Inhibition of Sodium Glucose Cotransporter-2 Mitigates Heart Failure Progression in Obesity

Abstract

Recent clinical outcome studies (EMPA-REG and CANVAS) have demonstrated that a novel class of anti-hyperglycemic agents, which act by inhibiting the sodium-glucose cotransporter-2 (SGLT2i), reduce the risk of hospitalization for heart failure in subjects with type 2 diabetes mellitus. However, the cardiovascular effects of SGLT2i in heart failure are poorly understood. The purpose of the present study was to examine the hypothesis that preventative SGLT2i administration attenuates the progression of heart failure in the setting of obesity. Ossabaw swine were fed a high fat/high carbohydrate diet for 3 months and chronically instrumented with a telemetry system and a pacing electrode. Following recovery from surgery, animals were randomized to treatment groups (control vs. canagliflozin (300 mg orally per day)). Canagliflozin treatment began immediately prior to initiation of high rate pacing and was continued until terminal procedure was performed. Animals in both groups (control, n = 5 and SGLT2i, n = 5) were paced at a heart rate of 182 beats/min for ∼3-4 weeks prior to terminal procedure at which time measurements were obtained. Body weights were similar between control (62 ± 4 kg) and SGLT2i treated swine (60 ± 5 kg) (P = 0.77) Chronic high rate pacing augmented left ventricular (LV) end-diastolic pressure to ∼31 ± 3 mmHg in control swine (LV end-diastolic pressure in normal swine typically