SGLT2 inhibitors and Cardiovascular Outcomes in Heart Failure with Mildly Reduced and Preserved Ejection Fraction: A Systematic Review and Meta-Analysis.

AIM: To provide a pooled effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on cardiovascular outcomes in patients with heart failure with preserved ejection fraction (HFpEF: ≥50%) or/and mildly reduced EF (HFmrEF: 41-49%) regardless of baseline diabetes.

METHODS: We systemically searched PubMed/MEDLINE, Embase, Web of Science databases and clinical trial registries using appropriate keywords till August 28, 2022, to identify randomized controlled trials (RCTs) or post-hoc analysis of RCTs, reporting cardiovascular death (CVD) and/or urgent visits/hospitalization for heart failure(HHF) in patients with HFmrEF/HFpEF receiving SGLTi vs. placebo. Hazard ratios (HR) with 95% confidence intervals (CI) for outcomes were pooled together using generic inverse variance method with fixed-effects model.

RESULTS: We identified six RCTs, pooling data retrieved from 15769 patients with HFmrEF/HFpEF. Pooled analysis showed that compared to placebo, SGLT2i use was significantly associated with improved CVD/HHF outcomes in HFmrEF/HFpEF (pooled HR 0.80, 95% CI: 0.74, 0.86, p<0.001, I2 =0%). When separately analyzed, benefits of SGLT2i remained significant across HFpEF (N=8891, HR 0.79, 95% CI: 0.71, 0.87, p<0.001, I2 =0%) and HFmrEF (N=4555, HR 0.77, 95% CI: 0.67, 0.89, p<0.001, I2 =40%). Consistent benefits were observed also in HFmrEF/HFpEF subgroup without baseline diabetes (N=6507, HR 0.80, 95% CI: 0.70, 0.91, p<0.001, I2 =0%). Sensitivity analysis including the DELIVER and EMPEROR-Preserved trials found a trend towards significant beneficial effects on CV deaths with no heterogeneity (HR 0.90, 95% CI: 0.79, 1.02, p=0.08, I2 =0%).

CONCLUSIONS: This meta-analysis established the place of SGLT2i as a foundational therapy among patients with HF with preserved and mildly reduced EF regardless of diabetes.