Which GLP-1s Are Proven to Protect Your Heart? 6 Trials Compared

As of October 2026, six GLP-1-based drugs carry an FDA label to reduce heart attacks, strokes, or cardiovascular death: Victoza, Ozempic, Trulicity, Rybelsus, Wegovy, and Mounjaro. Which one is "proven" for you depends mostly on two things: whether you have type 2 diabetes, and whether you already have heart disease. Wegovy is the only one with a heart-protection label for people without diabetes, and Zepbound has no heart label yet.

The six trials behind the heart labels

Each trial below compared the drug with placebo, except SURPASS-CVOT, which compared tirzepatide with another GLP-1. The hazard ratio (HR) shows relative risk: 0.80 means about 20% fewer events than the comparison group.

Cross-trial comparison: populations, follow-up, and comparators differ. Sources: ACC (LEADER), ACC (SUSTAIN-6), ACC (REWIND), HCPLive (SOUL), ACC (SELECT), ACC (SURPASS-CVOT).

What each trial really showed

LEADER (Victoza)

LEADER was the first GLP-1 trial to show heart protection. Beyond the 13% MACE reduction, cardiovascular death fell from 6.0% to 4.7% and all-cause death from 9.6% to 8.2%, per the American College of Cardiology. Victoza's label covers adults with type 2 diabetes and established cardiovascular disease. Saxenda, the higher-dose liraglutide for weight loss, has no heart indication on its label.

SUSTAIN-6 (Ozempic)

SUSTAIN-6 had the largest relative MACE reduction, driven mainly by fewer strokes (1.6% vs. 2.7%). Cardiovascular death was essentially unchanged (2.7% vs. 2.8%), according to the American College of Cardiology. It was also small and short, which widens the uncertainty around that 26% figure. Ozempic's label covers adults with type 2 diabetes and established heart disease, and separately covers kidney protection in type 2 diabetes with chronic kidney disease.

REWIND (Trulicity)

REWIND stands out because only about a third of participants (31.5%) had prior heart disease, per the American College of Cardiology. That is why Trulicity's label covers adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors. The effect was modest (12% fewer events) but held over more than five years.

SOUL (Rybelsus)

SOUL tested the daily semaglutide pill and found a 14% MACE reduction. The FDA added a heart indication to Rybelsus in October 2025, making it the first oral GLP-1 with one, per HCPLive. The label covers adults with type 2 diabetes at high cardiovascular risk, whether or not they have had a prior event.

SELECT (Wegovy)

SELECT is the trial that matters most if you do not have diabetes. It enrolled 17,604 adults with overweight or obesity and existing heart disease. Wegovy cut MACE by 20% and all-cause death from 5.2% to 4.3%, per the ACC summary. The drop in cardiovascular death alone (3.0% to 2.5%) did not reach statistical significance. The tradeoff: 16.6% stopped Wegovy because of side effects, versus 8.2% on placebo.

The FDA approved this use on March 8, 2024. Wegovy's current label lists the heart indication for both the injection and the Wegovy tablets in adults with established cardiovascular disease and obesity or overweight.

SURPASS-CVOT (Mounjaro)

SURPASS-CVOT did something different: it pitted tirzepatide against Trulicity, a drug already proven to protect the heart. Tirzepatide had 8% fewer events, which met the bar for noninferiority but not superiority, according to the trial publication summarized by the ACC. The FDA approved Mounjaro to reduce cardiovascular risk in adults with type 2 diabetes at high risk on August 28, 2026, per Lilly's announcement and the updated Mounjaro label. Because there was no placebo group, the trial cannot say exactly how much tirzepatide lowers risk compared with no GLP-1 at all.

Relative vs. absolute benefit: reading the numbers honestly

Headlines usually quote relative reductions, such as "20% fewer events." The absolute difference is smaller and often more useful. In SELECT, 8.0% of placebo patients had a major event over a mean follow-up of 40 months, versus 6.5% on Wegovy: a gap of 1.5 percentage points. In REWIND, the gap was 1.4 percentage points over about five years (12.0% vs. 13.4%), per the ACC. That works out to roughly 70 people taking dulaglutide for that long to prevent one major event.

That does not make the benefit small for an individual at high risk. It does mean the payoff grows with your baseline risk, which is why these labels target people with heart disease, kidney disease, or multiple risk factors. It also means the side effects that lead people to stop treatment, like the doubled discontinuation rate in SELECT, matter: a drug only protects you while you take it.

Which drug matches your situation

This is the practical sorting most people need. It reflects what labels say, not a personal recommendation.

• Type 2 diabetes plus established heart disease: All six drugs have labeled heart protection that covers you. Choice usually comes down to weight goals, dosing preference (weekly shot vs. daily pill), side effects, and coverage.
• Type 2 diabetes with risk factors but no prior heart disease: Trulicity, Rybelsus, and Mounjaro have labels written for high-risk patients that do not require a prior event. Victoza and Ozempic labels specify established cardiovascular disease.
• No diabetes, overweight or obesity, and existing heart disease: Wegovy is the only GLP-1 with a heart label for you.
• No diabetes and no heart disease: No GLP-1 currently carries a heart-protection label for you. SELECT required established heart disease.

What about Zepbound?

Zepbound is the same molecule as Mounjaro, but its label covers weight management and sleep apnea only, with no cardiovascular indication as of its August 2026 revision. Its dedicated trial, SURMOUNT-MMO, enrolled 15,374 adults with obesity and no diabetes, and its estimated primary completion date is October 2027, according to ClinicalTrials.gov. Results are therefore unlikely before late 2027. Lilly's pipeline page also lists a phase 3 cardiovascular outcomes trial for orforglipron, its oral GLP-1.

Until SURMOUNT-MMO reads out, any claim that Zepbound protects the heart in people without diabetes is an extrapolation, not a proven fact.

Sources

1. American College of Cardiology: LEADER trial summary
2. American College of Cardiology: SUSTAIN-6 trial summary
3. American College of Cardiology: REWIND trial summary
4. HCPLive: FDA approves oral semaglutide (Rybelsus) for CV risk reduction
5. American College of Cardiology: SELECT trial summary
6. FDA: First treatment to reduce risk of serious heart problems specifically in adults with obesity or overweight
7. American College of Cardiology: SURPASS-CVOT journal scan
8. Eli Lilly: FDA approves Mounjaro to reduce cardiovascular risk
9. Victoza (liraglutide) prescribing information
10. Saxenda (liraglutide) prescribing information
11. Ozempic (semaglutide) prescribing information
12. Trulicity (dulaglutide) prescribing information
13. Wegovy (semaglutide) prescribing information
14. Mounjaro (tirzepatide) prescribing information
15. Zepbound (tirzepatide) prescribing information
16. ClinicalTrials.gov: SURMOUNT-MMO (NCT05556512)
17. Eli Lilly: Research and development pipeline

Medical disclaimer: This article is general information, not medical advice, and does not replace a licensed clinician who knows your history. Approvals, labels, coverage and prices change; check the linked sources and talk with your prescriber or pharmacist before making decisions about any medication.