GLP-1 agonists reduce cardiovascular mortality and MACE

GLP-1 RAs cut deaths and MACE; GI risks rise. Systematic review and meta-analysis of randomized controlled trials (PRISMA, GRADE, trial sequential analysis); Level 1a (2011 OCEBM).

Background

Across 21 trials (99,599 participants), GLP-1 receptor agonists reduced all-cause and cardiovascular mortality and MACE beyond glycemic control; gastrointestinal and gallbladder adverse events increased.

Patients

  • Adults at high cardiovascular risk: type 2 diabetes, obesity, CKD, or heart failure.
  • Mean age 66.9 years; 32.7% female.

Intervention

Therapeutic-dose GLP-1 RAs (lixisenatide, liraglutide, exenatide, semaglutide, efpeglenatide, dulaglutide, albiglutide, tirzepatide).

Control

Placebo or standard care.

Outcome

Primary: all-cause death, cardiovascular death, MACE, serious adverse events (SAEs). Secondary: myocardial infarction, heart failure hospitalization, infections, acute kidney failure, gastrointestinal and gallbladder disorders; stroke, pancreatitis, neoplasms.

Follow up period

Mean 2.4 years.

Results

Type Outcome Effect (IRR, 95% CI) Absolute risk change NNT/NNH
Primary All-cause death 0.88 (0.84–0.92) −0.8% NNT 121
Primary Cardiovascular death 0.87 (0.81–0.92) −0.6% NNT 170
Primary MACE 0.87 (0.83–0.91) −1.5% NNT 66
Primary Serious adverse events 0.91 (0.87–0.96) −3.5% NNT 29
Secondary Myocardial infarction 0.85 (0.78–0.94) −0.6% NNT 167
Secondary HF hospitalization 0.85 (0.75–0.97) −0.6% NNT 167
Secondary Infections 0.90 (0.85–0.96) −1.1% NNT 91
Secondary Acute kidney failure 0.91 (0.83–1.00) −0.2% NNT 500
Secondary GI disorders 1.63 (1.36–1.97) +6.4% NNH 16
Secondary Gallbladder disorders 1.26 (1.12–1.41) +0.5% NNH 200
Secondary Stroke; pancreatitis; neoplasms No difference — —

Limitations

  • Study-level (not patient-level) meta-analysis; heterogeneous populations/endpoints.
  • Agent-specific effects suggested; few head-to-head comparisons.
  • Underrepresentation of advanced CKD and HFrEF; follow-up ≈2.4 years.

Funding

Academic-led; authors report industry ties—potential conflicts.

Citation

Galli M, Benenati S, Laudani C, et al. Cardiovascular Effects and Tolerability of GLP-1 Receptor Agonists: A Systematic Review and Meta-Analysis of 99,599 Patients. J Am Coll Cardiol. 2025;86:1805–1819. doi:10.1016/j.jacc.2025.08.027