Does gliflozin treatment for heart failure have greater benefits in diabetics?

Introduction

Heart failure remains a serious issue for the current population despite significant advancements in diagnosis and treatment. The presence of type 2 diabetes mellitus (DM2) increases the risk of heart failure and further complicates already existing heart failure, limiting treatment options.

Currently, much attention is given to studying the pharmacological effects and efficacy of sodium-glucose co-transporter inhibitors (SGLT2i) – gliflozines. Shortly after their registration, it became evident that besides their glycosuric effect, they also exhibit significant cardioprotective and renoprotective effects, which cannot be explained solely by the normalization of glycemia.

One of the clinical studies that analyzed the impact of SGLT2i, specifically empagliflozin, on clinical outcomes in patients with HFrEF was the multicenter phase III EMPEROR-Reduced study conducted between 2017 and 2020. In a predefined subanalysis of data from this study, an international team of researchers focused on potential differences in the efficacy of empagliflozin in diabetic and non-diabetic populations.

Study Methodology and Participant Population

The study included 3,730 patients with HFrEF classified as NYHA II-IV with a left ventricular ejection fraction (LVEF) ≤ 40%. Overall, 50% of the participants had diabetes, 34% fell into the prediabetes range characterized by glycated hemoglobin (HbA_1c) values of 5.7-6.4%, and 16% were normoglycemic (HbA_1c < 5.7%).

Participants were randomized in a 1:1 ratio to receive empagliflozin (10 mg daily) or placebo in addition to the recommended heart failure treatment. The primary endpoint was the time to the first event – confirmed hospitalization for heart failure or a confirmed cardiovascular (CV) death.

Who Gains Greater Cardiovascular and Renal Benefits?

Predictably, the risk of CV death or hospitalization for heart failure, as well as the risk of any hospitalization and adverse renal outcomes, was higher in patients with diabetes. Patients with prediabetes and normoglycemia had lower and similarly comparable risks.

Empagliflozin significantly reduced the risk of the primary endpoint compared to placebo, regardless of diabetes presence: hazard ratio (HR) 0.72 for diabetics (95% confidence interval [CI] 0.60-0.87) and HR 0.78 for non-diabetics (95% CI 0.64-0.97). Changes in HbA_1c during the treatment did not affect the occurrence of the primary endpoint.

The effects of empagliflozin did not differ between diabetic and non-diabetic populations in terms of total heart failure hospitalization rates, reduction in estimated glomerular filtration rate over time, and the risk of serious adverse renal outcomes. These parameters also did not differ when comparing patients with prediabetes or normoglycemia. Empagliflozin did not reduce HbA_1c in patients with prediabetes or normoglycemia and was not associated with an increased risk of hypoglycemia.

Conclusion

In the EMPEROR-Reduced study, empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure with reduced ejection fraction, regardless of the presence of diabetes or changes in HbA_1c during treatment. Empagliflozin has the potential to positively impact the lives of adult patients with various types of heart failure and comorbidities.

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Sources:
1. Anker S. D., Butler J., Filippatos G. et al. Effect of empagliflozin on cardiovascular and renal outcomes in patients with heart failure by baseline diabetes status: results from the EMPEROR-Reduced Trial. Circulation 2021, 143 (4): 337-349, doi: 10.1161/CIRCULATIONAHA.120.051824.
2. Fathi A., Vickneson K., Singh J. S. SGLT2-inhibitors; more than just glycosuria and diuresis. Heart Fail Rev 2021; 26 (3): 623-642, doi: 10.1007/s10741-020-10038-w.