Efficacy of SGLT2-inhibitors Across Different Definitions of Heart Failure with Preserved Ejection Fraction

Aims Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been evaluated in phase 3 randomized–controlled trials (RCTs) that enrolled individuals with heart failure and preserved ejection fraction (HFpEF) based on detailed clinical, biochemical, and echocardiographic criteria (hereafter HF-RCTs), and in cardiovascular outcomes trials (CVOTs) in diabetic patients, in which the diagnosis of HFpEF relied on medical history. Methods and results We performed a study-level meta-analysis of the efficacy of SGLT2i across different definitions of HFpEF. Three HF-RCTs (EMPEROR-Preserved, DELIVER, and SOLOIST-WHF) and four CVOTs (EMPA-REG OUTCOME, DECLARE-TIMI 58, VERTIS-CV, and SCORED) were included, for a total of 14 034 patients. SGLT2i reduced the risk of cardiovascular death or heart failure hospitalization (HFH) in all RCTs pooled together [risk ratio 0.75, 95% confidence interval (95% CI) 0.63–0.89, NNT 19], in HF-RCTs (risk ratio 0.71, 95% CI 0.52–0.97, NNT 13), and in CVOTs (risk ratio 0.78, 95% CI 0.60–0.99, NNT 26). SGLT2i also decreased the risk of HFH in all RCTs (risk ratio 0.81, 95% CI 0.73–0.90, NNT 45), in HF-RCTs (risk ratio 0.81, 95% CI 0.72–0.93, NNT 37), and in CVOTs (risk ratio 0.78, 95% CI 0.61–0.99, NNT 46). By contrast, SGLT2i were not superior to placebo for cardiovascular death or all-cause death in all RCTs, HF-RCTs, or CVOTs. Results were comparable after excluding one RCT at a time. Meta-regression analysis confirmed that the type of RCT (HF-RCT vs. CVOT) did not influence the SGLT2i effect. Conclusions In RCTs, SGLT2i improved the outcomes of patients with HFpEF regardless of how the latter was diagnosed.