Empagliflozin Prevents Worsening of Cardiac Function in an Experimental Model of Pressure Overload-Induced Heart Failure

Visual Abstract

Highlights

• •

  Although empagliflozin markedly reduces heart failure and cardiovascular-related deaths in diabetic patients, whether empagliflozin improves cardiac outcomes in the absence of diabetes is unknown.

• •

  Nondiabetic mice subjected to pressure overload exhibited a decline in LV function, both in vivo and ex vivo.

• •

  Nondiabetic mice with significantly reduced LV function treated with empagliflozin demonstrated systolic function that was preserved compared to that in vehicle-treated mice, which continued to worsen.

• •

  Preserved cardiac function in empagliflozin-treated mice with heart failure was sustained ex vivo in the absence of ketones or hemodynamic changes.

Summary

This study sought to determine whether the sodium/glucose cotransporter 2 (SGLT2) inhibitor empagliflozin improved heart failure (HF) outcomes in nondiabetic mice. The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial demonstrated that empagliflozin markedly prevented HF and cardiovascular death in subjects with diabetes. However, despite ongoing clinical trials in HF patients without type 2 diabetes, there are no objective and translational data to support an effect of SGLT2 inhibitors on cardiac structure and function, particularly in the absence of diabetes and in the setting of established HF. Male C57Bl/6 mice were subjected to either sham or transverse aortic constriction surgery to induce HF. Following surgery, mice that progressed to HF received either vehicle or empagliflozin for 2 weeks. Cardiac function was then assessed in vivo using echocardiography and ex vivo using isolated working hearts. Although vehicle-treated HF mice experienced a progressive worsening of cardiac function over the 2-week treatment period, this decline was blunted in empagliflozin-treated HF mice. Treatment allocation to empagliflozin resulted in an improvement in cardiac systolic function, with no significant changes in cardiac remodeling or diastolic dysfunction. Moreover, isolated hearts from HF mice treated with empagliflozin displayed significantly improved ex vivo cardiac function compared to those in vehicle-treated controls. Empagliflozin treatment of nondiabetic mice with established HF blunts the decline in cardiac function both in vivo and ex vivo, independent of diabetes. These data provide important basic and translational clues to support the evaluation of SGLT2 inhibitors as a treatment strategy in a broad range of patients with established HF.