By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: After comparing empagliflozin to placebo for patients with heart failure and preserved left ventricular ejection fraction, researchers found no differences in the significant reduction of the primary outcome of cardiovascular death or heart failure hospitalization over 36 months based on whether patients were diabetic.
SOURCE: Filippatos G, Butler J, Farmakis D, et al. Empagliflozin for heart failure with preserved left ventricular ejection fraction with and without diabetes. Circulation 2022;Jun 28:101161CIRCULATIONAHA122059785. doi: 10.1161/CIRCULATIONAHA.122.059785. [Online ahead of print].
The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) study demonstrated heart failure with preserved ejection fraction (HFpEF) patients treated with empagliflozin were at lower risk of reaching the composite primary endpoint of cardiovascular death or HF hospitalization. These patients exhibited a slower rate of the secondary outcome of renal function decline vs. those treated with placebo over the 36-month follow-up period. The authors of a prespecified analysis of EMPEROR-Preserved explored whether these effects were related to the patient’s diabetes status.
EMPEROR-Preserved was an international trial that included 5,988 patients with symptomatic HF and an EF > 40%, elevated natriuretic peptide levels, and evidence of structural heart disease or a previous admission for HF. Diabetes status was determined at baseline (HbA1c ≥ 6.5%) and was found in 49% of patients, almost all of whom had type 2 diabetes. Baseline clinical characteristics of diabetic patients differed from the non-diabetics in several aspects. The primary outcome occurred more frequently in diabetic patients (10.25 vs. 7.21 per 100 patient-years), but empagliflozin lowered the risk of reaching the primary outcome, regardless of diabetic status (HR, 0.79; 95% CI, 0.67-0.94 for patients with diabetes vs. HR, 0.78; 95% CI, 0.64-0.95 for those without; P = 0.92 for the interaction). Also, empagliflozin significantly attenuated the decline in estimated glomerular filtration rate in those with and without diabetes vs. placebo, but was more pronounced in those with diabetes. Genital and urinary tract infections and hypovolemia were more common with empagliflozin, but did not differ by diabetic status. The authors concluded empagliflozin significantly lowered the risk of HF outcomes in patients with HFpEF vs. placebo, regardless of diabetes status at baseline.
COMMENTARY
Empagliflozin is one of a new class of hypoglycemic agents for diabetes — sodium-glucose cotransporter-2 inhibitors (SGLT2i), which have been shown to improve the composite outcome of cardiovascular death, myocardial infarction, stroke, HF hospitalization, and renal events in diabetics. EMPEROR-Preserved produced better outcomes vs. placebo, but any differential effects in diabetic patients have not been studied sufficiently. Hence, this analysis of EMPEROR-Preserved demonstrated that despite a higher rate of the primary outcome in diabetics, patients experienced the same magnitude of benefit from empagliflozin therapy. This is even more impressive considering the diabetic group included more obese young men with hypertension and coronary artery disease. Interestingly, the diabetic group presented with less atrial fibrillation, perhaps because of the association of atrial fibrillation with age. Thus, empagliflozin is beneficial across the entire HF spectrum of patients with reduced and preserved EF, regardless of diabetes status. This is important because diabetes is common in HFpEF patients, and diabetic patients experience worse outcomes. Accordingly, perhaps SGLT2i agents should be the first-line therapy for almost all patients with HF clinical syndromes.
Empagliflozin also lowers weight, especially for patients with diabetes. This could be caused by its diuretic effect; perhaps SGLT2i drugs are just fancy diuretics. Also, these agents have not been shown to affect all-cause or cardiovascular mortality as lone endpoints. Another criticism of the EMPEROR-Preserved trial is the inclusion EF criterion was > 40%. Some of these patients probably experienced reduced EF, as preserved EF likely is ≥ 50%. In addition, about 75% of the patient population was white; less than 5% of the population was Black. Finally, empagliflozin is too expensive.
Nevertheless, EMPEROR-Preserved met its primary endpoint, which is remarkable. Whether the benefits seen with empagliflozin will translate to other SGLT2i drugs is unclear, but studies with dapagliflozin are underway.
After comparing empagliflozin to placebo for patients with heart failure and preserved left ventricular ejection fraction, researchers found no differences in the significant reduction of the primary outcome of cardiovascular death or heart failure hospitalization over 36 months based on whether patients were diabetic.
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