THE SGLT2 INHIBITOR EMPAGLIFLOZIN REDUCES MORTALITY IN EXPERIMENTAL PULMONARY HYPERTENSION

Abstract

Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, enhances urinary glucose excretion and profoundly reduces hospitalization for heart failure and cardiovascular mortality in individuals with type 2 diabetes. While empagliflozin has been reported to reduce blood pressure, its effect on pulmonary hypertension (PH) is unknown. PH is a severe and progressive disease that is characterized by pulmonary artery vasoconstriction, vascular remodeling, right ventricular hypertrophy, and ultimately heart failure. This study investigated the impact of empagliflozin on PH-associated mortality and the progression as well as the reversal of PH in monocrotaline (MCT)-treated Sprague-Dawley rats. A total of 83 male Sprague-Dawley rats (220-250 g) were randomly assigned to one of three studies. PH was induced with a single intraperitoneal injection of MCT on day 0 and empagliflozin (10 mg/kg) or vehicle (0.5% hydroxyethyl cellulose) was administered daily by oral gavage. Some rats were injected with an equal volume of saline in place of MCT. Survival study: PH was induced with 60 mg/kg MCT. Starting on day 1, rats were treated with empagliflozin (n=16) or vehicle (n=15) for 28 days and monitored for up to 45 days of post-MCT injection. Prevention study: Rats were administered 60 mg/kg MCT and treated with empagliflozin (n=12) or vehicle (n=12) for 20 days from day 1 onwards. Reversal study: 21 days after being injected with 40 mg/kg MCT, rats were given empagliflozin (n=8) or vehicle (n=8) for 14 days. At the end of the treatment window, rats in the latter two studies underwent hemodynamic assessments before key tissues were harvested for molecular and histological review. Compared to its vehicle, empagliflozin significantly improved survivability in rats with MCT-induced PAH (Figure). Furthermore, the MCT-empagliflozin group, relative to the MCT-vehicle-treated rats, had significantly lower mean pulmonary artery pressure, right ventricular systolic pressure, higher pulmonary acceleration time in both the Prevention and Reversal study groups. The decreased afterload resulted in less right ventricular hypertrophy in the empagliflozin-treated rats. Histological assessments of lung tissues revealed significantly less medial wall thickening and muscularization in pulmonary arterioles from empagliflozin-treated vs. vehicle-treated rats (Table). This is the first study demonstrating that SGLT2 inhibition with empagliflozin lowers mortality in experimental pulmonary hypertension in part via reduced pulmonary vascular remodeling.View Large Image Figure ViewerDownload Hi-res image Download (PPT)