Glucagon-Like Peptide-1 Receptor Agonists for Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: An Updated Meta-Analysis of Randomized Controlled Trials

Abstract

To assess the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for treatment of nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH), we performed a systematic review and meta-analysis of randomized controlled trials (RCTs). Three large electronic databases were systematically searched (up to 15 December 2020) to identify placebo-controlled or active-controlled RCTs using different GLP-1 RAs. We included eleven placebo-controlled or active-controlled phase-2 RCTs (involving a total of 936 middle-aged individuals) that used liraglutide (n = 6 RCTs), exenatide (n = 3 RCTs), dulaglutide (n = 1 RCT) or semaglutide (n = 1 RCT) to specifically treat NAFLD or NASH, detected by liver biopsy (n = 2 RCTs) or imaging techniques (n = 9 RCTs). Compared to placebo or reference therapy, treatment with GLP-1 RAs for a median of 26 weeks was associated with significant reductions in the absolute percentage of liver fat content on magnetic resonance-based techniques (pooled weighted mean difference: −3.92%, 95% confidence intervals (CI) −6.27% to −1.56%) and serum liver enzyme levels, as well as with greater histological resolution of NASH without worsening of liver fibrosis (pooled random-effects odds ratio 4.06, 95% CI 2.52–6.55; for liraglutide and semaglutide only). In conclusion, treatment with GLP-1 RAs (mostly liraglutide and semaglutide) is a promising treatment option for NAFLD or NASH that warrants further investigation.

Perspectives on Precision Medicine Approaches to NAFLD Diagnosis and Management

“…Also, particular consideration should be given to the potential benefits of antidiabetic drugs such as pioglitazone and sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have been shown to be effective in patients with concurrent T2D and NAFLD [164,165], although larger RCTs are required. Similarly, the use of the glucagon-like peptide 1 (GLP-1) receptor agonists such as liraglutide or semaglutide is very promising as there is evidence that these agents impact liver histology and can also improve cardiovascular outcomes in patients with T2D [166][167][168][169]. Finally, as T2D itself is heterogeneous in its etiology, pathogenesis, and clinical presentation, precision medicine approaches to treat and prevent the disease are being actively investigated but significant barriers to their implementation and research gaps still exist [170].…”

Efficacy and Safety of Semaglutide in Glycemic Control and Body Weight Management Among Obese Type 2 Diabetes Patients Initiated or Switched to Semaglutide From Other GLP-1 Receptor Agonists

“…Liver function parameters also showed signi cant improvements, and considering the decrease in triglycerides, semaglutide was considered to have a bene cial effect on fatty liver. A meta-analysis of the therapeutic effects of GLP-1 RAs, including semaglutide, on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis indicated that GLP-1 RAs reduce hepatic brosis on imaging and decrease ALT and γ-GTP, suggesting the possibility of treating fatty liver with GLP-1 RAs [24].…”

Metabolic Spectrum of Liver Failure in Type 2 Diabetes and Obesity: From NAFLD to NASH to HCC

“…Liraglutide-induced anorexia is also related with glutamatergic POMC neuron, leading to weight loss [ 169 ]. In patients with NAFLD and NASH, it decreases liver fat contents and improves histological resolution and serum liver enzyme levels without worsening fibrosis [ 170 , 171 ]. It is thought that the effect of liraglutide on weight loss and reduced cardiovascular risk is critical for treatment of NAFLD because the development of NAFLD is based on lipotoxicity and insulin resistance [ 171 , 172 ].…”

“…In patients with NAFLD and NASH, it decreases liver fat contents and improves histological resolution and serum liver enzyme levels without worsening fibrosis [ 170 , 171 ]. It is thought that the effect of liraglutide on weight loss and reduced cardiovascular risk is critical for treatment of NAFLD because the development of NAFLD is based on lipotoxicity and insulin resistance [ 171 , 172 ]. As studies associated with NAFLD and NASH in rodents showed, liraglutide protects pancreatic β-cells from apoptosis through AKT-mediated survival signaling [ 173 ].…”