GLP-1 heart outcomes are among the best-proven benefits of these drugs. A 2025 meta-analysis of 10 large trials with 71,351 people with type 2 diabetes found long-acting GLP-1 drugs cut the combined risk of heart attack, stroke and cardiovascular death by 14%, and death from any cause by 12%.[7] In people with heart disease and obesity but no diabetes, the SELECT trial found semaglutide 2.4 mg lowered that risk by 20%.[1]
For how these drugs work, see the GLP-1 basics hub. Profiles: semaglutide, liraglutide, dulaglutide and tirzepatide.
Bottom line: the major trials
All trials below measured “MACE,” major adverse cardiovascular events: cardiovascular death, nonfatal heart attack or nonfatal stroke.
| Trial | Drug | People | Follow-up | MACE result |
|---|---|---|---|---|
| LEADER (2016)[3] | Liraglutide vs placebo | 9,340 with type 2 diabetes | Median 3.8 years | 13.0% vs 14.9%; 13% lower risk |
| SUSTAIN-6 (2016)[2] | Semaglutide injection vs placebo | 3,297 with type 2 diabetes | About 2 years | 6.6% vs 8.9%; 26% lower risk |
| REWIND (2019)[4] | Dulaglutide vs placebo | 9,901 with type 2 diabetes | Median 5.4 years | 12.0% vs 13.4%; 12% lower risk |
| SELECT (2023)[1] | Semaglutide 2.4 mg vs placebo | 17,604 with heart disease and overweight, no diabetes | Mean 3.3 years | 6.5% vs 8.0%; 20% lower risk |
| SOUL (2025)[5] | Oral semaglutide vs placebo | 9,650 with type 2 diabetes and heart or kidney disease | Median about 4 years | 12.0% vs 13.8%; 14% lower risk |
| SURPASS-CVOT (2025)[6] | Tirzepatide vs dulaglutide | 13,165 with type 2 diabetes and heart disease | Not stated in abstract | 12.2% vs 13.1%; noninferior, not superior |
The key trials in more detail
LEADER. Liraglutide reduced MACE by 13% (hazard ratio 0.87). It also lowered cardiovascular death (4.7% vs 6.0%) and death from any cause (8.2% vs 9.6%).[3]
SUSTAIN-6. Weekly semaglutide reduced MACE by 26%, driven mainly by fewer nonfatal strokes (1.6% vs 2.7%). Cardiovascular death rates were similar. Retinopathy complications were higher on semaglutide (hazard ratio 1.76), which we cover in our GLP-1 eye health guide.[2]
REWIND. This trial stood out because most participants did not have established heart disease. Dulaglutide still lowered MACE by 12% over 5.4 years. Death from any cause did not differ significantly.[4]
SELECT. The first trial to test a GLP-1 drug for heart protection in people without diabetes. Adults aged 45 or older with prior heart disease and a BMI of 27 or more took semaglutide 2.4 mg or placebo. MACE fell from 8.0% to 6.5% (hazard ratio 0.80). Side effects led 16.6% to stop semaglutide, versus 8.2% on placebo.[1] Wegovy is now FDA-approved to reduce MACE in adults with established heart disease and obesity or overweight.[9]
SOUL. Oral semaglutide (up to 14 mg daily) lowered MACE by 14% in people with type 2 diabetes and heart disease, chronic kidney disease or both. Kidney outcomes did not differ significantly.[5] The oral semaglutide label now includes a cardiovascular risk-reduction indication.[11]
SURPASS-CVOT. Instead of placebo, this trial compared tirzepatide (up to 15 mg) with dulaglutide, a drug already proven to protect the heart. Tirzepatide met the bar for noninferiority. Its 8% lower risk (hazard ratio 0.92) did not reach statistical significance for superiority. Stomach side effects were more common with tirzepatide.[6] The Mounjaro label now includes a cardiovascular risk-reduction indication for adults with type 2 diabetes at high risk.[10]
What the meta-analyses show
A 2021 meta-analysis of 8 trials found GLP-1 drugs lowered MACE, death from any cause, heart failure hospitalization and a composite kidney outcome.[8] The updated 2025 analysis, adding SOUL and the FLOW kidney trial, pooled 10 trials and 71,351 people with type 2 diabetes:[7]
- MACE: 14% lower
- Heart failure hospitalization: 14% lower
- Composite kidney outcome: 17% lower
- Death from any cause: 12% lower
- No increase in severe low blood sugar, retinopathy or pancreatic events at the pooled level
Results were similar for injected and oral forms. For kidney-specific data, see our Ozempic and kidney disease guide.
Who the results apply to
The trials enrolled specific groups, and the evidence is strongest for people who match them:
- Type 2 diabetes with heart disease or high risk: LEADER, SUSTAIN-6, SOUL and SURPASS-CVOT. In SUSTAIN-6, 83% already had heart disease, kidney disease or both.[2]
- Type 2 diabetes, mostly without prior heart disease: REWIND, with a mean age of 66.[4]
- Heart disease plus overweight or obesity, no diabetes: SELECT, which required age 45 or older and a BMI of 27 or more.[1]
People with obesity alone and no heart disease were not studied in these trials.
What’s established vs preliminary
Established:
- GLP-1 drugs lower MACE in people with type 2 diabetes and high cardiovascular risk.[7]
- Semaglutide 2.4 mg lowers MACE in people with heart disease and overweight or obesity without diabetes.[1]
Preliminary:
- Benefit in people at lower risk, such as those with obesity but no heart disease.
- Whether tirzepatide or newer drugs protect the heart more than older GLP-1 drugs.
- How much of the benefit comes from weight loss versus direct effects on blood vessels and inflammation.
Limitations
- Most trials were funded by the drug’s maker.
- Absolute benefits are modest: in SELECT, about 1.5 fewer people per 100 had an event over roughly three years.[1]
- Participants were mostly older adults with established disease, so results may not apply to younger, healthier people.
- Stopping due to side effects was common, especially stomach upset.[1] Muscle changes during weight loss are covered in our GLP-1 muscle loss guide.
What’s next
SURMOUNT-MMO is testing tirzepatide against placebo in 15,374 adults with obesity, measuring heart events and death. It is active but no longer recruiting, with primary completion expected in October 2027.[12] The answer will show whether Zepbound earns a heart-risk indication like Wegovy’s.
GLP-1 drugs have not shown the same success in the brain; see GLP-1 drugs for Alzheimer’s and Parkinson’s.
Questions to discuss with a clinician
- Do I have established heart disease or high risk that makes a GLP-1 with a heart indication a good fit?
- How does this fit with my statin, blood pressure medicine and SGLT2 inhibitor?
- Does my insurance cover it for heart risk reduction specifically?
- What side effects should I expect, and what if I can’t tolerate the full dose?
