The Impact of SGLT 2 Inhibitors on Calcium Cycling and Fibrosis in Cardiac Tissues of Patients with Type 2 Diabetes Mellitus and Heart Failure
Background: Type 2 Diabetes Mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia due to defective insulin secretion by pancreatic beta cells and insulin resistance.1 T2DM patients have a higher risk of mortality with cardiovascular diseases, such as heart failure, being the highest cause of morbidity and mortality.1,2 Hyperglycemic states alter metabolic and cellular homeostasis leading to inefficient contractility of the heart and increased ROS which alters energy-dependent processes and induces pathological changes in the myocardium.1-4 Current treatment involves antihyperglycemic medications, such as Metformin, however, an antihyperglycemic medication with additional cardioprotection is desirable.5,6 Sodium-glucose cotransporter 2 (SGLT-2) protein inhibitors are a novel antihyperglycemic that has been shown to decrease heart failure and cardiovascular mortality.6 These findings have facilitated studies on the mechanisms by which SLGT 2 inhibitors influence cardiac pathology in T2DM with data highlighting improvement in calcium handling and profibrotic signaling pathways.7-10
Objectives: In this narrative review, we explored the mechanisms by which SGLT 2 inhibitors improve cardiac function through calcium cycling and fibrotic signals in T2DM.
Search Methods: An online search in the PubMed database was conducted from 2017 to 2023 using the following keywords: “diabetes mellitus,” “cardiac failure,” “calcium,” “fibrosis,” and “SGLT 2 inhibitors.”
Results: In a genetic diabetic mice model, improved ventricular function following SGLT-2 inhibitor treatment was observed in order to prove the cardioprotective property of the drug.7 Treatment groups exhibited decreased WGA staining indicating decreased CSA, decreased picrosirius red staining for fibrosis, and improved echocardiographic assessments after 15 weeks of drug treatment.7 Calcium handing was proposed as the mechanism by which ventricular function improved due to significantly increased phosphorylation of phospholamban, decreased expression of phospholamban, and a greater ratio of SERCA2a/PLN ratio indicating a state of efficient calcium recycling into the SR during diastole.5,7 Calcium leak from ryanodine receptors decreases myocardial contractility and is noted in heart failure, however, following treatment, significantly decreased levels of CAMKII were observed.7 Decreased CAMKII led to decreased phosphorylation of ryanodine and decreased calcium leak indicating a separate mechanism in improving diastolic function via calcium cycling.7 Furthermore, following treatment, western blot analysis indicated reduced expression of TGF- β and increased expression of the TGF- β inhibitor, Smad 7.8,9 The alteration in profibrotic signals resulted in decreased levels of collagen I and II indicating less cardiac remodeling following treatment.8.9 Lastly, in a 6-month human clinical trial, the treatment group experienced significantly reduced LV mass when compared to the placebo, and the trial noted a 14% decrease in adverse cardiac events when treating with SGLT-2 inhibitors.10
Conclusion: During heart failure, the combined state of high levels of ROS, fibrosis, and calcium leak inhibits the heart from ejecting adequate amounts of blood volume into circulation. Treatment with SGLT-2 inhibitors in T2DM patients leads to a significant reduction in cardio pathological indexes associated with heart failure. Calcium handling and decreased profibrotic signals are the currently proposed mechanisms by which SGLT-2 inhibitors alleviate heart failure in T2DM patients and should be considered when treating a population at risk for developing heart failure.
- Galicia-Garcia U, Benito-Vicente A, Jebari S, et al. Pathophysiology of Type 2 Diabetes Mellitus. Int J Mol Sci. 2020;21(17):6275. Published 2020 Aug 30. doi:10.3390/ijms21176275
- Kenny HC, Abel ED. Heart Failure in Type 2 Diabetes Mellitus. Circ Res. 2019;124(1):121-141. doi:10.1161/CIRCRESAHA.118.311371
- Salah HM, Verma S, Santos-Gallego CG, et al. Sodium-Glucose Cotransporter 2 Inhibitors and Cardiac Remodeling. J Cardiovasc Transl Res. 2022;15(5):944-956. doi:10.1007/s12265-022-10220-5
- Petersmann A, Müller-Wieland D, Müller UA, et al. Definition, Classification and Diagnosis of Diabetes Mellitus. Exp Clin Endocrinol Diabetes. 2019;127(S 01):S1-S7. doi:10.1055/a-1018-9078
- Hammoudi N, Jeong D, Singh R, et al. Empagliflozin Improves Left Ventricular Diastolic Dysfunction in a Genetic Model of Type 2 Diabetes. Cardiovasc Drugs Ther. 2017;31(3):233-246. doi:10.1007/s10557-017-6734-1
- Hsia DS, Grove O, Cefalu WT. An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2017;24(1):73-79. doi:10.1097/MED.0000000000000311
- 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
- Habibi J, Aroor AR, Sowers JR, et al. Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovasc Diabetol. 2017;16(1):9. Published 2017 Jan 13. doi:10.1186/s12933-016-0489-z
- 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. Published 2019 Feb 2. doi:10.1186/s12933-019-0816-2
- Verma S, Mazer CD, Yan AT, et al. Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The EMPA-HEART CardioLink-6 Randomized Clinical Trial. Circulation. 2019;140(21):1693-1702. doi:10.1161/CIRCULATIONAHA.119.042375