The Cardiovascular Benefits of Empagliflozin, A Sodium Glucose Cotransporter Inhibitor: Is NHE1 a Viable Target?

Abstract

Empagliflozin (EMPA), an SGLT2 inhibitor (with a low affinity for SGLT1) has attracted much attention due to a recent clinical trial, the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME). In this trial, treatment with EMPA over 2.6 years decreased cardiovascular vascular events (14% reduction). Whether EMPA induces cardioprotection independent of diabetes remains unclear. A previous report has demonstrated that EMPA inhibited NHE1 activity, which led to a reduction in intracellular sodium and calcium. In our study, we examine the cellular interplay between NHE1 and SGLT1/SGLT2 in a non-diabetic in vitro model. We characterized H9c2 cardiomyoblasts stimulated with Angiotensin II (ANG II) 100nM in the presence and absence of EMPA (500nM) and measured cardiomyocyte hypertrophy and the expression of NHE1 and SGLT1/2. Stimulation of H9c2 cardiomyoblasts with ANG II (100nM) resulted in cardiomyocyte hypertrophy, an effect that was regressed in the presence of EMPA (500nM). No changes in SGLT2 and NHE1 protein expression were detected in H9c2 cardiomyoblasts. However, stimulation with ANG II in the presence of EMPA reduced the expression of SGLT1. We demonstrate that the inhibition of SGLT using EMPA following stimulation with ANG II, a hypertrophic stimulator of cardiomyocyte hypertrophy and NHE1, regressed the hypertrophic response of H9c2 cardiomyoblasts and SGLT1 protein expression. The inhibition of SGLT1 protein expression may be contributing to the anti-hypertrophic effect of EMPA. Whether EMPA reduces NHE1 activity remains to be elucidated