Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02302-4

Effects of Empagliflozin on cardio-renal interaction in heart failure with reduced ejection fraction: Results from in-vivo experiments and the CINNAMON-study

F. Sinha1, S. Klatt1, P. Tauber2, A. Rietmann1, L. S. Maier1, F. Schweda2, S. Wagner1

1Klinik und Poliklinik für Innere Med. II, Kardiologie, Universitätsklinikum Regensburg, Regensburg; 2Physiologie II, Universität Regensburg, Regensburg;

Background: Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, showed beneficial effects on both cardiovascular and renal endpoints. However, in the EMPEROR trials, there was a significant interaction on renal endpoints in patients with heart failure and reduced ejection fraction (HFrEF) compared with patients with preserved EF, warranting further investigation. Purpose: We investigated kidney function and ejection fraction in mice with transverse aortic constriction (TAC) and correlated these findings with clinical data from a novel prospective trial. Methods and results: Male C57Bl6J mice underwent TAC and were randomly assigned for 5 weeks to oral vehicle and Empagliflozin treatment (30 mg/kg body weight). Sham-operated mice served as controls. Kidney function was assessed by transdermal FITC-Sinistrin measurement and urinary albumin/creatinine ratio (UACR) after 24-hour collection of urine. After 5 weeks, echocardiography confirmed the TAC induced pressure-overload, leading to left ventricular hypertrophy accompanied by reduced left ventricular ejection fraction (LVEF), diastolic dysfunction and reduced cardiac output. Empagliflozin attenuated changes in LVEF, improved diastolic dysfunction and cardiac output but had no effect on left ventricular hypertrophy (Fig. 1A). Interestingly, at 5 weeks, GFR significantly correlated with TAC-dependent reduction in LVEF (p=0.046, r²=0.213) (fig. 1B) and empagliflozin tended to prevent GFR decline after TAC treatment (p=0.12). Surprisingly and in contrast to GFR, the UACR was even increased in EMPA-treated mice after TAC (fig. 1C) suggesting that tubular mechanisms independent from filtration may play a role. Empagliflozin-dependent changes in GFR and UACR were also investigated in patients with HF (prospective, single-arm CINNAMON-study, DRKS00031101) (Fig. D). After 30 days of Empagliflozin treatment (10 mg), there was a significant improvement in Kansas City Cardiomyopathy questionnaire (KCCQ-12) Scores (Fig 1E). In contrast, neither GFR nor UACR were significantly changed after 30 days of empagliflozin treatment. Conclusion: This is the first study investigating GFR and UACR in mice after TAC. Empagliflozin treatment prevented deterioration of GFR after TAC but, surprisingly, increased UACR, which warrants further investigation of the mechanisms of albuminuria after empagliflozin treatment.

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