Network meta-analysis compares glucose-lowering therapies for heart failure with reduced ejection fraction and type 2 diabetes

BackgroundThis systematic review and network meta-analysis synthesizes evidence from randomized controlled trials (RCTs) investigating three novel glucose-lowering therapies in patients with coexisting heart failure with reduced ejection fraction (HFrEF) and type 2 diabetes mellitus(T2DM). We evaluated composite cardiovascular outcomes in this high-risk cohort.MethodsA comprehensive literature search without language restrictions was performed across PubMed, EMBASE, and the Cochrane Library from inception to September 1, 2025. The network meta-analysis assessed the following endpoints: Composite of cardiovascular death and heart failure hospitalization; Hospitalization for heart failure; Left ventricular ejection fraction (LVEF); N-terminal pro-B-type natriuretic peptide (NT-proBNP); Estimated glomerular filtration rate (eGFR); Glycated hemoglobin (HbA1c). Quality appraisal of included RCTs using the Cochrane Risk of Bias Tool 2.0 (ROB2) and Confidence in Network Meta-Analysis (CINeMA) for grading evidence certainty. The study protocol was prospectively registered with PROSPERO (CRD420251269519).ResultsThe final analysis pooled data from 16 randomized trials encompassing 14,710 patients. For the composite of cardiovascular death or hospitalization for heart failure, Sotagliflozin demonstrated the most substantial risk reduction (OR = 0.49; 95% CI 0.39, 0.62). This agent also showed significant efficacy against heart failure readmission (OR = 0.53; 95% CI 0.45, 0.63). Notably, Dapagliflozin improved LVEF more effectively than controls (MD −2.94%; 95% CI −3.89, −1.99). Among patients with HFrEF and T2DM, Empagliflozin significantly reduced NT-proBNP plasma levels vs. placebo (SMD −0.61; 95% CI −0.91, −0.31). Empagliflozin additionally exhibited superior preservation of eGFR (MD −2.08; 95% CI −3.38, −0.78), whereas Vildagliptin achieved the greatest reduction in HbA1c (MD −0.62%; 95% CI −1.12, −0.12).ConclusionsThis meta-analysis provides evidence that Sodium-dependent glucose transporter 2 inhibitors (SGLT2i) may be associated with a reduction in major adverse cardiovascular events (MACE) and exert superior renoprotective effects in patients with HFrEF and comorbid T2DM. Notably, Sotagliflozin demonstrates potentially favorable effects for primary cardiovascular endpoints, whereas Vildagliptin appears to be more effective for HbA1c reduction in this analysis.Systematic Review RegistrationPROSPERO CRD420251269519.