Effects of semaglutide on mortality, cardiovascular, and kidney outcomes across the cardio-kidney-metabolic continuum: a systematic review and meta-analysis

Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated cardiometabolic benefits in randomized controlled trials (RCTs). However, its overall effects on mortality, cardiovascular (CV) and kidney outcomes have not been comprehensively synthesized. This meta-analysis aimed to assess the prognostic impact of semaglutide across the cardio-kidney-metabolic continuum. A systematic literature search was conducted to identify all eligible RCTs comparing the prognostic effects of semaglutide with placebo across diverse patient populations. Primary outcomes were all-cause and CV mortality. Secondary outcomes included major CV and kidney events, while major adverse limb events (MALE) were analyzed as an exploratory endpoint. A random-effects model was used to pool hazard ratios (HRs) and 95% confidence intervals (CIs). Eight trials encompassing 39,204 patients were included. In patients treated with semaglutide a significant reduction of all-cause (HR, 0.84; 95% CI, 0.77–0.92; p = 0.0001) and CV mortality (HR, 0.83; 95% CI, 0.72–0.95; p = 0.0078), major adverse CV events (MACE, HR, 0.82; 95% CI, 0.77–0.87; p < 0.0001), nonfatal myocardial infarction (MI, HR, 0.75; 95% CI, 0.68–0.84; p < 0.0001), worsening heart failure (HF, HR, 0.84; 95% CI, 0.73–0.98; p = 0.0245), and kidney outcomes (HR, 0.83; 95% CI, 0.73–0.95; p = 0.0080) was observed compared to placebo. No significant effects were observed for nonfatal stroke. Treatment with semaglutide, compared to placebo, is associated with significant lower incidence of all-cause and CV mortality, as well major CV and kidney events across the continuum of cardio-kidney-metabolic syndrome.