SGLT2 Inhibitors: A Novel Player in the Treatment and Prevention of Diabetic Cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM) characterized by diastolic and systolic dysfunction independently of hypertension and coronary heart disease, eventually develops into heart failure, which is strongly linked to a high prevalence of mortality in people with diabetes mellitus (DM). Sodium-glucose cotransporter type2 inhibitors (SGLT2Is) are a novel type of hypoglycemic agent in increasing urinary glucose and sodium excretion. Excitingly, the EMPA-REG clinical trial proved that empagliflozin significantly reduced the relative risk of cardiovascular (CV) death and hospitalization for heart failure (HHF) in patients with type 2 DM (T2DM) plus CV disease (CVD). The EMPRISE trial showed that empagliflozin decreased the risk of HHF in T2DM patients with and without a CVD history in routine care. These beneficial effects of SGLT2Is could not be entirely attributed to glucose-lowering or natriuretic action. There could be potential direct mechanisms of SGLT2Is in cardioprotection. Recent studies have shown the effects of SGLT2Is on cardiac iron homeostasis, mitochondrial function, anti-inflammation, anti-fibrosis, antioxidative stress, and renin-angiotensin-aldosterone system activity, as well as GlcNAcylation in the heart. This article reviews the current literature on the effects of SGLT2Is on DCM in preclinical studies. Possible molecular mechanisms regarding potential benefits of SGLT2Is for DCM are highlighted, with the purpose of providing a novel strategy for preventing DCM.

Keywords: SGLT2 inhibitor; cardioprotection; diabetes; diabetic cardiomyopathy; molecular mechanism.

Figure 1

Mechanisms of diabetic cardiomyopathy. Hyperglycemia and hyperlipidemia induce metabolic changes in the heart that cause mitochondrial dysfunction, oxidative stress, inflammation, and endoplasmic reticulum (ER) stress in cardiomyocytes. Oxidative stress, ER stress, and inflammation can trigger the renin–angiotensin–aldosterone system (RAAS), enhance cardiac sympathetic nerve activity, and calcium-handling dysfunction. These changes mediate cardiac hypertrophy, apoptosis, fibrosis, and microvascular dysfunction, resulting in diastolic and systolic dysfunction.

Figure 2

Glucose-lowering mechanisms of SGLT2 inhibitors. The renal proximal tubule accounts for the absorption of all the filtered glucose (~180 g/day) while SGLT2, which is located in the early part of the proximal tubule (S1), accounts for the 80%–90% of filtered glucose reabsorption. Therefore, SGLT2Is prevent major reabsorption (80–90%) of filtered glucose in the early proximal tubule and increase urinary glucose excretion.

Figure 3

Potential molecular mechanisms of SGLT2 inhibitors on iron homeostasis, mitochondrial function, and cardiac microvasculature in diabetic cardiomyopathy. SGLT2Is can reduce cardiomyocyte sodium (Na⁺) and calcium (Ca²⁺) by inhibition of NHE activity in cardiomyocytes. In addition, SGLT2Is also regulate Ca²⁺ through enhancing SERCA2α function and CaMKII activation. SGLT2Is can enhance mitochondrial function by improvement of mitochondrial fusion–fission proteins, such as Mfn1:Mfn2 ratio and Fis1, as well as Drp1, which is dependent of AMPK activation. Activation of the PGC1α–NRF1–Tfam signaling pathway by SGLT2Is play a crucial role in regulation of mitochondrial biogenesis in the diabetic heart. Microcirculation can be improved by SGLT2Is by eNOS phosphorylation and NO-dependent improvement of endothelial function. All these changes have beneficial effects on attenuation of cardiac stiffness and diastolic dysfunction

Figure 4

Potential molecular mechanisms of SGLT2 inhibitors on oxidative stress, endoplasmic reticulum stress, inflammation factors, and fibrosis in diabetic cardiomyopathy. SGLT2Is can inhibit oxidative stress by rising levels of free Zn²⁺ in cardiomyocytes, translocation of Nrf2 to the cell nucleus, activation of the Nrf2–ARE signal, and activation of the sGC–cGMP–PKG pathway. SGLT2Is also inhibit ERS through inhibition of CHOP and GRP78. Inflammation factors, such as NLRP3, ASC, caspase 1, IL6, TNFα, and MCP1, are all attenuated by SGLT2Is dependent of AMPK activation. SGLT2Is prevent cardiac fibrosis through the SGK1–ENac and TGFβ–Smad pathways. All these changes by SGLT2Is lead to attenuation of cardiomyocyte apoptosis, hypertrophy, and fibrosis.