The role of anti-diabetic drugs in NAFLD. Have we found the Holy Grail? A narrative review

Abstract

Purpose Non-alcoholic fatty liver disease (NAFLD) has become a leading cause of liver disease, affecting 30% of the global population. NAFLD prevalence is particularly high in obese individuals and patients with type 2 diabetes mellitus (T2DM). NAFLD ranges from simple fat deposition in the liver to necroinflammation and fibrosis (non-alcoholic steatohepatitis (NASH)), NASH-cirrhosis, and/or hepatocellular carcinoma. Insulin resistance plays a key role in NAFLD pathogenesis, alongside dysregulation of adipocytes, mitochondrial dysfunction, genetic factors, and changes in gut microbiota. Since insulin resistance is also a major predisposing factor of T2DM, the administration of anti-diabetic drugs for the management of NAFLD seems reasonable. Methods In this review we provide the NAFLD-associated mechanisms of action of some of the most widely used anti-diabetic drugs, namely metformin, pioglitazone, sodium-glucose transport protein-2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor analogs (GLP1 RAs), and dipeptyl-peptidase-4 inhibitors (DPP4i) and present available data regarding their use in patients with NAFLD, with and without T2DM. Results Both metformin and DPP4i have shown rather contradictory results, while pioglitazone seems to benefit patients with NASH and is thus the only drug approved for NASH with concomitant significant liver fibrosis by all major liver societies. On the other hand, SGLT2i and GLP1 RAs seem to be beneficiary in patients with NAFLD, showing both remarkable results, with SGLT2i proving to be more efficient in the only head-to-head study so far. Conclusion In patients with NAFLD and diabetes, pioglitazone, GLP1 RAs, and SGLT2i seem to be logical treatment options. Larger studies are needed before these drugs can be recommended for non-diabetic individuals.

Metabolic Dysfunction–Associated Steatotic Liver Disease: From Pathogenesis to Current Therapeutic Options

“…This step is partly responsible for the indirect decrease in hepatic lipid accumulation since SGLT-2 is not expressed in the liver [ 264 ]. A number of studies have documented the beneficial effects of SGLT-2 inhibitors on the steatotic liver (including liver fibrosis), although the majority of observations are in patients with T2DM or included a limited number of subjects [ 266 ]. Among the oral SGLT2 inhibitors, dapagliflozin reduces hepatic lipid accumulation without significant effects on insulin sensitivity [ 239 , 267 ].…”

“…In fact, a number of studies documented beneficial effects on the liver linked with the use of GLP-1 analogs, mainly in terms of regression of hepatic steatosis and improvement of NASH. Results, however, are less dramatic in terms of reduced hepatic fibrosis [ 266 ]. GLP-1 receptor analogs represent a promising tool primarily in patients with MASLD associated with T2DM and obesity.…”

A web-based scoping review assessing the influence of smoking and smoking cessation on antidiabetic drug meabolism: implications for medication efficacy

“…Metformin represents the first-line treatment for T2DM since 1957, from the point of diagnosis onwards ( Nathan et al, 2009 ; Zachou et al, 2024 ). Half-life is reported to be between 1.5 and 5 h. It does not tend to accumulate in the liver as a result of its modest lipophilicity.…”

Exploring the interconnected between type 2 diabetes mellitus and nonalcoholic fatty liver disease: Genetic correlation and Mendelian randomization analysis

“…In the only head-to-head study to date, SGLT2 inhibitors have proven to be more efficient than GLP1 receptor agonists. [ 16 ] However, there is currently no clear target for the treatment of comorbidities, and no drugs have been approved or applied in the clinic for both diseases.…”