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Cardiovascular Drugs and Therapy

, Volume 31, Issue 3, pp 233–246 | Cite as

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

  • Nadjib Hammoudi
  • Dongtak Jeong
  • Rajvir Singh
  • Ahmed Farhat
  • Michel Komajda
  • Eric Mayoux
  • Roger Hajjar
  • Djamel LebecheEmail author
ORIGINAL ARTICLE

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.

Keywords

Diastolic dysfunction Diabetes ob/ob mice SGLT2 inhibitor Empagliflozin Calcium handling 

Notes

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).

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

Not applicable.

Informed Consent

Not applicable.

References

  1. 1.
    Abel ED, Litwin SE, Sweeney G. Cardiac remodeling in obesity. Physiol Rev. 2008;88:389–419.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Riva E, Andreoni G, Bianchi R, Latini R, Luvara G, Jeremic G, Traquandi C, Tuccinardi L. Changes in diastolic function and collagen content in normotensive and hypertensive rats with long-term streptozotocin-induced diabetes. Pharmacol Res. 1998;37:233–40.CrossRefPubMedGoogle Scholar
  3. 3.
    Singleton JR, Smith AG, Russell JW, Feldman EL. Microvascular complications of impaired glucose tolerance. Diabetes. 2003;52:2867–73.CrossRefPubMedGoogle Scholar
  4. 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. 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. 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. 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
  8. 8.
    Abdul-Ghani MA, Norton L, Defronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011;32:515–31.CrossRefPubMedGoogle Scholar
  9. 9.
    Tahrani AA, Barnett AH, Bailey CJ. SGLT inhibitors in management of diabetes. The Lancet. Diabetes & Endocrinology. 2013;1:140–51.CrossRefGoogle Scholar
  10. 10.
    Vallon V, Platt KA, Cunard R, Schroth J, Whaley J, Thomson SC, Koepsell H, Rieg T. SGLT2 mediates glucose reabsorption in the early proximal tubule. Journal of the American Society of Nephrology : JASN. 2011;22:104–12.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Raskin P. Sodium-glucose cotransporter inhibition: therapeutic potential for the treatment of type 2 diabetes mellitus. Diabetes Metab Res Rev. 2013;29:347–56.CrossRefPubMedGoogle Scholar
  12. 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
  13. 13.
    Ferrannini E, Seman L, Seewaldt-Becker E, Hantel S, Pinnetti S, Woerle HJ. A phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15:721–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Haring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Broedl UC, Woerle HJ. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2014;37:1650–9.CrossRefPubMedGoogle Scholar
  15. 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. 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. 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. 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. 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
  20. 20.
    Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.CrossRefPubMedGoogle Scholar
  21. 21.
    Schannwell CM, Schneppenheim M, Perings S, Plehn G, Strauer BE. Left ventricular diastolic dysfunction as an early manifestation of diabetic cardiomyopathy. Cardiology. 2002;98:33–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Kawase Y, Hajjar RJ. The cardiac sarcoplasmic/endoplasmic reticulum calcium ATPase: a potent target for cardiovascular diseases. Nature Clinical Practice Cardiovascular Medicine. 2008;5:554–65.CrossRefPubMedGoogle Scholar
  23. 23.
    Abel ED. Myocardial insulin resistance and cardiac complications of diabetes. Current drug targets. Immune, Endocrine and Metabolic Disorders. 2005;5:219–26.CrossRefPubMedGoogle Scholar
  24. 24.
    Matsui T, Li L, del Monte F, Fukui Y, Franke TF, Hajjar RJ, Rosenzweig A. Adenoviral gene transfer of activated phosphatidylinositol 3′-kinase and Akt inhibits apoptosis of hypoxic cardiomyocytes in vitro. Circulation. 1999;100:2373–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Shiraishi I, Melendez J, Ahn Y, Skavdahl M, Murphy E, Welch S, Schaefer E, Walsh K, Rosenzweig A, Torella D, et al. Nuclear targeting of Akt enhances kinase activity and survival of cardiomyocytes. Circ Res. 2004;94:884–91.CrossRefPubMedGoogle Scholar
  26. 26.
    Liang L, Jiang J, Frank SJ. Insulin receptor substrate-1-mediated enhancement of growth hormone-induced mitogen-activated protein kinase activation. Endocrinology. 2000;141:3328–36.CrossRefPubMedGoogle Scholar
  27. 27.
    Grandi AM, Piantanida E, Franzetti I, Bernasconi M, Maresca A, Marnini P, Guasti L, Venco A. Effect of glycemic control on left ventricular diastolic function in type 1 diabetes mellitus. Am J Cardiol. 2006;97:71–6.CrossRefPubMedGoogle Scholar
  28. 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
  29. 29.
    Kadambi VJ, Ponniah S, Harrer JM, Hoit BD, Dorn GW 2nd, Walsh RA, Kranias EG. Cardiac-specific overexpression of phospholamban alters calcium kinetics and resultant cardiomyocyte mechanics in transgenic mice. J Clin Invest. 1996;97:533–9.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    del Monte F, Harding SE, Dec GW, Gwathmey JK, Hajjar RJ. Targeting phospholamban by gene transfer in human heart failure. Circulation. 2002;105:904–7.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 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
  32. 32.
    Matsui T, Tao J, del Monte F, Lee KH, Li L, Picard M, Force TL, Franke TF, Hajjar RJ, Rosenzweig A. Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation. 2001;104:330–5.CrossRefPubMedGoogle Scholar
  33. 33.
    Chen J, Williams S, Ho S, Loraine H, Hagan D, Whaley JM, Feder JN. Quantitative PCR tissue expression profiling of the human SGLT2 gene and related family members. Diabetes Therapy : Research, Treatment and Education of Diabetes and Related Disorders. 2010;1:57–92.CrossRefGoogle Scholar
  34. 34.
    Poornima IG, Parikh P, Shannon RP. Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res. 2006;98:596–605.CrossRefPubMedGoogle Scholar
  35. 35.
    Sattar N, McLaren J, Kristensen SL, Preiss D, McMurray JJ. SGLT2 inhibition and cardiovascular events: why did EMPA-REG outcomes surprise and what were the likely mechanisms? Diabetologia. 2016;59:1333–9.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Dobrin JS, Lebeche D. Diabetic cardiomyopathy: signaling defects and therapeutic approaches. Expert Rev Cardiovasc Ther. 2010;8:373–91.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.CrossRefPubMedGoogle Scholar
  38. 38.
    Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.CrossRefPubMedGoogle Scholar
  39. 39.
    Terry T, Raravikar K, Chokrungvaranon N, Reaven PD. Does aggressive glycemic control benefit macrovascular and microvascular disease in type 2 diabetes? Insights from ACCORD, ADVANCE, and VADT. Current Cardiology Reports. 2012;14:79–88.CrossRefPubMedGoogle Scholar
  40. 40.
    de Leeuw AE, de Boer RA. Sodium-glucose cotransporter 2 inhibition: cardioprotection by treating diabetes-a translational viewpoint explaining its potential salutary effects. European Heart Journal Cardiovascular Pharmacotherapy. 2016;2:244–55.CrossRefPubMedGoogle Scholar
  41. 41.
    Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care. 2016;39:1108–14.CrossRefPubMedGoogle Scholar
  42. 42.
    Borlaug BA. Exercise haemodynamics and outcome in patients with dyspnoea. Eur Heart J. 2014;35:3085–7.CrossRefPubMedGoogle Scholar
  43. 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
  44. 44.
    Imprialos KP, Sarafidis PA, Karagiannis AI. Sodium-glucose cotransporter-2 inhibitors and blood pressure decrease: a valuable effect of a novel antidiabetic class? J Hypertens. 2015;33:2185–97.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Cardiovascular Research Institute, Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkUSA
  2. 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 1166ParisFrance
  3. 3.Graduate School of Biological Sciences, Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkUSA
  4. 4.Boehringer Ingelheim Pharma GmbH & Co. KG, Cardio-metabolic DiseasesIngelheim am RheinGermany
  5. 5.Diabetes, Obesity and Metabolism Institute, Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkUSA

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