Diabetic cardiomyopathy: merely a complication or a distinct understudied disease?

Since the 1970s, researchers have investigated a specific disorder of myocardial structure and function in diabetes mellitus (DM) — diabetic cardiomyopathy (DC) – whose primary clinical manifestation is heart failure (HF). Numerous studies demonstrate a high risk of HF in patients with type 2 diabetes mellitus (T2DM), alongside worsened prognosis when these conditions coexist. For instance, the Kaiser Permanente population study demonstrated a 3- to 4-fold higher HF risk in T2DM patients under 75 years compared to non-diabetic individuals. Despite accumulated research, DCM remains classified by many experts as a complication of DM rather than a distinct entity, fueling ongoing discussion. At the same time, ongoing studies increasingly reveal characteristic disorders of heart function with pathophysiological features, suggesting that DCM may constitute a separate condition occurring within the diabetic context. To date, there are no generally accepted clinical guidelines for DCM diagnosis and management, and therefore there is a need for standardized diagnostic criteria to identify high-risk populations. The review analyzes current literature data on terminology, etiology, pathogenesis, and treatment. Systematisation of existing knowledge and clear diagnostic criteria would facilitate greater focus on novel treatment strategies.

1. Karavaev PG, Veklich AS, Koziolova NA. Diabetic cardiomyopathy: features of cardiovascular remodeling. Russian Journal of Cardiology. 2019;24(11):42-7. (In Russ.) DOI:10.15829/1560-4071-2019-11-42-47.

2. MacDonald MR, Petrie MC, Varyani F, et al. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J. 2008;29(11):1377-85. DOI:10.1093/eurheartj/ehn153.

3. Khan H, Anker SD, Januzzi JL Jr, et al. Heart Failure Epidemiology in Patients With Diabetes Mellitus Without Coronary Heart Disease. J Card Fail. 2019;25(2):78-86. DOI:10.1016/j.cardfail.2018.10.015.

4. Nichols GA, Hillier TA, Erbey JR, Brown JB. Congestive heart failure in type 2 diabetes: prevalence, incidence, and risk factors. Diabetes Care. 2001;24(9):1614-9. DOI:10.2337/diacare.24.9.1614.

5. Sorokina AG, Orlova YaA. A modern view on the mechanisms of diabetic cardiomyopathy development and the its modification options. Russian Journal of Cardiology. 2019;24(11):142-7 (In Russ.) DOI:10.15829/1560-4071-2019-11-142-147.

6. Kobalava ZhD. Eshniyazov NB, Medovshchikov VV, et al. Type 2 diabetes mellitus and heart failure: innovative possibilities for prognosis management. Kardiologiia. 2019;59(4):76-87. (In Russ.) DOI:10.18087/cardio.2019.4.10253.

7. Aneja A, Tang WH, Bansilal S, et al. Diabetic cardiomyopathy: insights into pathogenesis, diagnostic challenges, and therapeutic options. Am J Med. 2008;121(9):748-57. DOI: 10.1016/j.amjmed.2008.03.046.

8. Lorenzo-Almorós A, Cepeda-Rodrigo JM, Lorenzo Ó. Diabetic cardiomyopathy. Rev Clin Esp. 2020:S0014-2565(20)30025-4. DOI:10.1016/j.rce.2019.10.013.

9. Marcinkiewicz A, Ostrowski S, Drzewoski J, et al. Can the onset of heart failure be delayed by treating diabetic cardiomyopathy? Diabetol Metab Syndr. 2017;9:21. DOI:10.1186/s13098-017-0219-z.

10. Bagriy AE, Suprun YV, Mykhailichenko IS, et al. Chronic heart failure and type 2 diabetes: state of the problem. Russian Journal of Cardiology. 2020;25(4):3858. (In Russ.) DOI:10.15829/1560-4071-2020-3858.

11. Park JJ. Epidemiology, Pathophysiology, Diagnosis and Treatment of Heart Failure in Diabetes. Diabetes Metab J. 2021;45(2):146-57. DOI:10.4093/dmj.2020.0282.

12. Bertoni AG, Tsai A, Kasper EK, Brancati FL. Diabetes and idiopathic cardiomyopathy: a nationwide case-control study. Diabetes Care. 2003;26(10):2791-5. DOI:10.2337/diacare.26.10.2791.

13. Maack C, Lehrke M, Backs J, et al. Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology. Eur Heart J. 2018;39(48):4243-54. DOI:10.1093/eurheartj/ehy596.

14. Li X, Wu F, Günther S, Looso M, et al. Inhibition of fatty acid oxidation enables heart regeneration in adult mice. Nature. 2023;622(7983):619-26. DOI:10.1038/s41586-023-06585-5.

15. Lambert R, Srodulski S, Peng X, et al. Intracellular Na+ Concentration ([Na+]i) Is Elevated in Diabetic Hearts Due to Enhanced Na+-Glucose Cotransport. J Am Heart Assoc. 2015;4(9):e002183. DOI:10.1161/JAHA.115.002183.

16. Nielsen R, Jorsal A, Iversen P, et al. Heart failure patients with prediabetes and newly diagnosed diabetes display abnormalities in myocardial metabolism. J Nucl Cardiol. 2018;25(1):169-76. DOI:10.1007/s12350-016-0622-0.

17. Obokata M, Reddy YNV, Pislaru SV, et al. Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure With Preserved Ejection Fraction. Circulation. 2017;136(1):6-19. DOI:10.1161/CIRCULATIONAHA.116.026807.

18. Kaur R, Kaur M, Singh J. Endothelial dysfunction and platelet hyperactivity in type 2 diabetes mellitus: molecular insights and therapeutic strategies. Cardiovasc Diabetol. 2018;17(1):121. DOI:10.1186/s12933-018-0763-3.

19. De Keulenaer GW, Brutsaert DL. Systolic and diastolic heart failure are overlapping phenotypes within the heart failure spectrum. Circulation. 2011;123(18):1996- 2004; discussion 2005. DOI:10.1161/CIRCULATIONAHA.110.981431.

20. Nuzhdina EV, Davydova EV. Cardiac autonomic neuropathy and left ventricular myocardial remodeling in patients with diabetes mellitus and concomitant diseases of the circulatory system and kidneys. Russian Journal of Preventive Medicine. 2020;23(1):127-34. (In Russ.) DOI:10.17116/profmed202023011127.

21. Jani Y, Kamberi A, Xhunga S, et al. The influence of type 2 diabetes and gender on ventricular repolarization dispersion in patients with sub-clinic left ventricular diastolic dysfunction. Am J Cardiovasc Dis. 2015;5(4):155-66.

22. Silverii GA, Toncelli L, Casatori L, et al. Assessment of left ventricular global longitudinal strain in patients with type 2 diabetes: Relationship with microvascular damage and glycemic control. Nutr Metab Cardiovasc Dis. 2022;32(4):994-1000. DOI:10.1016/j.numecd.2022.01.014.

23. Stanton AM, Vaduganathan M, Chang LS, et al. Asymptomatic diabetic cardiomyopathy: An underrecognized entity in type 2 diabetes. Curr Diabetes Rep. 2021;21(10):41. DOI:10.1007/s11892-021-01407-2.

24. Seferovic PM, Paulus WJ. Clinical diabetic cardiomyopathy: A two-faced disease with restrictive and dilated phenotypes. Eur Heart J. 2015;36(27):1718-27, 1727a-1727c. DOI:10.1093/eurheartj/ehv134.

25. Liu X, Yang ZG, Gao Y, et al. Left ventricular subclinical myocardial dysfunction in uncomplicated type 2 diabetes mellitus is associated with impaired myocardial perfusion: a contrast-enhanced cardiovascular magnetic resonance study. Cardiovasc Diabetol. 2018;17(1):139. DOI:10.1186/s12933-018-0782-0.

26. Shivu GN, Phan TT, Abozguia K, et al. Relationship between coronary microvascular dysfunction and cardiac energetics impairment in type 1 diabetes mellitus. Circulation. 2010;121(10):1209-15. DOI:10.1161/CIRCULATIONAHA.109.873273.

27. Ledwidge MT, O’Connell E, Gallagher J, et al. Cost-effectiveness of natriuretic peptide-based screening and collaborative care: a report from the STOP-HF (St Vincent’s Screening TO Prevent Heart Failure) study. Eur J Heart Fail. 2015;17(7):672-9. DOI:10.1002/ejhf.286.

28. Ihm SH, Youn HJ, Shin DI, et al. Serum carboxy-terminal propeptide of type I procollagen (Pip) is a marker of diastolic dysfunction in patients with early type 2 diabetes mellitus. Int J Cardiol. 2007;122(3):e36-e8. DOI:10.1016/j.ijcard.2007.07.057.

29. Li Q, Li P, Su J, et al. LncRNA NKILAwas upregulated in diabetic cardiomyopathy with early prediction values. Exp Ther Med. 2019;18(2):1221-5. DOI:10.3892/etm.2019.7671.

30. Galyavich AS, Tereshchenko SN, Uskach TM, et al. 2024 Clinical practice guidelines for Chronic heart failure. Russian Journal of Cardiology. 2024;29(11):6162. (In Russ.) DOI:10.15829/1560-4071-2024-6162. EDN: WKIDLJ

31. Ruyatkina LA, Ruyatkin DS. Multidimensional effects of metformin in patients with type 2 diabetes. Diabetes mellitus. 2017;20(3):210-9. (In Russ.) DOI:10.14341/DM2003458-64.

32. Eurich DT, Weir DL, Majumdar SR, et al. Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circ Heart Fail. 2013;6(3):395-402. DOI:10.1161/CIRCHEARTFAILURE.112.000162.

33. Morris A. Diabetes: A new hope for insulin-sensitizing drugs. Nat Rev Endocrinol. 2017;13(12):687. DOI:10.1038/nrendo.2017.150.

34. Mamedov MN, Mardanov BU, Dudinskaya EN. Heart failure patients with diabetes: diagnosis, treatment, prevention. Moscow: Fond “Kardioprogress”, 2015 (In Russ.)

35. Ussher JR, Baggio LL, Campbell JE, et al. Inactivation of the cardiomyocyte glucagonlike peptide-1 receptor (GLP-1R) unmasks cardiomyocyteindependent GLP-1R-mediated cardioprotection. Mol Metab. 2014;3(5):507-17. DOI:10.1016/j.molmet.2014.04.009.

36. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-22. DOI:10.1056/NEJMoa1603827.

37. Cowie MR, Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol. 2020;17(12):761-72. DOI:10.1038/s41569-020-0406-8.

38. Sattar N, McLaren J, Kristensen SL, et al. SGLT2 inhibition and cardiovascular events: why did EMPA-REG outcomes surprise and what were the likely mechanisms? Diabetologia. 2016;59(7):1333-9. DOI:10.1007/s00125-016-3987-3.

39. Connelly KA, Mazer CD, Puar P, et al. Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial. Circulation. 2023;147(4):284-95. DOI:10.1161/CIRCULATIONAHA.122.062769.

40. Sato T, Aizawa Y, Yuasa S, et al. The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc Diabetol. 2018;17(1):6. DOI:10.1186/s12933-017-0658-8.

41. Soucek F, Covassin N, Singh P, et al. Effects of atorvastatin (80 mg) therapy on quantity of epicardial adipose tissue in patients undergoing pulmonary vein isolation for atrial fibrillation. Am J Cardiol. 2015;116(9):1443-6. DOI:10.1016/j.amjcard.2015.07.067.