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

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. 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. 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; I2 = 0 %; p < 0.05), consistent with their effects on cardiovascular mortality (RR = 0.88; 95%CI: 0.81–0.95; I2 = 0 %; p < 0.01) in T2D. Compared to placebo, SGLT2i significantly reduced noncardiovascular mortality (RR = 0.90; 95%CI: 0.82–0.99; I2 = 0 %; p < 0.05) along with cardiovascular mortality (RR = 0.84; 95%CI: 0.77–0.92; I2 = 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). The impact of GLP-1RAs and SGLT2i on mortality in people with T2D extends beyond their cardiovascular benefits.