Sodium-glucose cotransporter 2 inhibitors in heart failure with reduced or preserved ejection fraction: a meta-analysis

Abstract

Aims: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to be an effective therapy in improving heart failure outcomes. We conducted a meta-analysis of randomized controlled trials to evaluate the efficacy of SGLT2 inhibitors in heart failure patients with either a reduced or preserved ejection fraction.

Methods and results: We searched MEDLINE and EMBASE for large (≥1000 patients) randomized controlled trials evaluating the effects of SGLT2 inhibitors compared with placebo in the setting of heart failure until September 2021. Our primary outcome was the composite of heart failure hospitalization and cardiovascular death, and secondary outcomes included all-cause mortality and total heart failure hospitalizations. We pooled hazard ratios and risk ratios and evaluated risk of bias with the Cochrane Collaboration tool. Four randomized controlled trials (DAPA HF, EMPEROR-Preserved, EMPEROR-Reduced, and SOLOIST-WHF) were included (n = 15 684); two of which evaluated patients with a reduced LVEF, one of which evaluated patients with a preserved LVEF, and one of which included both. Treatment with SGLT2 inhibitors resulted in a significant reduction in the composite of CV death and heart failure hospitalization (HR: 0.76, 95% CI: 0.70, 0.82, I² : 0%, P < 0.00001). This was consistent in sub-groups of patients with LVEF ≤40% (n = 9199, HR: 0.74, 95% CI: 0.68, 0.81, I² : 0%) and LVEF >40% (n = 6482, HR: 0.78, 95% CI: 0.68, 0.89, I² : 0%, P-for-interaction: 0.57), as well as in sub-groups of patients with and without diabetes mellitus at baseline (P-for-interaction: 0.81). SGLT2 inhibitors were associated with a significant reduction in cardiovascular death (HR: 0.87, 95% CI: 0.79, 0.97, I² : 0%, P < 0.00001) and total heart failure hospitalization (RR: 0.71, 95% CI: 0.67, 0.76, I² : 0%, P < 0.00001); although a potential trend towards reduced all-cause mortality was noted with SGLT2 inhibitors, no statistically significant difference was observed (HR: 0.91, 95% CI: 0.83, 1.00, I² : 14%, P = 0.05).

Conclusions: Sodium-glucose cotransporter 2 inhibitors reduce cardiovascular death and heart failure hospitalization among patients with heart failure, regardless of LVEF status.

Keywords: Diabetes; HFpEF; HFrEF; SGLT2i.

Figure 1

Forest plot demonstrating clinical outcomes between patients on SGLT2 inhibitors vs. placebo in randomized controlled trials in the setting of heart failure. Square markers represent point estimate of HR for individual studies, with square size representing proportional weight given to each study in the meta‐analysis. Horizontal lines indicate 95% CIs. The solid diamonds represent the estimated 95% CI for effect size of all meta‐analysed data. Abbreviations: CI, confidence interval; CV, cardiovascular; HFH, heart failure hospitalization; HR, hazard ratio; RR, risk ratio; SGLT, sodium glucose cotransporter.

Figure 2

Forest plot demonstrating composite of heart failure hospitalization or cardiovascular death between patients on SGLT2 inhibitors vs. placebo/control in randomized controlled trials stratified by (A) LVEF at baseline and (B) DM status at baseline. Square markers represent point estimate of HR for individual studies, with square size representing proportional weight given to each study in the meta‐analysis. Horizontal lines indicate 95% CIs. The solid diamonds represent the estimated 95% CI for effect size of all meta‐analysed data. Abbreviations: CI, confidence interval; CV, cardiovascular; DM, diabetes mellitus; EF, ejection fraction; HFH, heart failure hospitalization; HR, hazard ratio; RR, risk ratio; SGLT, sodium glucose cotransporter.