Empagliflozin Improves Left Ventricular Diastolic Dysfunction in a Genetic Model of Type 2 Diabetes
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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.
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.
KeywordsDiastolic dysfunction Diabetes ob/ob mice SGLT2 inhibitor Empagliflozin Calcium handling
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).
Compliance with Ethical Standards
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).
Research Involving Human Participants
- 4.Hemmingsen B, Lund SS, Gluud C, Vaag A, Almdal TP, Hemmingsen C, Wetterslev J. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. The Cochrane Database of Systematic Reviews. 2013;11:Cd008143.Google Scholar
- 5.Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R, Marinopoulos SS, Puhan MA, Ranasinghe P, Block L, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011;154:602–13.CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Esposito K, Chiodini P, Bellastella G, Maiorino MI, Giugliano D. Proportion of patients at HbA1c target <7% with eight classes of antidiabetic drugs in type 2 diabetes: systematic review of 218 randomized controlled trials with 78 945 patients. Diabetes Obes Metab. 2012;14:228–33.CrossRefPubMedGoogle Scholar
- 7.Schernthaner G, Barnett AH, Betteridge DJ, Carmena R, Ceriello A, Charbonnel B, Hanefeld M, Lehmann R, Malecki MT, Nesto R, et al. Is the ADA/EASD algorithm for the management of type 2 diabetes (January 2009) based on evidence or opinion? A critical analysis. Diabetologia. 2010;53:1258–69.CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, Bakker RA, Mark M, Klein T, Eickelmann P. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012;14:83–90.CrossRefPubMedGoogle Scholar
- 15.Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, Broedl UC. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. The Lancet. Diabetes & Endocrinology. 2014;2:369–84.CrossRefGoogle Scholar
- 16.Haring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Woerle HJ, Broedl UC. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2013;36:3396–404.CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Kovacs CS, Seshiah V, Swallow R, Jones R, Rattunde H, Woerle HJ, Broedl UC. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab. 2014;16:147–58.CrossRefPubMedGoogle Scholar
- 18.Roden M, Weng J, Eilbracht J, Delafont B, Kim G, Woerle HJ, Broedl UC. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. Diabetes & Endocrinology. 2013;1:208–19.CrossRefGoogle Scholar
- 19.Cherney DZ, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, Woerle HJ, von Eynatten M, Broedl UC. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol. 2014;13:28.CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–200.CrossRefPubMedGoogle Scholar
- 31.Zinman B, Inzucchi SE, Lachin JM, Wanner C, Ferrari R, Fitchett D, Bluhmki E, Hantel S, Kempthorne-Rawson J, Newman J, et al. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME). Cardiovasc Diabetol. 2014;13:102.CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Hammoudi N, Laveau F, Helft G, Cozic N, Barthelemy O, Ceccaldi A, Petroni T, Berman E, Komajda M, Michel PL, et al. Low level exercise echocardiography helps diagnose early stage heart failure with preserved ejection fraction: a study of echocardiography versus catheterization. Clin Res Cardiol. 2017;106:192–201.Google Scholar