Insufficient evidence regarding benefits from sodium-glucose cotransporter-2 inhibitors in heart failure with preserved ejection fraction

Abstract

Aim: Sodium-glucose cotransporter-2 (SGLT2)-inhibitors improve survival in adults with reduced ejection fraction. Clinical outcomes in adults with heart failure (HF) with preserved ejection fraction (HFpEF) have not been systematically reviewed. Methods: We conducted a systematic rapid literature review and appraised the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation methodology. Results: We identified post-hoc subgroup analyses of four randomized controlled clinical trials (RCTs) and unpublished results from 2 RCTs. In 2 RCTs vs . placebo, Canagliflozin reduced the risk of fatal or hospitalized HF in adults with HF and documented or assumed left ventricular ejection fraction (LVEF) ≥ 50% (hazard rate ratio, HR = 0.71, 95%CI: 0.52-0.97) but had no effect in a subpopulation with documented LVEF ≥ 50% (HR = 0.83, 95%CI: 0.55-1.25). Dapagliflozin or ertugliflozin did not improve all-cause or cardiovascular death or hospitalization for HF in adults with HF and LVEF > 45% in two pivotal RCTs vs . placebo. Empagliflozin did not improve exercise ability, patient-reported outcomes or congestion, diuretic use and all-cause healthcare resource utilization in unpublished RCT vs . placebo. Various definitions of HFpEF, post-hoc interaction analyses suggesting outcome improvement regardless of heart failure type, small number of events, and probable publication bias hampered the quality of evidence. Conclusion: Existing evidence is insufficient to support definitive clinical recommendations for use of SGLT2-inhibitors in adults with HFpEF. Future research should employ consistent definitions of HFpEF and examine the effects from SGLT2- Inhibitors in patients with various HFpEF phenotypes and underlying causes.