Empagliflozin for Heart Failure With Preserved Left Ventricular Ejection Fraction With and Without Diabetes

Abstract

Background: Empagliflozin improves outcomes in patients with heart failure with a preserved ejection fraction, but whether the effects are consistent in patients with and without diabetes remains to be elucidated. Methods: Patients with class II through IV heart failure and a left ventricular ejection fraction >40% were randomized to receive empagliflozin 10 mg or placebo in addition to usual therapy. We undertook a prespecified analysis comparing the effects of empagliflozin versus placebo in patients with and without diabetes. Results: Of the 5988 patients enrolled, 2938 (49%) had diabetes. The risk of the primary outcome (first hospitalization for heart failure or cardiovascular death), total hospitalizations for heart failure, and estimated glomerular filtration rate decline was higher in patients with diabetes. Empagliflozin reduced the rate of the primary outcome irrespective of diabetes status (hazard ratio, 0.79 [95% CI, 0.67, 0.94] for patients with diabetes versus hazard ratio, 0.78 [95% CI, 0.64, 0.95] in patients without diabetes; P interaction =0.92). The effect of empagliflozin to reduce total hospitalizations for heart failure was also consistent in patients with and without diabetes. The effect of empagliflozin to attenuate estimated glomerular filtration rate decline during double-blind treatment was also present in patients with and without diabetes, although more pronounced in patients with diabetes (1.77 in diabetes versus 0.98 mL/min/1.73m 2 in patients without diabetes; P interaction =0.01). Across these 3 end points, the effect of empagliflozin did not differ in patients with prediabetes or normoglycemia (33% and 18% of the patient population, respectively). When investigated as a continuous variable, baseline hemoglobin A1c did not modify the effects on the primary outcome ( P interaction =0.26). There was no increased risk of hypoglycemic events in either subgroup as compared with placebo. Conclusions: In patients with heart failure and a preserved ejection fraction enrolled in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), empagliflozin significantly reduced the risk of heart failure outcomes irrespective of diabetes status at baseline. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03057951.

Cardiovascular and renal efficacy and safety of sodium-glucose cotransporter-2 inhibitors in patients without diabetes: a systematic review and meta-analysis of randomised placebo-controlled trials

“…By evaluating a total of 10 safety outcomes, the results of our study showed that treatment with SGLT2 inhibitors elicited some adverse events though had lower risk for any serious adverse events and acute renal failure in the population without diabetes. It is also important to note that there were no events of hypoglycaemia or ketoacidosis in the included trials, except for EMPEROR-Preserved trial reported by Filippatos et al 30 that showed a similar hypoglycaemic event in both groups. Compared with those in the placebo group, participants in the SGLT2 inhibitors group experienced an increased risk of urinary tract infection by 29% (RR: 1.29, 95% CI: 1.05 to 1.58, p=0.02; figure 3G ; low certainty evidence, online supplemental table S2 ) and a 2.44-fold higher risk of genital infection (RR: 2.44, 95% CI: 1.14 to 5.25, p=0.02; figure 3H ; low certainty evidence, online supplemental table S2 ).…”

“…Figure 2 shows the pooled estimates of CV and renal outcomes. The composite renal outcome generally included renal death, ESKD and a sustained reduction in eGFR of 50% or greater in the DAPA-HF trial 26 and DAPA-CKD trial 29 and 40% or greater in the EMPEROR-Reduced trial 28 and EMPEROR-Preserved trial 30 ; the composite renal outcome did not include renal-related death in the EMPEROR-Reduced trial 28 and EMPEROR-Preserved trial 30 ( online supplemental table S3 ). Between-study heterogeneity was not present in the CV and renal outcomes ( figure 2A–F ).…”

“…Figure 3 displays the pooled estimates for the safety outcomes. All four trials26 28–30 reported data on adverse events, including any serious adverse event, discontinuation of the study drug due to adverse events, hypoglycaemia, ketoacidosis, amputation, volume depletion and acute renal failure. Three trials26 28 29 reported the risk of fracture.…”

“…Three trials26 28 29 reported the risk of fracture. Three trials28–30 reported the risk of urinary tract infection and genital infection. Three trials26 28 29 reported that there was no event of hypoglycaemia in either group and one trial30 reported two hypoglycaemic events in each group.…”

“…Three trials28–30 reported the risk of urinary tract infection and genital infection. Three trials26 28 29 reported that there was no event of hypoglycaemia in either group and one trial30 reported two hypoglycaemic events in each group. All four trials reported that there was no event of ketoacidosis in either group.…”