Cardiovascular and renal outcomes of Semaglutide in patients with Type 2 Diabetes Mellitus with established Atherosclerotic Cardiovascular Disease and/or Chronic Kidney Disease: A Meta-Analysis

Abstract

Type 2 diabetes mellitus (T2DM), atherosclerotic cardiovascular disease (ASCVD) and chronic kidney disease (CKD) constitute a high risk triad for major adverse cardiovascular and renal events. Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP 1-RA), has emerged as an important therapeutic option. Current evidence is limited by short follow up and small sample size, warranting an updated meta-analysis to elucidate semaglutide's cardio-renal benefits. We systematically searched for randomized controlled trials from inception until 30th of November 2025 comparing semaglutide over placebo in T2DM with established ASCD and/or CKD. Key outcomes were major adverse cardiovascular events (MACE), major adverse kidney events (MAKE), non-fatal stroke, non-fatal myocardial infarction (MI), cardiovascular death, and all-cause mortality. Four trials encompassing 19, 663 participants (semaglutide: 9831, placebo, 9832) were included. Semaglutide significantly reduced MACE at 16% (risk ratio: [RR] 0.84, 95% confidence interval [CI] 0.78-.0.91; p < 0.0001, non-fatal MI at 20% (RR 0.80, 95% CI 0.68-0.94; p = 0.006), all-cause mortality at 15% (RR 0.85, 95% CI 0.72-1.00; p = 0.05) and MAKE at 21% (RR 0.79, 95% CI 0.71-0.89; p < 0.0001). Cardiovascular death (RR 0.78, p = 0.05) showed borderline significance, while non-fatal stroke was not significantly reduced. Subgroup analysis demonstrated a significant reduction in cardiovascular death with subcutaneous semaglutide only (RR 0.63; p = 0.01; interaction: p = 0.04). Semaglutide confers significant cardio-renal benefit in patients with T2DM with established ASCVD and/or CKD by reducing MACE, non-fatal MI, all-cause mortality and MAKE. Cardiovascular death was reduced with subcutaneous administration, while further studies are needed to clarify cerebrovascular outcomes.