Systematic review and meta-analysis of 8 randomised trials (39,204 patients) on semaglutide versus placebo across the full cardio-kidney-metabolic (CKM) spectrum. Semaglutide significantly reduced all-cause mortality (HR 0.84; 95% CI 0.77-0.92), cardiovascular mortality (HR 0.83), MACE (HR 0.82), non-fatal myocardial infarction (HR 0.75), worsening heart failure (HR 0.84) and adverse kidney outcomes (HR 0.83). No significant effect on non-fatal stroke. The breadth of CKM benefit — kidney, heart and mortality together — distinguishes semaglutide from many other classes and aligns with the recognition of CKM as an integrated disease entity.
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.
