Two Tales: One Story

Abstract

A lthough the sodium-glucose cotransporter-2 (SGLT2) inhibitors were originally developed to manage hyperglycemia in people with type 2 diabetes, they have consistently been found to improve heart failure and kidney outcomes. In contrast to the initial SGLT2 inhibitor outcome trials that demonstrated robust reductions for incident heart failure in people with type 2 diabetes, 2 recent trials-EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction; with empagliflozin) 1 and DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; with dapagliflozin) 2,3-have examined the efficacy of SGLT2 inhibitors to treat patients with heart failure with reduced ejection fraction (HFrEF), with or without type 2 diabetes. We compare the 2 trials and their results. Although both EMPEROR-Reduced (n=3730) 1 and DAPA-HF (n=4744) 2 enrolled patients with chronic heart failure and a left ventricular ejection fraction of ≤40%, they differed with respect to their NT-proBNP (N-terminal pro-B-type natriuretic peptide) eligibility criteria (Table), with the former requiring a sliding scale NT-proB-NP level according to baseline left ventricular ejection fraction. Such a strategy, by design, was used with an intent to target patients with more advanced HFrEF. Indeed, the baseline left ventricular ejection fraction was lower (27% versus 31%) and the median NT-proBNP levels higher (≈1900 pg/mL versus ≈1430 pg/mL) in EMPEROR Reduced compared with DAPA-HF. However, interestingly, fewer patients in EMPEROR-Reduced were hospitalized for heart failure (HHF) within the preceding 12 months (≈31% versus 47%), and numerically more patients in EMPEROR-Reduced were in New York Heart Association functional class II. Baseline estimated glomeru-lar filtration rate (eGFR) was lower in EMPEROR-Reduced (≈61 mL·min −1 ·1.73 m-2) compared with DAPA-HF (≈66 mL·min −1 ·1.73 m-2), and proportionally more EMPEROR Reduced patients had an eGFR that was ≤60 mL·min −1 ·1.73 m-2. Both trials recruited similar proportions of patients with and without type 2 diabetes (≈50%). Background therapy for HFrEF was excellent in both trials, with high rates of goal-directed medical therapy including β-blockers, renin-angiotensin-aldosterone system inhibitors, and mineralocorticoid antagonists. The use of sacubitril/valsartan was almost twice as high in EMPEROR-Reduced compared with DAPA-HF but remained still relatively low overall. As a reflection of these differences in patient populations, the placebo event rates also differed between the 2 trials. Specifically, for the composite outcome of cardio-vascular death or HHF, the event rate per 100 patient-years was 21% in EMPEROR-Reduced versus 15% in DAPA-HF. This was a result of a higher rate of HHF with similar rates of cardiovascular death in both trials (Table). There was remarkable consistency for the outcome of cardiovascular death or HHF-both trials demonstrated a 25% reduction in the groups assigned to the SGLT2 inhibitors, with absolute risk reductions of 5.2 and 3.9 per 100 person-years in EMPEROR-Reduced and DAPA-HF,