Semaglutide across cardiovascular and kidney outcome trials: a systematic review and stratified synthesis

Antonio Maria Labate; Provvidenza Villari

Antonio Maria Labate Outpatient Diabetology Service, ASST Mantova, Mantova, Italy https://orcid.org/0009-0006-4619-6565
Provvidenza Villari Outpatient Diabetology Service, ASST Garda, Desenzano del Garda, Italy

Keywords: type 2 diabetes mellitus, obesity, GLP-1 receptor agonists, major adverse cardiovascular events, chronic kidney disease, cardiorenal risk

Abstract

Semaglutide outcome trials span distinct cardiometabolic populations and endpoint hierarchies, complicating a single pooled interpretation. We synthesized cardiovascular and kidney evidence using prespecified clinical strata. Following PRISMA 2020 and SWiM (PROSPERO CRD420261441534), we included phase 3 randomized, double-blind, placebo-controlled cardiovascular or kidney outcome trials of oral or subcutaneous semaglutide. PubMed/MEDLINE, CENTRAL, ClinicalTrials.gov and WHO ICTRP were searched through 15 July 2026. Risk of bias was assessed with RoB 2 and certainty with GRADE. Within the type 2 diabetes cardiovascular stratum, MACE hazard ratios were combined by inverse-variance common-effect meta-analysis; no estimates were pooled across strata. Five trials (37,267 participants) were included: SUSTAIN-6, PIONEER-6, SOUL, SELECT and FLOW. The type 2 diabetes MACE summary was 0.83 (95% CI 0.76–0.92; I2=0%). SELECT showed a MACE hazard ratio of 0.80 (0.72–0.90), while FLOW showed a primary kidney composite hazard ratio of 0.76 (0.66–0.88). Semaglutide reduced cardiovascular events in type 2 diabetes and obesity without diabetes and kidney events in type 2 diabetes with chronic kidney disease. Stratified interpretation preserves clinically important differences across trial populations and endpoint hierarchies.