The relationship between diabetes mellitus and heart rhythm disorders: a focus on common pathophysiological mechanisms and modern treatment strategies.[:]

Prof. Zhuravlyova L.V., PHD Sokolnikova N.V., PHD Rogachova T.A. 

Kharkiv National Medical University

The aim of this review article is the analysis the latest evidence based scientific data on the pathophysiological association between diabetes mellitus and heart arrhythmias and the most acceptable treatment possibilities for their correction. In recent decades, the worldwide prevalence of diabetes mellitus type 2 and associated cardiovascular complications has increased expeditiously. Diabetes mellitus has been proven to increase the risk of atrial fibrillation and ventricular arrhythmias regardless of the development of coronary heart disease. The pathophysiological link between diabetes mellitus and arrhythmias has been found to include cardiac diabetic autonomic neuropathy, structural and metabolic myocardial remodeling, endothelial dysfunction, and oxidative stress. Chronic hyperglycemia has been shown to increase risk of atrial dibrillation and ventricular arrhythmias in a dose-dependent manner. Intensive treatment with sulfonylureas and insulin is accompanied by episodes of hypoglycemia, which increases the risk of QTc prolongation and life-threatening arrhythmias. Treatment with dipeptidyl peptidase-4 (iDPP-4) inhibitors does not reduce the risk of arrhythmias and is not recommended due to the increased risk of heart failure. Metformin effectively and safely reduces risk of arrhythmias in diabetes mellitus type 2. Sodium glucose transporter inhibitors and neprilysin inhibitors are promising medications to reduce the risk of cardiovascular death, including arrhythmias, in diabetes mellitus type 2.

Key Words: diabetes mellitus, atrial fibrillation, ventricular arrhythmias, cardiac diabetic autonomic neuropathy, structural and metabolic myocardial remodeling, metformin, sodium-glucose transporter inhibitors, neprilysin inhibitors.



  1. Adameova A, Shah A, Dhalla N. Role of Oxidative Stress in the Genesis of Ventricular Arrhythmias. International Journal of Molecular Sciences. 2020;21(12):4200.
  2. Agarwal G, Singh S. Arrhythmias in type 2 diabetes mellitus. Indian Journal of Endocrinology and Metabolism. 2017;21(5):715.
  3. Seyed Ahmadi S, Svensson A, Pivodic A, Rosengren A, Lind M. Risk of atrial fibrillation in persons with type 2 diabetes and the excess risk in relation to glycaemic control and renal function: a Swedish cohort study. Cardiovascular Diabetology. 2020;19(1):.
  4. Andersen A, Jørgensen P, Knop F, Vilsbøll T. Hypoglycaemia and cardiac arrhythmias in diabetes. Therapeutic Advances in Endocrinology and Metabolism. 2020;11:204201882091180.
  5. Anselmino M, Matta M, D’ascenzo F, Pappone C, Santinelli V, Bunch T, Neumann T, Schilling R, Hunter R, Noelker G, Fiala M, Frontera A, Thomas G, Katritsis D, Jais P, Weerasooriya R, Kalman J, Gaita F. Catheter ablation of atrial fibrillation in patients with diabetes mellitus: a systematic review and meta-analysis. Europace. 2015;17(10):1518-1525.
  6. Aune D, Feng T, Schlesinger S, Janszky I, Norat T, Riboli E. Diabetes mellitus, blood glucose and the risk of atrial fibrillation: A systematic review and meta-analysis of cohort studies. Journal of Diabetes and its Complications. 2018;32(5):501-511.
  7. Axelsen L, Calloe K, Braunstein T, Riemann M, Hofgaard J, Liang B, Jensen C, Olsen K, Bartels E, Baandrup U, Jespersen T, Nielsen L, Holstein-Rathlou N, Nielsen M. Diet-induced pre-diabetes slows cardiac conductance and promotes arrhythmogenesis. Cardiovascular Diabetology. 2015;14(1):.
  8. Babapoor-Farrokhran S, Tarighati Rasekhi R, Gill D, Alzubi J, Mainigi S. How transforming growth factor contributes to atrial fibrillation?. Life Sciences. 2021;266:118823.
  9. Benjamin E. Independent Risk Factors for Atrial Fibrillation in a Population-Based Cohort. JAMA. 1994;271(11):840.
  10. Bohne L, Johnson D, Rose R, Wilton S, Gillis A. The Association Between Diabetes Mellitus and Atrial Fibrillation: Clinical and Mechanistic Insights. Frontiers in Physiology. 2019;10:.
  11. Cannavale G, Francone M, Galea N, Vullo F, Molisso A, Carbone I, Catalano C. Fatty Images of the Heart: Spectrum of Normal and Pathological Findings by Computed Tomography and Cardiac Magnetic Resonance Imaging. BioMed Research International. 2018;2018:1-13.
  12. Chang C, Yeh Y, Chan Y, Liu J, Chang S, Lee H, Wu L, Yen K, Kuo C, See L. Dipeptidyl peptidase-4 inhibitor decreases the risk of atrial fibrillation in patients with type 2 diabetes: a nationwide cohort study in Taiwan. Cardiovascular Diabetology. 2017;16(1):.
  13. Chen H, Huang J, Siao W, Jong G. The association between SGLT2 inhibitors and new-onset arrhythmias: a nationwide population-based longitudinal cohort study. Cardiovascular Diabetology. 2020;19(1):.
  14. Chow E, Bernjak A, Williams S, Fawdry R, Hibbert S, Freeman J, Sheridan P, Heller S. Risk of Cardiac Arrhythmias During Hypoglycemia in Patients With Type 2 Diabetes and Cardiovascular Risk. Diabetes. 2014;63(5):1738-1747.
  15. Christensen R, von Scholten B, Lehrskov L, Rossing P, Jørgensen P. Epicardial adipose tissue: an emerging biomarker of cardiovascular complications in type 2 diabetes?. Therapeutic Advances in Endocrinology and Metabolism. 2020;11:204201882092882.
  16. Clemente D, Pereira T, Ribeiro S. Repolarização ventricular em pacientes diabéticos: caracterização e implicações clínicas. Arquivos Brasileiros de Cardiologia. 2012;99(5):1015-1022.×2012005000095
  17. Creta A, Providência R, Adragão P, de Asmundis C, Chun J, Chierchia G, Defaye P, Schmidt B, Anselme F, Finlay M, Hunter R, Papageorgiou N, Lambiase P, Schilling R, Combes S, Combes N, Albenque J, Pozzilli P, Boveda S. Impact of Type-2 Diabetes Mellitus on the Outcomes of Catheter Ablation of Atrial Fibrillation (European Observational Multicentre Study). The American Journal of Cardiology. 2020;125(6):901-906.
  18. El-Battrawy I, Pilsinger C, Liebe V, Lang S, Kuschyk J, Zhou X, Borggrefe M, Röger S, Akin I. Impact of Sacubitril/Valsartan on the Long-Term Incidence of Ventricular Arrhythmias in Chronic Heart Failure Patients. Journal of Clinical Medicine. 2019;8(10):1582.
  19. Eriksson J, Bodegard J, Nathanson D, Thuresson M, Nyström T, Norhammar A. Sulphonylurea compared to DPP-4 inhibitors in combination with metformin carries increased risk of severe hypoglycemia, cardiovascular events, and all-cause mortality. Diabetes Research and Clinical Practice. 2016;117:39-47.
  20. Gerstein H. Effects of Intensive Glucose Lowering in Type 2 Diabetes. New England Journal of Medicine. 2008;358(24):2545-2559.
  21. González N, Moreno-Villegas Z, González-Bris A, Egido J, Lorenzo Ó. Regulation of visceral and epicardial adipose tissue for preventing cardiovascular injuries associated to obesity and diabetes. Cardiovascular Diabetology. 2017;16(1):.
  22. Grisanti L. Diabetes and Arrhythmias: Pathophysiology, Mechanisms and Therapeutic Outcomes. Frontiers in Physiology. 2018;9:.
  23. Hegyi B, Bers D, Bossuyt J. CaMKII signaling in heart diseases: Emerging role in diabetic cardiomyopathy. Journal of Molecular and Cellular Cardiology. 2019;127:246-259.
  24. Karam B, Chavez-Moreno A, Koh W, Akar J, Akar F. Oxidative stress and inflammation as central mediators of atrial fibrillation in obesity and diabetes. Cardiovascular Diabetology. 2017;16(1):.
  25. Khan A, Thomas G, Lip G, Shantsila A. Endothelial function in patients with atrial fibrillation. Annals of Medicine. 2020;52(1-2):1-11.
  26. Leonard C, Han X, Brensinger C, Bilker W, Cardillo S, Flory J, Hennessy S. Comparative risk of serious hypoglycemia with oral antidiabetic monotherapy: A retrospective cohort study. Pharmacoepidemiology and Drug Safety. 2017;27(1):9-18.
  27. Leonard C, Brensinger C, Dawwas G, Deo R, Bilker W, Soprano S, Dhopeshwarkar N, Flory J, Bloomgarden Z, Gagne J, Aquilante C, Kimmel S, Hennessy S. The risk of sudden cardiac arrest and ventricular arrhythmia with rosiglitazone versus pioglitazone: real-world evidence on thiazolidinedione safety. Cardiovascular Diabetology. 2020;19(1):.
  28. Liang X, Zhang Q, Wang X, Yuan M, Zhang Y, Xu Z, Li G, Liu T. Reactive oxygen species mediated oxidative stress links diabetes and atrial fibrillation. Molecular Medicine Reports. 2018;:.
  29. Li X, Ren H, Xu Z, Liu Y, Yang X, Liu J. Prevalence and Risk Factors of Prolonged QTc Interval among Chinese Patients with Type 2 Diabetes. Experimental Diabetes Research. 2012;2012:1-6.
  30. Mesubi O, Rokita A, Abrol N, Wu Y, Chen B, Wang Q, Granger J, Tucker-Bartley A, Luczak E, Murphy K, Umapathi P, Banerjee P, Boronina T, Cole R, Maier L, Wehrens X, Pomerantz J, Song L, Ahima R, Hart G, Zachara N, Anderson M. Oxidized CaMKII and O-GlcNAcylation cause increased atrial fibrillation in diabetic mice by distinct mechanisms. Journal of Clinical Investigation. 2021;131(2):.
  31. Nantsupawat T, Wongcharoen W, Chattipakorn S, Chattipakorn N. Effects of metformin on atrial and ventricular arrhythmias: evidence from cell to patient. Cardiovascular Diabetology. 2020;19(1):.
  32. Ninkovic V, Ninkovic S, Miloradovic V, Stanojevic D, Babic M, Giga V, Dobric M, Trenell M, Lalic N, Seferovic P, Jakovljevic D. Prevalence and risk factors for prolonged QT interval and QT dispersion in patients with type 2 diabetes. Acta Diabetologica. 2016;53(5):737-744.
  33. Okumura Y. Cardiac Arrhythmia Due to Epicardial Fat: Is It a Modifiable Risk?. Current Cardiovascular Risk Reports. 2017;11(8):.
  34. Ostropolets A, Elias P, Reyes M, Wan E, Pajvani U, Hripcsak G, Morrow J. Metformin Is Associated With a Lower Risk of Atrial Fibrillation and Ventricular Arrhythmias Compared With Sulfonylureas. Circulation: Arrhythmia and Electrophysiology. 2021;14(3):.
  35. Ozturk N, Uslu S, Ozdemir S. Diabetes-induced changes in cardiac voltage-gated ion channels. World Journal of Diabetes. 2021;12(1):1-18.
  36. Rhee C, Kovesdy C, Kalantar-Zadeh K. Risks of Metformin in Type 2 Diabetes and Chronic Kidney Disease: Lessons Learned from Taiwanese Data. Nephron. 2016;135(2):147-153.
  37. Ritchie R, Abel E. Basic Mechanisms of Diabetic Heart Disease. Circulation Research. 2020;126(11):1501-1525.
  38. Russo I, Frangogiannis N. Diabetes-associated cardiac fibrosis: Cellular effectors, molecular mechanisms and therapeutic opportunities. Journal of Molecular and Cellular Cardiology. 2016;90:84-93.
  39. Addendum. Diabetes Technology: Standards of Medical Care in Diabetes-2020. Diabetes Care 2020;43(Suppl. 1):S77-S88. Diabetes Care. 2020;43(8):1981-1981.
  40. Seferovic J, Claggett B, Seidelmann S, Seely E, Packer M, Zile M, Rouleau J, Swedberg K, Lefkowitz M, Shi V, Desai A, McMurray J, Solomon S. Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial. The Lancet Diabetes & Endocrinology. 2017;5(5):333-340.
  41. Seferovic J, Solomon S, Seely E. Potential mechanisms of beneficial effect of sacubitril/valsartan on glycemic control. Therapeutic Advances in Endocrinology and Metabolism. 2020;11:204201882097044.
  42. Tabit C, Chung W, Hamburg N, Vita J. Endothelial dysfunction in diabetes mellitus: Molecular mechanisms and clinical implications. Reviews in Endocrine and Metabolic Disorders. 2010;11(1):61-74.
  43. Tse G, Li K, Cheung C, Letsas K, Bhardwaj A, Sawant A, Liu T, Yan G, Zhang H, Jeevaratnam K, Sayed N, Cheng S, Wong W. Arrhythmogenic Mechanisms in Hypokalaemia: Insights From Pre-clinical Models. Frontiers in Cardiovascular Medicine. 2021;8:.
  44. Vasheghani M, Sarvghadi F, Beyranvand M, Emami H. The Relationship between QT Interval Indices with Cardiac Autonomic Neuropathy in Diabetic Patients. 2020;:.
  45. Wang A, Green J, Halperin J, Piccini J. Atrial Fibrillation and Diabetes Mellitus. Journal of the American College of Cardiology. 2019;74(8):1107-1115.
  46. Zelniker T, Raz I, Sabatine M, Wiviott S. Response by Zelniker et al to Letter Regarding Article, “Effect of Dapagliflozin on Atrial Fibrillation in Patients With Type 2 Diabetes Mellitus: Insights From the DECLARE-TIMI 58 Trial”. Circulation. 2020;142(10):.