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.
Highlights
Worldwide, the increasing prevalence of type 2 diabetes is occurring alongside a corresponding increase in the prevalence of non-alcoholic fatty liver disease (NAFLD)
These parameters were additively improved with combination treatment versus ipragliflozin monotherapy [59]. This state-of-the-art review explores the current literature reporting the efficacy of SGLT-2 inhibitors in patients with type 2 diabetes and non-alcoholic liver steatohepatitis (NASH) and presents arguments for and against the use of SGLT-2 inhibitors in this patient population, where it plays a regulatory role in adipocyte differentiation, adipogenesis, and lipid metabolism
This review has highlighted the challenges faced in the treatment of patients with concurrent type 2 diabetes mellitus and NAFLD or NASH, including the impact of comorbidities, lack of efficacy, and long-term safety issues
Summary
The increasing prevalence of type 2 diabetes is occurring alongside a corresponding increase in the prevalence of non-alcoholic fatty liver disease (NAFLD). The proposed mechanism explaining the action of SGLT-2 inhibitors in NAFLD/NASH is based on the reduction of plasma glucose due to glucosuria, and reversal of glucotoxicity, as well as reductions in circulating insulin and body weight These collectively result in decreased peripheral and hepatic insulin resistance, and lead, in turn, to a reduction of de novo lipogenesis in the liver. A recent preclinical study using a mouse model of type 2 diabetes showed that a combination of the SGLT-2 inhibitor ipragliflozin plus pioglitazone significantly improved multiple NASH parameters, including hyperglycemia, insulin resistance, hyperlipidemia and liver injury (hepatic steatosis and fibrosis). These parameters were additively improved with combination treatment versus ipragliflozin monotherapy [59]
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