P1266Empagliflozin improves left ventricular diastolic function in db/db mice without altering cardiac expression of enzymes relevant for ketone body or branched chain amino acid catabolism

Abstract

Background: Empagliflozin dependent SGLT2-Inhibition was recently found to reduce cardiovascular mortality and heart failure hospitalization in patients with type 2 diabetes in the EMPAREG-OUTCOME trial. The relevant mechanisms for this favorable effect remain poorly understood but might relate to a switch of cardiac substrate utilization toward oxidation of ketone and branched chain amino acid catabolism. Methods and results: To investigate the effects of Empagliflozin on cardiac function and substrate utilization in diabetes we treated db/db mice (n=13/group; 6 weeks of age) on a high fat diet with or without Empagliflozin (150 mg/kg diet) and compared these to heterozygote db/wt controls (n=12/group). Empagliflozin significantly increased urinary glucose excretion (534.6 mmol/L vs 409.5 mmol/L vs.; p<0.01) and reduced fasting blood glucose levels (99.2 mg/dl vs 168.3 mg/dl; p<0.001), while not affecting body weight. After a period of 4.5 weeks 6 control db/db mice died, but none of the Empagliflozin treated db/db or heterozygote db/wt controls. This was accompanied by improved left ventricular diastolic function of Empagliflozin treated db/db vs. db/db control mice during a dobutamine stress test (dp/dt min:-7560.01 mmHg/s vs-3947 mmHg/s; p<0.05). At a molecular level Empagliflozin significantly increased cardiac Akt-phosphorylation as an indicator of insulin sensitivity and augmented cardiac expression of the fatty acid transporter CD36. The rate limiting enzymes of ketone body (BDH-1, SCOT) or branched chain amino acid catabolism (BCKDHA-P) were not altered by Empagliflozin treatment, despite BDH-1 being significantly reduced in db/db relative to heterozygote db/wt control mice. Conclusion: Empagliflozin treatment significantly improves diastolic left ventricular function and reduces mortality of db/db mice. This is associated with an increased cardiac insulin sensitivity, while level expression of enzymes involved in the catabolism of ketone or branched chain amino acid were not changed. However the rate of oxidation of each substrate with Empagliflozin versus placebo need to be further investigated.