Brittany Landavazo

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.

Works Cited:

1. 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
2. Kenny HC, Abel ED. Heart Failure in Type 2 Diabetes Mellitus. Circ Res. 2019;124(1):121-141. doi:10.1161/CIRCRESAHA.118.311371
3. 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
4. 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
5. 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
6. 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
7. 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
8. 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
9. 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
10. 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