<p>SGLT-2 inhibitors as promising therapeutics for non-alcoholic fatty liver disease: pathophysiology, clinical outcomes, and future directions</p>

Abstract

Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as a major expanding national and international health problem. Despite numerous investigations using a variety of therapeutic agents, the positive result on any single medication has not been established enough to gain widespread approval. This is in part related to concerns regarding side effects of agents, but is also related to the complex etiology of NAFLD. An often discussed question has been whether insulin resistance that is frequently present in those with NAFLD is a cause of NAFLD or is merely associated with the condition. Nevertheless, it is clear that a very high proportion of patients with NAFLD are obese, have elements of metabolic syndrome, or have type 2 diabetes (T2DM). Also, much progress has been made toward a better understanding of the pathophysiology of NAFLD. Life-style interventions resulting in weight loss remain the foundation for the prevention and treatment of NAFLD. In addition, agents such as Vitamin E and pioglitazone as well as other glycemia-lowering agents including Glucagon Like Peptide-1 (GLP-1) receptor agonists and Sodium Glucose Contransporter-2 inhibitors (SGLT-2i(s)) exhibit positive effects on the clinical course of NAFLD. This narrative review summarizes the current understanding of the diagnosis, epidemiology, and pathophysiology of NAFLD and specifically focuses on the efficacy of SGLT2i (s) as a potentially promising group of agents for the management of patients with NAFLD. Plain language summaryNonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are major growing national and international health problems. NAFLD is commonly associated with obesity, metabolic syndrome, type 2 diabetes. There is high insulin resistance that is irrespective of presence of diabetes. Hepatic lipid content is a function of food intake and fatty acid delivery from adipose tissue, de novo synthesis in liver (a process stimulated by elevated glucose and insulin levels), βoxidation of fatty acids (a process stimulated by glucagon), and export of triglycerides from the liver by VLDL particles. Use of SGLT2 inhibitors has been shown to reduce insulin resistance, glucose and insulin concentrations while increasing glucagon levels and glucagon/insulin ratios, all changes that decrease liver fat content. Recent evidence suggests that use of SGLT2 inhibitors represents a promising new approach for the management of patients with NAFLD and NASH.

Effect of Empagliflozin on Liver Steatosis and Fibrosis in Patients With Non-Alcoholic Fatty Liver Disease Without Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial

“…We also showed a significant decrease in fasting insulin level in the empagliflozin group, while no changes were observed in the placebo group. Decrease in insulin and glucose levels is reported with SGLT2i inhibitors and may have led to a decrease in synthesis of fatty acid in the liver [8]. However, we found no significant changes in insulin resistance state in either group as estimated by the HOMA2 index.…”

“…Their use is associated with a significant increase in fatty acid (FA) mobilization from adipose tissues and FA uptake and β-oxidation in the liver [ 7 ]. The beneficial effects of empagliflozin and other SGLT2 inhibitors on liver fat content in patients with T2DM and NAFLD has been reported [ 8 , 9 ].…”

<p>Glucocorticoid-Induced Fatty Liver Disease</p>

“…Elevated circulating glucocorticoid levels induce insulin resistance that is a hallmark of metabolic syndrome, type 2 diabetes, and fatty liver disease. 12 GC-induced increase in hepatic deposition of lipids (mostly triglycerides) is mediated by multiple mechanisms including increased food intake, stimulated gluconeogenesis, stimulation of de novo fatty acid synthesis by high glucose, insulin, and GC levels, and increased release of FFAs from adipose tissue and their uptake and deposition in liver as TGs. While there is an increase in hepatic VLDL synthesis and secretion that in part accounts for the elevated circulating triglycerides, the effect of glucocorticoids on increasing plasma TG levels is largely mediated by inhibition of plasma lipoprotein lipase activity.…”

“…The topic is of importance because increases in hepatic fat deposits over time can lead to inflammation, fibrosis and cirrhosis of the liver that can be a precursor to hepatocellular carcinoma in a subset of patients. [8][9][10][11][12] Major Pathways Contributing to Hepatic Lipid Content Hepatic lipid content reflects the contribution input and output pathways depicted in Figure 1. Input (entry) pathways leading to increased deposition of lipids (mostly triglycerides in lipid droplets) include (1) Food intake, (2) Glucose derived from gluconeogenesis, (3) Hyperglycemia, insulin resistance Figure 1 Metabolic pathways leading to excess triglyceride deposition in the liver and the effect of increased glucocorticoids on the pathways.…”

Molecular Mechanisms of SGLT2 Inhibitor on Cardiorenal Protection

“…In high fat and cholesterol diet-fed T2DM mice, SGLT2i both alone and with metformin improved fatty liver by alleviating hepatic inflammation and oxidative stress. The most postulated mechanism of SGLT2i in improving insulin sensitivity focused on lowering insulin secretion from beta islet cells when the body’s glucose burden decreased [ 91 ]. Hepatic de novo synthesis of fatty acid and cholesterol decreased with a decrease in insulin levels.…”