Resumen
La miocardiopatía diabética (MCD) es una complicación de la diabetes mellitus tipo 2 (DM2) que es capaz de evolucionar hasta desarrollar insuficiencia cardiaca (IC) sintomática, independientemente de los factores de riesgo tradicionales para esta, como la enfermedad de las arterias coronarias y la hipertensión. No hay un tratamiento específico para la MCD; sin embargo, los inhibidores del cotransportador sodio-glucosa tipo 2 (iSGLT2) son fármacos hipoglucemiantes que actúan en los canales SGLT2 e inhiben la reabsorción de glucosa en el riñón; además, tienen efectos cardioprotectores, por lo que sus mecanismos a nivel cardiaco se han estudiado. De acuerdo con resultados de estudios preclínicos, los iSGLT2 actúan al interferir en la fisiopatología de la MCD. Sus principales efectos son: mejoramiento en la función diastólica y la fracción de eyección del ventrículo izquierdo (FEVI), atenuación en el progreso de la fibrosis cardiaca, reducción del estrés oxidativo y marcadores proinflamatorios. Los ensayos clínicos en humanos que se han realizado específicamente con MCD son limitados; no obstante, ensayos clínicos aleatorizados en pacientes portadores de IC han evidenciado beneficios con iSGLT2, independientemente del control glucémico en la reducción de hospitalización por IC y mortalidad por causas cardiovasculares. Resumiendo, los iSGLT2 nos sugieren un tratamiento en la MCD por sus beneficios cardiovasculares, en modelos preclínicos y clínicos de MCD y en el control glucémico de la DM2.
Abstract
Diabetic cardiomyopathy (DCM) is a complication of type 2 diabetes mellitus (T2DM) capable of progressing to the development of symptomatic heart failure (HF), independently of traditional risk factors for it, such as coronary artery disease and hypertension. There is no specific treatment for DCM; however, sodium-glucose cotransporter 2 inhibitors (SGLT2i) are hypoglycemic drugs that act on SGLT2 channels, inhibiting glucose reabsorption in the kidney. In addition, they have cardioprotective effects, which is why their mechanisms at the cardiac level have been studied. According to the results of preclinical studies, SGLT2i act by interfering in the pathophysiology of DCM. Their main effects are: improvement in diastolic function and left ventricular ejection fraction (LVEF), attenuation in the progress of cardiac fibrosis, reduction of oxidative stress and proinflammatory markers. The clinical trials in humans specifically with DCM that have been carried out are limited; however, randomized clinical trials in patients with HF have shown benefits with SGLT2i, regardless of glycemic control in the reduction of hospitalization for HF and mortality from cardiovascular causes. In summary, SGLT2i suggest a treatment in DCM due to their cardiovascular benefits, in preclinical and clinical models of DCM and in the glycemic control of T2DM.
Brieler J, Breeden MA, Tucker J. Cardiomyopathy: An overview. Am Fam Physician. 2017;96(10):640-6.
Lorenzo A, Cepeda JM, Lorenzo O. Diabetic cardiomyopathy. Rev Clic Esp. 2020;S0014-2565(20)30025-4. doi: 10.1016/j.rce.2019.10.013.
Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the management of heart failure: Executive summary: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79(17):1757-80. doi: 0.1016/j.jacc.2021.12.011.
Levelt E, Gulsin G, Neubauer S, et al. Diabetic cardiomyopathy: Pathophysiology and potential metabolic interventions state of the art review. Eur J Endocrinol. 2018;178(4):R127-39. doi: 10.1530/EJE-17-0724.
Wang J, Huang X, Liu H, et al. Empagliflozin ameliorates diabetic cardiomyopathy via attenuating oxidative stress and improving mitochondrial function. Oxid Med Cell Longev. 2022;2022:1122494. doi: 10.1155/2022/1122494.
Gil I, Kaski JC. Miocardiopatía diabética. Med Clin (Barc). 2006;127(15):584-94. doi: 10.1157/13094003.
Paolillo S, Marsico F, Prastaro M, et al. Diabetic cardiomyopathy: Definition, diagnosis, and therapeutic implications. Heart Fail Clin. 2019;15(3):341-7. doi: 10.1016/j.hfc.2019.02.003.
Nakamura K, Miyoshi T, Yoshida M, et al. Pathophysiology and treatment of diabetic cardiomyopathy and heart failure in patients with diabetes mellitus. Int J Mol Sci. 2022;23(7):3587. doi: 10.3390/ijms23073587.
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-28. doi: 10.1056/NEJMoa1504720.
Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-57. doi: 10.1056/NEJMoa1812389.
Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-57. doi: 10.1056/NEJMoa1611925.
Gopal K, Chahade JJ, Kim R, et al. The Impact of antidiabetic therapies on diastolic dysfunction and diabetic cardiomyopathy. Front Physiol. 2020;11:603247. doi: 10.3389/fphys.2020.603247.
Li N, Zhou H. SGLT2 Inhibitors: A Novel Player in the treatment and prevention of diabetic dardiomyopathy. Drug Des Devel Ther. 2020;14:4775-88. doi: 10.2147/DDDT.S269514.
Croteau D, Baka T, Young S, et al. SGLT2 inhibitor ertugliflozin decreases elevated intracellular sodium, and improves energetics and contractile function in diabetic cardiomyopathy. Biomed Pharmacother. 2023;160:114310. doi: 10.1016/j.biopha.2023.114310.
Croteau D, Luptak I, Chambers JM, et al. Effects of sodium-glucose linked transporter 2 inhibition with ertugliflozin on mitochondrial function, energetics, and metabolic gene expression in the presence and absence of diabetes mellitus in mice. J Am Heart Assoc. 2021;10(13):e019995. doi: 10.1161/JAHA.120.019995.
Moellmann J, Klinkhammer BM, Droste P, et al. Empagliflozin improves left ventricular diastolic function of db/db mice. Biochim Biophys Acta Mol Basis Dis. 2020;1866(8):165807. doi: 10.1016/j.bbadis.2020.165807.
Li C, Zhang J, Xue M, et al. SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart. Cardiovasc Diabetol. 2019;18(1):15. doi: 10.1186/s12933-019-0816-2.
Trang NN, Chung CC, Lee TW, et al. Empagliflozin and liraglutide differentially modulate cardiac metabolism in diabetic cardiomyopathy in rats. Int J Mol Sci. 2021;22(3):1177. doi: 10.3390/ijms22031177.
Tian J, Zhang M, Suo M, et al. Dapagliflozin alleviates cardiac fibrosis through suppressing EndMT and fibroblast activation via AMPKα/TGF-β/Smad signalling in type 2 diabetic rats. J Cell Mol Med. 2021;25(16):7642-59. doi: 10.1111/jcmm.16601.
Arow M, Waldman M, Yadin D, et al. Sodium-glucose cotransporter 2 inhibitor dapagliflozin attenuates diabetic cardiomyopathy. Cardiovasc Diabetol. 2020;19(1):7. doi: 10.1186/s12933-019-0980-4.
El-Shafey M, El-Agawy MSE, Eldosoky M, et al. Role of Dapagliflozin and liraglutide on diabetes-induced cardiomyopathy in rats: Implication of oxidative stress, inflammation, and apoptosis. Front Endocrinol (Lausanne). 2022;13:862394. doi: 10.3389/fendo.2022.862394.
Du S, Shi H, Xiong L, et al. Canagliflozin mitigates ferroptosis and improves myocardial oxidative stress in mice with diabetic cardiomyopathy. Front Endocrinol (Lausanne). 2022;13:1011669. doi: 10.3389/fendo.2022.1011669.
Thirunavukarasu S, Jex N, Chowdhary A, et al. Empagliflozin treatment is associated with improvements in cardiac energetics and function and reductions in myocardial cellular volume in patients with type 2 diabetes. Diabetes. 2021;70(12):2810-22. doi: 10.2337/db21-0270.
Oka S, Kai T, Hoshino K, et al. Effects of empagliflozin in different phases of diabetes mellitus-related cardiomyopathy: a prospective observational study. BMC Cardiovasc Disord. 2021;21(1):217. doi: 10.1186/s12872-021-02024-3.
Wang C, Qin Y, Zhang X, et al. Effect of dapagliflozin on indicators of myocardial fibrosis and levels of inflammatory factors in heart failure patients. Dis Markers. 2022;2022:5834218. doi: 10.1155/2022/5834218.
Feng B, Yu P, Yu H, et al. Therapeutic effects on the development of heart failure with preserved ejection fraction by the sodium-glucose cotransporter 2 inhibitor dapagliflozin in type 2 diabetes. Diabetol Metab Syndr. 2023;15(1):141. doi: 10.1186/s13098-023-01116-8.
Yu YW, Zhao XM, Wang YH, et al. Effect of sodium–glucose cotransporter 2 inhibitors on cardiac structure and function in type 2 diabetes mellitus patients with or without chronic heart failure: a meta-analysis. Cardiovasc Diabetol. 2021;20(1):25. doi: 10.1186/s12933-020-01209-y.
Huang K, Luo X, Liao B, et al. Insights into SGLT2 inhibitor treatment of diabetic cardiomyopathy: focus on the mechanisms. Cardiovasc Diabetol. 2023;22(1):86. doi: 10.1186/s12933-023-01816-5.
Filippatos G, Butler J, Farmakis D, et al. Empagliflozin for heart failure with preserved left ventricular ejection fraction with and without diabetes. Circulation. 2022;146(9):676-86. doi: 10.1161/CIRCULATIONAHA.122.059785.
Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451-61. doi: 10.1056/NEJMoa2107038.
Paneni F, Costantino S, Hamdani N. Regression of left ventricular hypertrophy with SGLT2 inhibitors. Eur Heart J. 2020;41(36):3433-6. doi: 10.1093/eurheartj/ehaa530.
Kowalska K, Wilczopolski P, Buławska D, et al. The Importance of SGLT-2 inhibitors as both the prevention and the treatment of diabetic cardiomyopathy. Antioxidants (Basel). 2022;11(12):2500. doi: 10.3390/antiox11122500.
Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396(10254):819-29. doi: 10.1016/S0140-6736(20)31824-9.