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Large clinical trials established the benefits of sodium-glucose cotransporter 2 inhibitors in patients with diabetes and with heart failure with reduced ejection fraction (HFrEF). The early and significant improvement in clinical outcomes is likely explained by effects beyond a reduction in hyperglycemia.The purpose of this study was to assess the effect of empagliflozin on left ventricular (LV) function and volumes, functional capacity, and quality of life (QoL) in nondiabetic HFrEF patients.In this double-blind, placebo-controlled trial, nondiabetic HFrEF patients (n = 84) were randomized to empagliflozin 10 mg daily or placebo for 6 months. The primary endpoint was change in LV end-diastolic and -systolic volume assessed by cardiac magnetic resonance. Secondary endpoints included changes in LV mass, LV ejection fraction, peak oxygen consumption in the cardiopulmonary exercise test, 6-min walk test, and quality of life.Empagliflozin was associated with a significant reduction of LV end-diastolic volume (-25.1 ± 26.0 ml vs. -1.5 ± 25.4 ml for empagliflozin vs. placebo, respectively; p 0.001) and LV end-systolic volume (-26.6 ± 20.5 ml vs. -0.5 ± 21.9 ml for empagliflozin vs. placebo; p 0.001). Empagliflozin was associated with reductions in LV mass (-17.8 ± 31.9 g vs. 4.1 ± 13.4 g, for empagliflozin vs. placebo, respectively; p 0.001) and LV sphericity, and improvements in LV ejection fraction (6.0 ± 4.2 vs. -0.1 ± 3.9; p 0.001). Patients who received empagliflozin had significant improvements in peak OEmpagliflozin administration to nondiabetic HFrEF patients significantly improves LV volumes, LV mass, LV systolic function, functional capacity, and quality of life when compared with placebo. Our observations strongly support a role for sodium-glucose cotransporter 2 inhibitors in the treatment of HFrEF patients independently of their glycemic status. (Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity? [ATRU-4] [EMPA-TROPISM]; NCT03485222).

Beta-blockers (BBs) remain underused in elderly patients with reduced ejection fraction (REF). Our aim was to determine the prognostic impact of different doses of BB in this setting.A single-center observational study was conducted. Inclusion criteria were age≥75 and EF≤0.35. Six months after diagnosis, patients were divided into 3 groups depending on BB dose: no BB (NBB), low dose (50% of the target dose) (LD), and high dose (≥50%) (HD). Two different analytical approaches were employed: multivariate Cox model and propensity-score (PS) matching. Outcomes were all-cause death and heart failure (HF) admission. We included 559 patients (134 NBB, 259 LD, and 166 HD) with median follow-up of 29.9months. There were 212 deaths (NBB: 70 (52.2%); LD: 94 (36.3%); and HD: 48 (28.9%)) and 171 HF admissions (NBB: 42 (31.3%); LD: 85 (32.8%); and HD: 44 (26.5%)). On multivariate analysis, both LD and HD were associated with improved survival, with no differences between them (HD vs. NBB=0.67, 95% CI=[0.46-0.98], p=0.037; HD vs. LD=1.03, 95% CI=[0.72-1.46], p=0.894; and LD vs. NBB=0.65, 95% CI=[0.48-0.90], p=0.009). However, BB therapy failed to show benefits in HF admissions (p=NS, for each comparison). PS-matched analysis included 198 patients, with similar results to those mentioned above.BB therapy was associated with a significant reduction in mortality among elderly patients with REF, regardless of dose. Nevertheless, it was not associated with a decrease in HF admissions. Further studies are needed to determine the optimal BB dose in these patients.

We appreciate the comments by Baker and colleagues on our paper [(1)][1]. We described that empagliflozin ameliorates adverse cardiac remodeling, enhances systolic function, switches myocardial fuel utilization, and improves myocardial energetics in a nondiabetic heart failure (HF) model. Baker and

The SGTL2 inhibitor empagliflozin (Empa) reduces HF. We have recently demonstrated 1) the mechanism is due to a switch in myocardial metabolism towards ketone bodies (KB) consumption; and 2) KB infusion improves LV systolic function in a porcine HF model. However, there is no information about the