular risk, and it focused on those with prior heart disease. Whether GLP-1s prevent a *first* heart event in otherwise healthy people is still being studied. This distinction matters: the trial supports GLP-1s for secondary prevention (people who already have heart disease) more than primary prevention.

It is also worth noting the broader class evidence. Earlier trials such as SUSTAIN-6 and LEADER showed cardiovascular benefits of GLP-1s in people with type 2 diabetes, and the FLOW trial demonstrated kidney protection — which we cover in [what the FLOW trial found](/blog/glp1-kidney-health-flow-trial-what-it-means). Together these trials paint a consistent picture of organ protection across the GLP-1 class.

Not all GLP-1 medications have the same level of cardiovascular evidence — the strength of proof varies by drug and by trial. Semaglutide has the most robust data for heart protection, thanks to SELECT (in people without diabetes) and SUSTAIN-6 (in people with diabetes). This is why Wegovy carries a specific FDA cardiovascular indication.

Tirzepatide (Mounjaro, Zepbound), the dual GIP/GLP-1 medication, produces greater weight loss than semaglutide in head-to-head weight trials, and its dedicated cardiovascular outcomes trial, SURPASS-CVOT, has been running to confirm heart benefits. Early signals are encouraging, but as of 2025 tirzepatide does not yet carry the same standalone heart-protection approval that semaglutide does. If you are weighing the two, our comparison of [tirzepatide vs semaglutide](/blog/tirzepatide-vs-semaglutide-which-works-better-2026) breaks down the trade-offs.

The practical takeaway: if cardiovascular protection is a primary goal, semaglutide currently has the strongest evidence base. But the field is moving fast, and newer agents are being studied. Your provider can help match the medication to your specific risk profile — weight, heart history, blood sugar, and cost all factor in.

Curious how a GLP-1 fits your own heart-health picture? Lea can walk you through the questions to bring to your doctor.