Abstract
BACKGROUND: Cardiovascular disease (CVD) disproportionately affects type 2 diabetes (T2D) patients with chronic kidney disease (CKD). Although semaglutide shows cardiometabolic benefits, its efficacy across CVD endpoints and high-risk CKD subgroups remains underexplored. METHODS: We systematically reviewed PubMed, Embase, Cochrane, Web of Science (through September 2025) for randomized trials and observational studies evaluating oral semaglutide versus placebo in T2D. Data synthesis employed hazard ratios (HRs) and mean differences (MDs) with 95% confidence intervals (CIs). RESULTS: Across 17 studies (n = 40, 632 patients), semaglutide significantly reduced the risk of cardiovascular (CV) death by 23% [HR 0.77, 95% CI (0.68, 0.88)], major adverse cardiovascular events (MACE) by 18% [HR 0.82, 95% CI (0.75, 0.90)], expanded MACE by 22% [HR 0.78, 95% CI (0.70, 0.85)], nonfatal myocardial infarction (MI) by 18% [HR 0.82, 95% CI (0.68, 0.92)], and nonfatal stroke by 32% [HR 0.68, 95% CI (0.56, 0.83)]. The reductions in CV events were most pronounced in T2D patients with CKD (24-37% risk reduction vs. 13-35% in T2D alone or with CVD). Semaglutide also significantly improved modifiable CV risk factors, reducing systolic/diastolic blood pressure (SBP/DBP) decreased by 8.02/3.71 mmHg, and low-density Lipoprotein (LDL) decreased by 12.62 mg/dL, while increasing high-density lipoprotein (HDL) by 1.44 mg/dL. However, semaglutide had no significant effect on estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR). CONCLUSION: Semaglutide confers robust cardiovascular protection in T2D, with amplified benefits in patients with comorbid CKD. It confers a collective advantage by simultaneously addressing multiple risk factors including blood pressure and lipoprotein, positioning it as a comprehensive treatment strategy for high-risk populations. This analysis is the first to synthesize evidence across CKD subgroups, supporting prioritizing semaglutide in T2D patients with CKD. Further research should clarify mechanisms underlying CKD-specific benefits and refine risk-stratified treatment algorithms.