Top 10 PubMed Studies on GLP-1 Cardiovascular Outcomes (2026)

SELECT randomized 17,604 adults with established cardiovascular disease and overweight or obesity (BMI ≥27) but no diabetes to semaglutide 2.4 mg weekly or placebo over a mean 39.8 months. Primary three-point MACE occurred in 6.5% on semaglutide vs 8.0% on placebo — a 20% relative risk reduction (HR 0.80, 95% CI 0.72-0.90, p<0.001). Cardiovascular death dropped 15%. This was the first trial to show a weight-loss drug reduces hard cardiovascular events in patients without diabetes, and it drove the March 2024 FDA cardiovascular-risk-reduction indication for Wegovy.

PMID 37952131 ↗NCT03574597 ↗DOI 10.1056/NEJMoa2307563 ↗

LEADER was the first GLP-1 trial to demonstrate cardiovascular benefit, randomizing 9,340 high-risk type 2 diabetes patients to liraglutide 1.8 mg daily or placebo over a median 3.8 years. Three-point MACE occurred in 13.0% on liraglutide vs 14.9% on placebo (HR 0.87, 95% CI 0.78-0.97, p=0.01 for superiority). Cardiovascular death fell 22% and all-cause mortality 15%. LEADER moved GLP-1s from glucose-lowering drugs to cardioprotective therapy and grounded the FDA cardiovascular-risk-reduction label for Victoza in 2017.

PMID 27295427 ↗NCT01179048 ↗DOI 10.1056/NEJMoa1603827 ↗

SUSTAIN-6 was a pre-approval safety trial for injectable semaglutide, randomizing 3,297 type 2 diabetes patients at high cardiovascular risk to semaglutide 0.5 or 1.0 mg weekly versus placebo for 104 weeks. Primary three-point MACE occurred in 6.6% on semaglutide vs 8.9% on placebo — a 26% relative risk reduction (HR 0.74, 95% CI 0.58-0.95, p=0.02 for superiority). Nonfatal stroke fell 39%. Powered for noninferiority, SUSTAIN-6 unexpectedly delivered superiority and was the basis for the Ozempic cardiovascular-risk-reduction indication.

PMID 27633186 ↗NCT01720446 ↗DOI 10.1056/NEJMoa1607141 ↗

REWIND randomized 9,901 type 2 diabetes patients to dulaglutide 1.5 mg weekly or placebo over a median 5.4 years — the longest GLP-1 CVOT to date. Crucially, 69% had no prior cardiovascular event at enrollment, making REWIND the strongest primary-prevention trial in the class. Three-point MACE occurred in 12.0% on dulaglutide vs 13.4% on placebo (HR 0.88, 95% CI 0.79-0.99, p=0.026). Effect was consistent across primary and secondary prevention strata. Drove the 2020 FDA cardiovascular-risk-reduction indication for Trulicity in patients without prior CV disease.

PMID 31189511 ↗NCT01394952 ↗DOI 10.1016/S0140-6736(19)31149-3 ↗

FLOW randomized 3,533 patients with type 2 diabetes and chronic kidney disease (eGFR 25-75, UACR 100-5,000) to semaglutide 1.0 mg weekly or placebo. The trial stopped early for efficacy after a median 3.4 years. The composite primary kidney endpoint occurred 24% less often on semaglutide (HR 0.76, 95% CI 0.66-0.88, p=0.0003). Three-point MACE dropped 18% and all-cause mortality 20%. FLOW was the first dedicated kidney-outcomes trial for a GLP-1 and drove the January 2025 FDA kidney indication for Ozempic — the first non-glycemic kidney label for the class.

PMID 38785209 ↗NCT03819153 ↗DOI 10.1056/NEJMoa2403347 ↗

HARMONY OUTCOMES randomized 9,463 type 2 diabetes patients with established cardiovascular disease to albiglutide 30-50 mg weekly or placebo over a median 1.6 years. Three-point MACE occurred in 7% on albiglutide vs 9% on placebo — a 22% relative risk reduction (HR 0.78, 95% CI 0.68-0.90, p=0.0006 for superiority). Despite the strong cardioprotective signal, GSK had already withdrawn albiglutide for commercial reasons before publication, leaving the trial as a class-confirmatory data point rather than a marketed therapy.

PMID 30291013 ↗NCT02465515 ↗DOI 10.1016/S0140-6736(18)32261-X ↗

STEP-HFpEF randomized 529 patients with heart failure with preserved ejection fraction (LVEF ≥45%) and obesity (BMI ≥30) to semaglutide 2.4 mg weekly or placebo for 52 weeks — historically a heart-failure population with almost no effective drug therapy. Semaglutide improved KCCQ-CSS by 7.8 points more than placebo (95% CI 4.8-10.9, p<0.001) and reduced body weight by 10.7 percentage points more. Six-minute walk distance and hs-CRP also improved. STEP-HFpEF established GLP-1s as disease-modifying therapy for obesity-related HFpEF, not just weight-loss drugs.

PMID 37622681 ↗NCT04788511 ↗DOI 10.1056/NEJMoa2306963 ↗

PIONEER 6 was a pre-approval cardiovascular safety trial for oral semaglutide (Rybelsus), randomizing 3,183 high-risk type 2 diabetes patients to oral semaglutide 14 mg daily or placebo over a median 15.9 months. Three-point MACE occurred in 3.8% on oral semaglutide vs 4.8% on placebo (HR 0.79, 95% CI 0.57-1.11), meeting the noninferiority margin (p<0.001) but not reaching superiority. Cardiovascular death fell 51% (HR 0.49, p=0.03). The trial cleared the FDA cardiovascular-safety hurdle for the first oral GLP-1 in 2019.

PMID 31185157 ↗NCT02692716 ↗DOI 10.1056/NEJMoa1901118 ↗

AMPLITUDE-O randomized 4,076 type 2 diabetes patients with established cardiovascular disease or kidney disease plus risk factors to efpeglenatide 4 or 6 mg weekly or placebo over a median 1.8 years. Three-point MACE occurred in 7.0% on efpeglenatide vs 9.2% on placebo — a 27% relative risk reduction (HR 0.73, 95% CI 0.58-0.92, p=0.007 for superiority). A composite renal endpoint also fell 32%. Notably, 15% of participants were already on an SGLT2 inhibitor, demonstrating additive benefit. Sanofi discontinued efpeglenatide development before commercialization.

PMID 34215025 ↗NCT03496298 ↗DOI 10.1056/NEJMoa2108269 ↗

ELIXA was the first GLP-1 cardiovascular outcomes trial, randomizing 6,068 type 2 diabetes patients with a recent acute coronary syndrome to lixisenatide or placebo over a median 25 months. The primary composite endpoint occurred in 13.4% on lixisenatide vs 13.2% on placebo (HR 1.02, 95% CI 0.89-1.17, p=0.81 for superiority, p<0.001 for noninferiority). The neutral result confirmed cardiovascular safety but no benefit — important as the negative-control reference point that highlights how short-acting GLP-1s differ from longer-acting agents like liraglutide and semaglutide which followed.

PMID 26630143 ↗NCT01147250 ↗DOI 10.1056/NEJMoa1509225 ↗