Effects of dapagliflozin on mortality across the spectrum of cardiovascular-kidney-metabolic syndrome: a meta-analysis

Aims: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as key disease-modifying agents for patients with heart failure (HF) and chronic kidney disease (CKD), regardless of diabetes status. Despite their well-established benefits on cardiovascular (CV) and renal outcomes, individual effects on mortality have not been explored as primary endpoints. This meta-analysis evaluates the impact of dapagliflozin on mortality across phase III clinical trials in patients with cardiovascular-kidney-metabolic (CKM) syndrome. Data synthesis: This study is registered on PROSPERO (CRD42024564297). A systematic literature search was conducted according to PRISMA guidelines to identify all eligible randomized, placebo-controlled CV outcome trials on dapagliflozin in patients with CV, kidney, or metabolic diseases. Primary outcomes were all-cause and CV mortality. Secondary outcomes included major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, HF hospitalization, and a composite of HF hospitalization or CV death. Four trials encompassing 32,471 patients were included. Dapagliflozin significantly reduced all-cause (HR: 0.88; 95 % CI: 0.80–0.97; p = 0.008) and CV mortality (HR: 0.89; 95 % CI: 0.80–0.98; p = 0.015) and lowered the rate of MACE (HR: 0.92; 95 % CI: 0.85–0.99; p = 0.019), compared to placebo. Dapagliflozin substantially reduced HF hospitalization (HR: 0.72; 95 % CI: 0.66–0.79; p < 0.001) and the composite of HF hospitalization or CV death (HR: 0.79; 95 % CI: 0.73–0.85; p < 0.001). No significant effects were observed for MI or stroke. Conclusions: This meta-analysis confirms that dapagliflozin significantly reduces both all-cause and CV mortality, along with MACE and HF hospitalization, across a broad CKM spectrum.