SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection

Abstract

Non-alcoholic fatty liver disease (NAFLD) is an ‘umbrella’ term, comprising a spectrum ranging from benign, liver steatosis to non-alcoholic steatohepatitis, liver fibrosis and eventually cirrhosis and hepatocellular carcinoma. NAFLD has evolved as a major health problem in recent years. Discovering ways to prevent or delay the progression of NAFLD has become a global focus. Lifestyle modifications remain the cornerstone of NAFLD treatment, even though various pharmaceutical interventions are currently under clinical trial. Among them, sodium-glucose co-transporter type-2 inhibitors (SGLT-2i) are emerging as promising agents. Processes regulated by SGLT-2i, such as endoplasmic reticulum (ER) and oxidative stress, low-grade inflammation, autophagy and apoptosis are all implicated in NAFLD pathogenesis. In this review, we summarize the current understanding of the NAFLD pathophysiology, and specifically focus on the potential impact of SGLT-2i in NAFLD development and progression, providing current evidence from in vitro, animal and human studies. Given this evidence, further mechanistic studies would advance our understanding of the exact mechanisms underlying the pathogenesis of NAFLD and the potential beneficial actions of SGLT-2i in the context of NAFLD treatment.

Endothelial Cell Dysfunction and Nonalcoholic Fatty Liver Disease (NAFLD): A Concise Review

“…The most common predisposing factors for NAFLD are male sex, age > 50 years, hyperlipidemia, obesity, insulin resistance and T2DM, and a lack of physical exercise as well as genetic polymorphisms (e.g., patatin-like phospholipase domain-containing 3 (PNPLA3) I148M polymorphism) [ 9 , 17 , 18 , 19 ]. Reflecting the underlying pathogenesis and the cardiometabolic disorders associated with NAFLD, the term metabolic (dysfunction)-associated fatty liver disease (MAFLD) has recently been proposed [ 4 ].…”

“…Currently, lifestyle modification and the management of its associated comorbidities remain the cornerstones of the treatment of NAFLD. As an approved pharmacological treatment for NAFLD is still missing, the identification of promising targets and the development of effective therapies is an urgent need [ 4 ].…”

“…Hyperinsulinemia, hyperglycemia, lipotoxicity, and altered adipocytokine secretion can activate deleterious processes such as inflammation, oxidative stress, endoplasmic reticulum (ER) stress, and apoptosis, which lead to the development of NAFLD, demonstrating its multifactorial etiology. Despite its high prevalence, there are currently no US Food and Drug Administration (FDA)-approved treatments for NAFLD [ 4 ].…”

Autophagy Dysregulation in Metabolic Associated Fatty Liver Disease: A New Therapeutic Target

“…Till now, a number of SGLT-2i have been discovered and used to control blood sugar, body weight, and serum uric acid. Regulatory effects of SGLT-2i have been implicated in ER and oxidative stress, autophagy, apoptosis, and inflammation [ 96 ]. Ye, T. et al treated HFD-fed C57BL/6J mice with empagliflozin and found that empagliflozin reduced fat mass, body weight, plasma TG and FFA levels, fasting glucose levels, and NLRP3 inflammasome activity, and induced HO-1-adiponectin-dependent signaling pathway [ 97 ].…”

“…Androutsakos, T. et al recently summarized the current evidence for the effects of SGLT-2i on MAFLD in cellular and animal models as well as in human trials [ 96 ]. Most SGLT-2i inhibited cell proliferation by activating caspase 3 in human hepatocellular carcinoma cells—HepG2 cells [ 98 ].…”