Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Patients With Concurrent Type 2 Diabetes Mellitus and Non-Alcoholic Steatohepatitis: A Review of the Evidence

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and more than half of individuals diagnosed with type 2 diabetes concurrently present with NAFLD. There is a bidirectional pathological relationship between the two conditions, whereby NAFLD increases the risk of type 2 diabetes, and type 2 diabetes contributes to and accelerates the progression of NAFLD. Furthermore, over 30% of patients with NAFLD progress to non-alcoholic liver steatohepatitis (NASH), which then increases the risk of cirrhosis and hepatocellular carcinoma. Despite its high prevalence and the potential clinical implications, the underlying pathogenesis of NAFLD has yet to be fully elucidated, and there is no consensus regarding standard diagnosis and treatment for either NALFD or NASH. As patients with both NASH and type 2 diabetes have impaired hepatic function owing to chronic inflammation and the resulting structural changes caused by hepatic fat accumulation, they face reduced options for antidiabetic treatment. SGLT-2 inhibitors inhibit glucose reabsorption in the proximal tubule, with increased excretion of glucose in urine and decreased glucose levels in plasma, and their glycemia-lowering effect is insulin-independent. Several other beneficial effects have been reported for SGLT-2 inhibitors, including reduced risks of cardiovascular and renal diseases, improved blood pressure control, body weight reduction, and reductions in liver fat content. Experimental studies in mouse models have suggested that SGLT-2 inhibitors may have beneficial modulatory effects on NAFLD/NASH. Several trials in patients with type 2 diabetes have also suggested that these drugs may be useful in treating both type 2 diabetes and NAFLD or NASH. However, further research is needed to identify the mechanisms by which SGLT-2 inhibitors affect fatty liver and steatohepatitis. In this state-of-the-art review, we explore the literature on the efficacy of SGLT-2 inhibitors in patients with type 2 diabetes and NASH, and present arguments for and against the use of SGLT-2 inhibitors in this patient population.

The effect of metabolic dysfunction-associated fatty liver disease and diabetic kidney disease on the risk of hospitalization of heart failure in type 2 diabetes: a retrospective cohort study

“…However, our data suggested that individuals with MAFLD or DKD should be cautious about initiating pioglitazone due to the possible risk of heart failure. In this regard, glucose-lowering drugs, including SGLT2 inhibitors or glucagon-like peptide 1 receptor agonists (GLP-1 RAs) that confer protection against major cardiovascular diseases , are promising for preventing HF in NAFLD or MAFLD [ 46 ].…”

SGLT2 Inhibitors as the Most Promising Influencers on the Outcome of Non-Alcoholic Fatty Liver Disease

“…Several studies have shown that the administration of SGLT2 inhibitors has proven efficacy in terms of reducing plasma levels of ALT, body weight [ 77 ], and blood pressure and improving glycated hemoglobin (HbA1c) [ 78 ], reducing risks of cardiovascular and renal diseases, all of which are factors that inhibit the progression to NASH [ 79 ]. In addition, by reducing fat mass, SGLT2 inhibitors prevent the release of inflammatory cytokines by adipocytes, thus decreasing the inflammatory effect, which is one of the main causes of NASH progression [ 80 ].…”

Factors related to hypermetabolism in individuals with type 2 diabetes mellitus and non-alcoholic fatty liver disease

“…The prevalence of NAFLD including liver steatosis and liver fibrosis in T2DM has been estimated to be more considerable 3 , 7 . According to the recent evidence, over fifty percent of individuals with T2DM concurrently have NAFLD 8 , 9 . NAFLD is substantially caused by visceral adipose tissue and insulin resistance 10 .…”