Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status

Abstract

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events. Methods: Patients with class II-IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes. Results: Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (HbA1c 5.7-6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio 0.72 [95% CI 0.60-0.87] and 0.78 [95% CI 0.64-0.97], respectively, interaction P =0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these endpoints, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome (P-interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia. Conclusions: In the EMPEROR-Reduced trial, empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c.

Efficacy and safety of SGLT2 inhibitors in heart failure: systematic review and meta‐analysis

“…For the DAPA-HF and EMPEROR-Reduced trials, data of diabetes subgroups were taken from post hoc studies. 18,19 Subgroup analyses based on age, sex, and angiotensin receptor/neprilysin inhibitor use were conducted only for the HFrEF population, as data for these subgroups were only available for this population. The χ 2 test was used to test for subgroup differences.…”

Early initiation of SGLT2 inhibitors is important, irrespective of ejection fraction: SOLOIST‐WHF in perspective

“…Ongoing studies in patients with acute heart failure that include people with and without diabetes will help answer this question further (DAPA ACT HF‐TIMI 68, ClinicalTrials.gov Identifier: NCT04363697; EMPULSE, ClinicalTrials.gov Identifier: NCT04157751). While SOLOIST‐WHF studied patients with type 2 diabetes, evidence from both DAPA‐HF and EMPEROR‐Reduced point toward an entirely consistent benefit of dapagliflozin and empagliflozin in those with and without type 2 diabetes 27,31 . Therefore, it would be reasonable to hypothesize that the benefits noted in SOLOIST‐WHF would also extend to those without type 2 diabetes.…”

“…In two recently completed studies—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) and EMPEROR‐Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction)—dapagliflozin and empagliflozin, respectively, reduced the risk of cardiovascular death and HHF by 26% in patients with HFrEF 20–22 . Importantly, these benefits were observed consistently in those with and without type 2 diabetes, were in addition to excellent background heart failure therapies, and resulted in an improvement in patient reported quality of life indices 20–32 . Because both trials recruited patients with chronic ambulatory HFrEF [and excluded patients with hospitalization due to decompensated heart failure less than 4 weeks prior to enrolment (DAPA‐HF)], it can be argued that the question of in‐hospital initiation of SGLT2 inhibitors during a WHF event has remained unanswered.…”

“…While SOLOIST-WHF studied patients with type 2 diabetes, evidence from both DAPA-HF and EMPEROR-Reduced point toward an entirely consistent benefit of dapagliflozin and empagliflozin in those with and without type 2 diabetes. 27,31 Therefore, it would be reasonable to hypothesize that the benefits noted in SOLOIST-WHF would also extend to those without type 2 diabetes.…”

Renoprotective effects of sodium glucose cotransporter 2 inhibitors in type 2 diabetes patients with decompensated heart failure

“…Therefore, it remains unclear whether the renal bene cial effect is consistent across any SGLT2is. Lastly, the EMPEROR-Reduced trial revealed that SGLT2i reduced the risk of the composite renal endpoint, independently of diabetes status [23]. We also indicated that increases in eGFR during the observation period were independent of the HbA1c levels, whereas we did not include patients without T2DM in this study.…”