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.

Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin. CONCLUSIONSEmpagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951).

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OBJECTIVETo investigate the efficacy, safety, and tolerability of empagliflozin in patients with type 2 diabetes and hypertension. RESEARCH DESIGN AND METHODSPatients (N = 825) with type 2 diabetes and hypertension (mean seated systolic blood pressure [SBP] 130-159 mmHg and diastolic blood pressure [DBP] 80-99 mmHg) were randomized (double blind) to 10 mg or 25 mg empagliflozin or placebo once daily for 12 weeks. RESULTSAt week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h SBP (ambulatory blood pressure monitoring [ABPM]) was 23.44 mmHg (95% CI 24.78, 22.09) with 10 mg empagliflozin and 24.16 mmHg (25.50, 22.83) with 25 mg empagliflozin (both P < 0.001). At week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h DBP (ABPM) was 21.36 mmHg (95% CI 22.15, 20.56) with 10 mg empagliflozin and 21.72 mmHg (95% CI 22.51, 20.93) with 25 mg empagliflozin (both P < 0.001). Changes in office BP were consistent with ABPM. Adjusted mean difference versus placebo in change from baseline in HbA 1c at week 12 was 20.62% (95% CI 20.72, 20.52) (26.8 mmol/mol [95% CI 27.9, 25.7]) with 10 mg empagliflozin and 20.65% (95% CI 20.75, 20.55) (27.1 mmol/mol [95% CI 28.2, 26.0]) with 25 mg empagliflozin (both P < 0.001). Empagliflozin was well tolerated. One patient on placebo and one patient on 10 mg empagliflozin reported events consistent with volume depletion. CONCLUSIONSEmpagliflozin was associated with significant and clinically meaningful reductions in BP and HbA 1c versus placebo and was well tolerated in patients with type 2 diabetes and hypertension.The lifetime risk of cardiovascular disease in patients with diabetes is 67-78% (1). Management of patients with type 2 diabetes should not only aim to control glycemia but also include the modification of cardiovascular risk factors (2,3). Hypertension affects approximately two-thirds of patients with diabetes (4,5) and is a significant contributing factor to cardiovascular complications (3,6). Lowering blood pressure (BP) has been shown to reduce cardiovascular events in patients with diabetes and to exert a renoprotective effect (3,7,8). The Joint National Committee (JNC) 2003 guidelines recommended targets of systolic BP (SBP) ,130 mmHg and diastolic BP (DBP) ,80 mmHg in patients with hypertension and diabetes (9). The guidelines

Aims To report data from EMPEROR‐Preserved according to prespecified endpoints of DELIVER. Methods and results In order to assess the impact of DELIVER‐like definition on EMPEROR‐Preserved outcomes, the following differences were reconciled: (1) the primary outcome in DELIVER added urgent heart failure (HF) visits to cardiovascular death or HF hospitalizations; (2) the EMPEROR‐Preserved trial did not require documentation of physical findings or laboratory tests for confirming a HF hospitalization and it included events of 12–24 h if intensification of treatment was not only oral diuretics; (3) DELIVER excluded undetermined causes of deaths from the primary endpoint; (4) the composite renal endpoint in DELIVER included a sustained ≥50% decline in estimated glomerular filtration rate and incorporated renal death; and (5) DELIVER will assess outcomes in the overall population and in patients with ejection fraction (EF) <60% separately. Using the endpoint definitions from DELIVER, the primary outcome overall occurred in 13.1% in the empagliflozin and 16.8% in the placebo group (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.67–0.87; p < 0.0001). The relative risk reduction (RRR) changed from 21% to 24% when urgent HF visits were added, and undetermined death was eliminated. Compared to overall population RRR of 24%, it was 28% in patients with EF <60%. Death from cardiovascular causes excluding undetermined causes occurred in 6.2% in the empagliflozin and in 7.1% in the placebo group (HR 0.88, 95% CI 0.73–1.07). The RRR for the composite renal endpoint changed from 22% in the overall population (HR 0.78, 95% CI 0.54–1.13) to 40% when patients with EF <60% were assessed (p = 0.037). Conclusion Findings from EMPEROR‐Preserved were modestly altered when analysed using cardiovascular trial endpoint definitions of the DELIVER trial. For the composite renal endpoint, the effect of empagliflozin became statistically significant in patients with EF <60% using the DELIVER definition.