Abstract Body (Do not enter title and authors here): Background and Purpose: Heart failure is associated with renal dysfunction suggesting a pathophysiological link between heart and kidney. Empagliflozin, a SGLT2 inhibitor, showed beneficial effects on both cardiovascular and renal endpoints. However, mechanistically, it is unclear if empagliflozin-dependent kidney protection is mediated via inhibition of tubular SGLT2 or more indirectly via improved cardiac function.
We hypothesized that Empagliflozin treatment improves left ventricular ejection fraction (LVEF) independent of diuretic effect of renal SGLT2 inhibition.
Methods: We evaluated NTproBNP, hematocrit, hemoglobin and bodyweight in patients with HF with reduced (n=32) and preserved ejection fraction (n=59) after 30 and 180 days (prospective, single-arm CINNAMON-study, DRKS00031101). Furthermore, we conducted transverse aortic constriction (TAC) or sham surgery in C57BL/6J (wildtype, WT) and SGLT2 deficient mice (SGLT2^-/-). Animals received either Empagliflozin (10 mg/kg bodyweight) or vehicle by daily oral gavage. Water intake and output was evaluated by metabolic cages at 10 weeks and cardiac function by echocardiography.
Results: Empagliflozin treatment reduced NT-proBNP levels and increased hematocrit and hemoglobin levels especially in patients with reduced ejection fraction (Fig. A-C). Surprisingly, there was no change in body weight (Fig. D), which would be expected if the diuretic effects were dominant. In mice after 10 weeks, echocardiography confirmed TAC induced pressure-overload, leading to reduced LVEF. Empagliflozin attenuated changes in LVEF (Fig. G) and improved diastolic dysfunction (isovolumetric relaxation time, data not shown). To test if direct inhibition of SGLT2 in the heart and kidney is mechanistically involved, TAC surgery was repeated in SGLT2-deficient mice (SGLT2-KO). In fact, exposure to TAC resulted in comparable reduction of LVEF in SGLT2-KO and Empagliflozin prevented this deterioration similar to WT mice (Fig. G vs. I). Surprisingly, Empagliflozin did not increase drinking and urine volume neither in wildtype nor in SGLT2 deficient mice, suggesting a mechanism of cardioprotection independent of diuretic effects.
Conclusion and Outlook: This is the first study investigating the role of SGLT2 in Empagliflozin treated patients and mice with heart failure. Importantly, empagliflozin treatment prevented deterioration of LVEF independent of the presence of SGLT2 and diuresis.