GLP-1 receptor agonists, SGLT2 inhibitors and noncardiovascular mortality in type 2 diabetes: Insights from a meta-analysis

Objective: Type -2 diabetes (T2D) poses a higher risk of noncardiovascular mortality in addition to the burden of cardiovascular mortality. The well -established cardiovascular benefits of glucagon-like peptide -1 receptor agonists (GLP-1 RAs) and sodium -glucose cotransporter-2 inhibitors (SGLT2i) could solely explain their apparent effects on all -cause mortality in T2D. The present meta -analysis aims to pool their effects on noncardiovascular mortality in T2D and summarize the recent evidence on plausible pathways mediating these effects. Methods: PubMed, Embase, Web of Science, and clinical trial registries were searched for randomized controlled trials (RCTs) with >= 1 -year duration in adults with T2D reporting both cardiovascular and all -cause mortality in treatment versus placebo arms (PROSPERO: CRD42022337559). Noncardiovascular mortality was calculated by subtracting cardiovascular mortality events from all -cause mortality and risk ratios (RRs) were calculated. Random -effects meta -analysis was done. GRADE framework was used to assess evidence quality. Results: We identified 17 eligible RCTs pooling data retrieved from 109,892 patients. Randomization to GLP-1 RA treatment versus placebo was associated with reduced noncardiovascular mortality (RR = 0.90; 95%CI: 0.81-0.99; I-2 = 0 %; p < 0.05), consistent with their effects on cardiovascular mortality (RR = 0.88; 95%CI: 0.81-0.95; I-2 = 0 %; p < 0.01) in T2D. Compared to placebo, SGLT2i significantly reduced noncardiovascular mortality (RR = 0.90; 95%CI: 0.82-0.99; I-2 = 0 %; p < 0.05) along with cardiovascular mortality (RR = 0.84; 95%CI: 0.77-0.92; I-2 = 28 %; p < 0.001). Subgroup analysis showed no significant effects of heart failure or renal function on treatment benefits of SGLT2i on noncardiovascular mortality (p value > 0.2 for subgroup differences). Conclusion: The impact of GLP-1RAs and SGLT2i on mortality in people with T2D extends beyond their cardiovascular benefits.