SGLT2 Inhibitors and Cardiovascular Outcomes in Heart Failure: A Meta-Analysis of Randomized Trials

Background

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as a cornerstone therapy for heart failure. Initial trials such as DAPA-HF and EMPEROR-Reduced demonstrated benefits in heart failure with reduced ejection fraction (HFrEF), while DELIVER and EMPEROR-Preserved extended these findings to heart failure with preserved ejection fraction (HFpEF). This meta-analysis synthesizes evidence across the full ejection fraction spectrum.

Methods

We searched PubMed, Embase, and the Cochrane Library through November 2025 for randomized, placebo-controlled trials of SGLT2 inhibitors in patients with heart failure. The primary endpoint was the composite of cardiovascular death or first hospitalization for heart failure. Random-effects models were used to pool hazard ratios. Heterogeneity was assessed using the I-squared statistic. Prespecified subgroup analyses examined effects by ejection fraction category, diabetes status, and baseline kidney function.

Results

Twelve trials comprising 28,474 patients were included. The pooled hazard ratio for the primary composite endpoint was 0.77 (95% CI, 0.72-0.82; P<0.001), with low heterogeneity (I-squared=18%). The benefit was consistent across HFrEF (HR 0.74; 95% CI, 0.68-0.81), HFmrEF (HR 0.78; 95% CI, 0.67-0.91), and HFpEF (HR 0.80; 95% CI, 0.73-0.88). Cardiovascular death alone was reduced by 14% (HR 0.86; 95% CI, 0.79-0.93). Heart failure hospitalization was reduced by 28% (HR 0.72; 95% CI, 0.66-0.78). Benefits were independent of diabetes status (interaction P=0.54) and consistent across tertiles of baseline eGFR. SGLT2 inhibitors were associated with a higher rate of genital infections (RR 2.4; 95% CI, 1.9-3.0) but no excess of serious adverse events.

Conclusions

SGLT2 inhibitors produce robust reductions in cardiovascular death and heart failure hospitalization across the entire spectrum of left ventricular ejection fraction. These data support guideline recommendations for SGLT2 inhibitor therapy as foundational treatment for all patients with heart failure.