Diabetes Obes Metab. 2026 Oct 13. doi: 10.1111/dom.71411. Online ahead of print.
ABSTRACT
BACKGROUND: Cardiovascular disease and chronic kidney disease are the principal drivers of morbidity and mortality in type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated cardiorenal benefits in landmark trials, yet cross-trial inconsistencies in cardiovascular mortality, renal endpoints and drug-specific effects leave the class-level estimates incompletely synthesized.
METHODS: PubMed, Web of Science, Scopus and CENTRAL were searched from inception through 15 May 2026. Large placebo-controlled RCTs (≥ 1000 participants) and prespecified subgroup analyses in adults with T2DM were eligible. The primary outcome was the composite of first hospitalization for heart failure (HHF) or cardiovascular death (CV death). Secondary outcomes were 3-point major adverse cardiovascular events (MACE), CV DEATH, myocardial infarction (MI), stroke, first HHF and composite kidney outcomes. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using random-effects inverse-variance models.
RESULTS: Fourteen studies (76 969 patients; 41 761 SGLT2i, 35 208 placebo) were included. SGLT2i reduced the primary composite by 23% (HR: 0.77, 95% CI: 0.73-0.81, p < 0.0001; I2 = 0%), with no effect modification by baseline HF (p-interaction = 0.82) or established ASCVD (p-interaction = 0.46). MACE was reduced by 14% (HR: 0.86, 95% CI: 0.81-0.92), driven by significant reductions in CV DEATH (HR: 0.86, 95% CI: 0.79-0.93) and MI (HR: 0.88, 95% CI: 0.81-0.96), with no significant effect on stroke (HR: 0.93, 95% CI: 0.81-1.08). First, HHF was reduced by 29% (HR: 0.71, 95% CI: 0.66-0.77) and composite kidney outcomes by 31% (HR: 0.69, 95% CI: 0.60-0.79).
CONCLUSIONS: SGLT2i confer consistent and clinically meaningful cardiorenal protection in T2DM across the full spectrum of cardiovascular and renal risk. The ertugliflozin estimate and the moderate heterogeneity in kidney outcomes should be interpreted in the context of trial-level clinical differences and nonstandardized kidney endpoint definitions. These findings support proactive, guideline-concordant initiation of evidence-based SGLT2i agents by endocrinologists, cardiologists and primary care providers as foundational therapy in T2DM.
PMID:42865310 | DOI:10.1111/dom.71411