Introduction: SGLT2 inhibitors reduce hospitalization for heart failure in patients with and without diabetes. The underlying mechanisms remain incompletely understood. One hypothesis is to allocate the beneficial effects of SGLT2 inhibition to the induction of a fasting like state, which is based on low blood glucose and insulin levels and increased blood ketone bodies. Concomitant modulation of cardiac substrate metabolism and signaling pathways by this “fasting like state” might be of relevance for improved heart failure outcome in response to SGLT2 inhibition.

Methods and results: Cardiac hypertrophy was induced by transverse aortic constriction (TAC) surgery in 20-week-old C57Bl/6J mice. Mice were treated with the SGLT2 inhibitor ertugliflozin (225 mg/kg chow diet) or vehicle for a period of 10 weeks.

Ertugliflozin significantly reduced mortality (TAC control: 44% vs. TAC ertu: 18%; p<0.05) and interstitial cardiac fibrosis (collagen staining: TAC control: 5.76±0.78% vs. TAC ertu: 1.84±0.58%; p<0.01) 10 weeks after TAC. This was associated with a reduced hypertrophic response of cardiomyocytes from ertugliflozin treated animals (p<0.05). Left ventricular diastolic function was improved by trend (dp/dt_min: TAC control: - 7247±769.8 mmHg/s vs. TAC ertu: - 10501±898.4 mmHg/s; p=0.1581 by millar catheter with dobutamine stress).

At a molecular level ertugliflozin reduced cardiac insulin signaling as indicated by reduced AKT-phosphorylation with reduced expression of the insulin dependent glucose transporter GLUT4 (0.38-fold change, p=0.0005). Simultaneously cardiac expression of the inactive form of fatty acid synthesis p-ACC (by trend), and the ketone body catabolizing enzyme Beta-Hydroxybutyrate Dehydrogenase BDH-1 (1.57-fold change; p=0.012) were found to be increased while the inhibitory phosphorylation of the branched chain amino acid catabolizing enzyme Branched Chain Keto Acid Dehydrogenase (BCKDHA) was reduced This suggests a metabolic switch of cardiac substrate utilization from glucose oxidation to fatty acids, ketone bodies and branched chain amino acids mimicking a fasting state.

Consistently we found cardiac p-AMPK-signaling (1.49-fold change; p=0.0016) induced by ertugliflozin treatment while cardiac mTOR signaling ((p-p70S6K; 0.515-fold change; p=0.025);(p-4E-BP1; 0.73-fold change; p=0.073)) downregulated in response to ertugliflozin. The observed inhibition of cardiac mTOR signaling in response to ertugliflozin was most likely attributable to a combined modulation of upstream Tuberous Sclerosis Complex (TSC) ((p-TSC(Ser939); 0.50-fold change; p=0.0046);(p-TSC(Ser1387); by trend)) in response to reduced insulin signaling and increased AMPK activation. Consistently reduced mTOR signaling led to reduced inhibitory phosphorylation and therefor activation of the autophagy initiator ULK1(Ser757) (0.59-fold change; p=0.03).

Conclusion: The SGLT2 inhibitor ertugliflozin reduced mortality, cardiac fibrosis and hypertrophy in a murine model of cardiac hypertrophy. Mechanistically, this was associated with a metabolic switch of cardiac substrate utilization with reduced cardiac insulin signaling and increased cardiac AMPK-signaling leading to reduced cardiac mTOR-signaling as a likely mechanism for reduced cardiac hypertrophy and fibrosis in our model.

Fig.1: schematic illustration of the signaling pathway.