Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure

Abstract

BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction. METHODS In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure. RESULTS During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs.-2.28 ml per minute per 1.73 m 2 of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin. CONCLUSIONS Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.

Characterization of left ventricular myocardial sodium-glucose cotransporter 1 expression in patients with end-stage heart failure

“…Those with HF at baseline drived the most benefit [37], fueling speculations regarding the mechanism of cardioprotection mediated by SGLT2 inhibitors. However, in the DAPA-HF and the EMPEROR-Reduced trials-two dedicated HF trialsthe SGLT2 inhibitors dapagliflozin and empagliflozin reduced hospitalization for HF similarly in non-diabetic and diabetic HFrEF patients [5,6]. These data suggest that SGLT2 inhibitors have direct cardioprotective effects in HF, which are independent of the presence of T2DM [38,39].…”

“…Selective sodium-glucose cotransporter 2 (SGLT2) inhibitors are novel oral antidiabetic agents that block SGLT2 in the proximal convoluted tubule of the kidney, resulting in increased glucose excretion. Recent cardiovascular outcome trials in patients with type 2 diabetes mellitus (T2DM) [1][2][3], and dedicated heart failure (HF) trials in patients with HF and reduced ejection fraction (HFrEF) with or without T2DM [4][5][6] have demonstrated a consistently significant reduction in hospitalization for HF with SGLT2 inhibitor treatment versus placebo. Therefore, it has been postulated that SGLT2 inhibition in the kidney does not serve as full explanation for the marked clinical benefits associated with SGLT2 inhibitor treatment [7][8][9][10][11], suggesting direct cardiovascular mechanisms, which are currently incompletely understood given that SGLT2 is not expressed in the normal or diseased heart [9,[12][13][14][15][16][17].…”

Cardiology on the cutting edge: updates from the European Society of Cardiology (ESC) Congress 2020

“…In this study, the antidiabetic drug empagliflozin on top of optimized medical therapy reduced the composite primary endpoint of CV death and hospitalization in patients with HF and reduced ejection fraction (HFrEF), with the great majority of them presenting with a left ventricle ejection fraction (LVEF) of ≤ 30%. In addition, empagliflozin showed positive effects on reducing the progression of kidney disease [23]. A meta-analysis of EMPEROR-Reduced and DAPA-HF trials confirmed these findings [26].…”

“…In this commentary, we summarized the most important trials presented during the 2020 Virtual ESC Congress (Table 1) which we predict will improve our everyday clinical practice [12][13][14][15][16][17][18][19][20][21][22][23][24]. The EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trial [23] further strengthened the positive findings observed in the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial [25]. In this study, the antidiabetic drug empagliflozin on top of optimized medical therapy reduced the composite primary endpoint of CV death and hospitalization in patients with HF and reduced ejection fraction (HFrEF), with the great majority of them presenting with a left ventricle ejection fraction (LVEF) of ≤ 30%.…”

Sodium–Glucose Co-transporter 2 Inhibitors in Heart Failure: Recent Data and Implications for Practice

“…8 More recently, the Empagliflozin Outcome Trial in hospitalisation for HF, but failed to demonstrate benefit in terms of mortality. 9 This article aims to discuss the evidence supporting the use of dapagliflozin and empagliflozin in patients with HFrEF with and without T2D and the optimal place for SGLT2 inhibitors in HF therapy.…”