Impact of semaglutide on mortality, cardiovascular, and kidney outcomes across the cardio-kidney-metabolic continuum: a meta-analysis of randomized controlled trials

Background/Introduction Semaglutide, a glucagon-like peptide-1 receptor agonist, has shown cardiometabolic benefits in randomized controlled trials (RCTs) across different clinical settings. A consolidated estimate of its effects on mortality, cardiovascular (CV), and kidney outcomes across the cardio-kidney-metabolic continuum is still needed. Purpose The purpose of this meta-analysis was to quantify the impact of semaglutide versus placebo on all-cause and CV mortality, major CV events, and kidney outcomes across diverse patient populations enrolled in RCTs. Methods A systematic literature search was conducted according to PRISMA guidelines, to identify all eligible RCTs comparing the prognostic effects of semaglutide with placebo and reporting time-to-event outcomes across diverse patient populations. Primary endpoints were all-cause and CV mortality. Secondary endpoints included major adverse cardiovascular events (MACE), nonfatal myocardial infarction (MI), nonfatal stroke, worsening heart failure (HF), and kidney outcomes; major adverse limb events (MALE) were assessed as an exploratory endpoint. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Results Eight RCTs comprising 39,204 participants were included. Compared with placebo, semaglutide reduced all-cause mortality (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). Semaglutide also lowered MACE (HR 0.82, 95% CI 0.77–0.87; p<0.0001) and nonfatal MI (HR 0.75, 95% CI 0.68–0.84; p<0.0001), with no significant effects on nonfatal stroke. Risk reductions were observed for worsening 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). MALE were also reduced (HR 0.70, 95% CI 0.53–0.91; p=0.0092). Conclusion(s) Semaglutide is associated with significant reduction of all-cause and CV mortality, along with reduced risk of major adverse cardiovascular, kidney and limb events, providing consistent cardiometabolic benefits across the spectrum of cardio-kidney-metabolic syndrome.