The EMPEROR-Preserved trial randomized patients with heart failure with preserved ejection fraction (HFpEF) to receive empagliflozin, 10 mg, or placebo in addition to usual therapy, with a primary outcome of first hospitalization for HF or cardiovascular (CV) death. The current subgroup analysis looked at the effects of the drug by whether patients had diabetes and found that it reduced the rate of the primary outcome irrespective of diabetes status (hazard ratios, 0.79 [95% CI, 0.67 to 0.94] for patients with diabetes and 0.78 [95% CI, 0.64 to 0.95] in those without).
Although sodium–glucose cotransporter-2 (SGLT2) inhibitors were developed to treat diabetes mellitus, we have learned that they have beneficial effects in patients with diabetes plus cardiovascular disease, and with chronic kidney disease and HF, regardless of diabetes status.
HFpEF accounts for half of HF cases, and about 55% of patients with HFpEF do not have diabetes. The subgroup analysis of the EMPEROR-Preserved trial by Filippatos and colleagues showed that the relative risk reduction with empagliflozin was similar in patients with or without diabetes, although event rates, and therefore absolute risk reductions, were greater in patients with diabetes. The treatment effect was driven by a reduction in HF hospitalizations. Empagliflozin also attenuated the decline in estimated glomerular filtration rate in patients with and without diabetes, but the effect was more pronounced in patients with diabetes.
In the 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America guidelines, SGLT2 inhibitors carry a class I recommendation for HF with reduced EF and class IIa indication for HFpEF. Initiation of the drug in HF is not linked to hypotension, volume depletion, acute kidney injury, hypoglycemia, or amputation. Although the risk is low, SGLT2 inhibitors increase the risk for genital infections, urinary tract infections, and euglycemic diabetic ketoacidosis in patients with diabetes. The combination of efficacy and safety makes SGLT2 inhibitors an important treatment for HF across left ventricular EF levels, regardless of diabetes status.