Efficacy Comparison of Sodium-Glucose Cotransporter-2 Inhibitors, Glucagon-Like Peptide-1 Receptor Agonists, and Dipeptidyl Peptidase-4 Inhibitors in Heart Failure with Preserved Ejection Fraction: A Systematic Review And Network Meta-Analysis

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) represents a major unmet therapeutic need with limited evidence-based pharmacologic options. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated benefit, while the roles of glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) remain less clear. A direct and indirect comparison of these antihyperglycemic drug classes on cardiovascular outcomes in HFpEF is required.

Methods: We conducted a systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs). Databases (MEDLINE, Embase, Scopus, Web of Science, CENTRAL,  were searched from inception to 2024-10-27. RCTs enrolling adults with HFpEF (LVEF ≥40%) comparing an SGLT2i, GLP-1 RA, or DPP-4i against placebo or active control were included. Primary outcomes were a composite of first hospitalization for heart failure (HHF) or cardiovascular (CV) death, and total HHF events. Secondary outcomes included CV death, all-cause death, and Kansas City Cardiomyopathy Questionnaire (KCCQ) score change. Data were pooled using frequentist random-effects NMA, with ranking via P-scores. Risk of bias was assessed using Cochrane RoB 2.

Results: From 5,317 records, 12 RCTs (n=25,147 participants) were included. For the composite of HHF/CV death, SGLT2i significantly reduced risk compared to placebo (hazard ratio [HR] 0.80, 95% CI 0.73–0.88) and were superior to both DPP-4i (HR 0.77, 95% CI 0.66–0.89) and GLP-1 RA (HR 0.84, 95% CI 0.72–0.99). GLP-1 RA showed a non-significant trend towards benefit versus placebo (HR 0.94, 95% CI 0.81–1.10). DPP-4i did not differ from placebo (HR 1.03, 95% CI 0.89–1.20). For total HHF, SGLT2i were superior to all comparators. SGLT2i also ranked highest for improving KCCQ total symptom score. No significant difference was observed between drug classes for CV or all-cause mortality.

Conclusion: In patients with HFpEF, SGLT2i provide the most robust reduction in heart failure events and improvement in health status compared to GLP-1 RA, DPP-4i, and placebo. GLP-1 RA show a neutral effect on primary HFpEF outcomes, while DPP-4i should not be used for HFpEF management. These findings strongly support the preferential use of SGLT2i in the HFpEF population.