Sglt-2 Inhibitors: A Useful Addition for Treatment of Heart Failure with Mildly Preserved and Preserved Ejection Fraction

Abstract

Background: The use of sodium-glucose cotransporters type 2 (SGLT2) inhibitors is associated with reduction in cardiorenal outcomes in patients with heart failure and reduced left ventricular ejection fraction (HFrEF). Objective: To clarify the therapeutic role of SGLT2 inhibitors in patients with heart failure and mildly preserved ejection fraction (HFmpEF) and heart failure with preserved ejection fraction (HFpEF). Methods: Pubmed search until October 13, 2022. Search terms included: heart failure, SGLT2 inhibitors, hospitalization, mortality, safety. Randomized clinical trials and guidelines of major societies were reviewed. Results: 2 well-designed trials, the EMPEROR-Preserved and DELIVER trials, have shown that use of SGLT2 inhibitors was associated with decrease cardiac events in patients with HFmpEF and HFpEF. In the EMPEROR-Preserved, empagliflozin 10 mg/d decreased a composite primary outcome of cardiovascular (CV) death or hospitalization for heart failure (HHF) compared with placebo, hazard ratio (HR) 0.79 (95% CI, 0.69-0.90, P<0.001). In the DELIVER Trial, dapagliflozin 10 mg/d decreased the primary outcome of CV death or worsening HF, HR 0.82 (95% CI 0.73-0.92, P<0.001). The effects of empagliflozin and dapagliflozin on the primary outcome were evident and statistically significant versus placebo after 13-18 days post randomization. In both EMPEROR-Preserved and DELIVER trials, no significant effects on CV death were demonstrated. By pooling data from the 2 trials, the effects of empagliflozin and dapagliflozin on CV death was close but did not reach statistical significance, HR 0.88 (95% CI 0.77-1.00, P=0.052). Meanwhile, after pooling 2 dapagliflozin trials to include patients with HFrEF (DAPA-HF trial) and HFmpEF + HFpEF (DELIVER trial), dapagliflozin significantly decreased CV death, HR 0.86 (95% CI, 0.75-0.98, P=0.02) and all-cause mortality, HR 0.90 (95% CI, 0.82-0.99, P=0.03). The CV effects of empagliflozin and dapagliflozin were consistent regardless of age, gender, presence or absence of diabetes or atrial fibrillation. Yet, the effect of empagliflozin on decreasing HHF was attenuated in patients with baseline left ventricular ejection fraction (LVEF) of ≥60% and disappeared at LVEF ≥65%. On the other hand, dapagliflozin effects on cardiac outcomes remained consistent regardless of baseline LVEF. Both empagliflozin and dapagliflozin were generally well tolerated, with rates of drug discontinuation due to adverse effects similar to those with placebo. Conclusions: SGLT2 inhibitors should be the standard of care in patients with HFmpEF and HF pEF similar to their established indication in patients with HFrEF. Until direct comparison between empagliflozin and dapagliflozin becomes available, dapagliflozin should be the SGLT2 inhibitor of choice, particularly in patients with HFmpEF and HFpEF.