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Empagliflozin Improves Left Ventricular Diastolic Dysfunction in a Genetic Model of Type 2 Diabetes

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Abstract

Purpose

Cardiovascular (CV) diseases in type 2 diabetes (T2DM) represent an enormous burden with high mortality and morbidity. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently emerged as a new antidiabetic class that improves glucose control, as well as body weight and blood pressure with no increased risk of hypoglycemia. The first CV outcome study terminated with empagliflozin, a specific SGLT2 inhibitor, has shown a reduction in CV mortality and in heart failure hospitalization, suggesting a beneficial impact on cardiac function which remains to be demonstrated. This study was designed to examine the chronic effect of empagliflozin on left ventricular (LV) systolic and diastolic functions in a genetic model of T2DM, ob/ob mice.

Methods and Results

Cardiac phenotype was characterized by echocardiography, in vivo hemodynamics, histology, and molecular profiling. Our results demonstrate that empagliflozin significantly lowered HbA1c and slightly reduced body weight compared to vehicle treatment with no obvious changes in insulin levels. Empagliflozin also improved LV maximum pressure and in vivo indices of diastolic function. While systolic function was grossly not affected in both groups at steady state, response to dobutamine stimulation was significantly improved in the empagliflozin-treated group, suggesting amelioration of contractile reserve. This was paralleled by an increase in phospholamban (PLN) phosphorylation and increased SERCA2a/PLN ratio, indicative of enhanced SERCA2a function, further supporting improved cardiac relaxation and diastolic function. In addition, empagliflozin reconciled diabetes-associated increase in MAPKs and dysregulated phosphorylation of IRS1 and Akt, leading to improvement in myocardial insulin sensitivity and glucose utilization.

Conclusion

The data show that chronic treatment with empagliflozin improves diastolic function, preserves calcium handling and growth signaling pathways and attenuates myocardial insulin resistance in ob/ob mice, findings suggestive of a potential clinical utility for empagliflozin in the treatment of diastolic dysfunction.

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Acknowledgements

The authors thank Shihong Zhang for the technical assistance. This work was supported in part by a grant from the National Institutes of Health R01HL097357 (DL), by an unrestricted research grant from Boehringer Ingelheim (Agr-6547) (DL), and by a grant from the French Federation of Cardiology (NH).

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Authors and Affiliations

  1. Cardiovascular Research Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Nadjib Hammoudi, Dongtak Jeong, Rajvir Singh, Ahmed Farhat, Roger Hajjar & Djamel Lebeche

  2. Sorbonne Universités, UPMC University Paris 06, Institut de Cardiologie (AP-HP), Centre Hospitalier Universitaire Pitié-Salpêtrière, Institute of Cardiometabolism and Nutrition (ICAN), INSERM UMRS 1166, Paris, France

    Nadjib Hammoudi & Michel Komajda

  3. Graduate School of Biological Sciences, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Ahmed Farhat & Djamel Lebeche

  4. Boehringer Ingelheim Pharma GmbH & Co. KG, Cardio-metabolic Diseases, Binger Straße 173, 55216, Ingelheim am Rhein, Germany

    Eric Mayoux

  5. Diabetes, Obesity and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Djamel Lebeche

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  1. Nadjib Hammoudi
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Correspondence to Djamel Lebeche.

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Conflict of Interest

Some of the results in this paper have been published previously in an abstract at the American Diabetes Association 76th Scientific Sessions Boston, in June 2015. DL received unrestricted funding for an investigator initiated proposal from Boerhinger Ingelheim to perform this study. EM is an employee of Boehringer Ingelheim. Dr. Komajda has performed consulting/advisory activities for Servier, Bristol-Myers Squibb, AstraZeneca, Menarini, Novartis, MSD, and Sanofi-Aventis. All other authors declare no interests.

Animal Ethical Approval

Animals were obtained and handled as approved by the Mount Sinai Institutional Animal Care and Use Committee in accordance with the “Principles of Laboratory Animal Care by the National Society for Medical research and the Guide for the Care and Use of Laboratory Animals” (National Institutes of Health Publication No. 86-23, revised 1996).

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Hammoudi, N., Jeong, D., Singh, R. et al. Empagliflozin Improves Left Ventricular Diastolic Dysfunction in a Genetic Model of Type 2 Diabetes. Cardiovasc Drugs Ther 31, 233–246 (2017). https://doi.org/10.1007/s10557-017-6734-1

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