Journey from EMPA-REG to CARMELINA to EMPEROR-Preserved: Empagliflozin/linagliptin in heart failure and diabetes

Abstract

Diabetes mellitus is present in more than two-fifths of the patients suffering from heart failure (HF), with the incidence being more than twice that found in the non-diabetic population. It doubles the risk of hospitalization and increases the risk of fatal outcomes, thus negatively affecting the prognosis in HF patients. The available pharmacological treatment options are limited, particularly in HF with preserved ejection fraction (EF). Empagliflozin is a sodium-glucose transporter-2 inhibitor, which has shown a protective effect against cardiomyocyte dysfunction through various mechanisms. The benefits of empagliflozin has been seen in multiple studies: EMPA-REG (April 2015), EMPRISE (June 18, 2019), EMPIRE-HF (2019), EMPA-AHF-RESPONSE (January 7, 2020), The EMPEROR Reduced (May 28, 2020), The RECEDE-CHF (November 3, 2020), SUGAR-DM (February 9, 2021), and EMPEROR-Preserved (April 26, 2021). Empagliflozin reduced the risk of all-cause mortality, HF hospitalizations, and biomarkers in patients with HF both with reduced and preserved EF in prospective and retrospective studies, regardless of the presence of diabetes. Linagliptin is a DPP-4i that has demonstrated renal safety with potential albuminuria benefits as well. Both these agents in combination have shown favorable effects on elevated blood pressure and intima-media thickness. Unlike some other gliptins, linagliptin was not associated with an increased risk of HF, rather a nominal reduction noted in CARMELINA (January 18, 2018). When added to the standard of care, it reduced the dose of insulin in high-risk diabetic patients with HF. The risk of hypoglycemia is significantly less in patients treated with linagliptin compared with sulfonylurea regimen as seen in CAROLINA (August 21, 2018). Thus, considering the plethora of clinical benefits demonstrated, a combination of empagliflozin and linagliptin in patients of diabetes at high risk of HF may be a suitable option for primary and secondary prevention.