**Background:** Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, with a global prevalence of 25–30% among adults, predicted to reach 55.7% by 2040. More than 50% of patients with type 2 diabetes mellitus (T2DM) have NAFLD, and the relationship between the two conditions is bidirectional—diabetes promotes progression to advanced liver disease, while NAFLD increases the risk of diabetes-related complications. Despite this high burden, no pharmacologic therapies are specifically approved for NAFLD. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), already established as first-line therapy for T2DM due to glucose-lowering effects and cardiovascular benefits, have emerged as potential candidates for NAFLD treatment. This narrative review summarizes evidence on GLP-1RA effectiveness in managing T2DM complicated by NAFLD.
**Methods:** The authors conducted an extensive literature search of PubMed and ClinicalTrials.gov databases up to February 2023, using terms combining 'GLP-1 receptor agonist' or specific drug names (exenatide, liraglutide, dulaglutide, semaglutide, lixisenatide, albiglutide, efpeglenatide) with 'fatty liver,' 'NAFLD,' 'NASH,' or 'fibrosis' and diabetes-related terms. Clinical trials, randomized controlled trials (RCTs), and multicenter studies examining GLP-1RA effectiveness on NAFLD in T2DM patients were included. Studies without T2DM subjects were excluded. Reviews, guidelines, systematic reviews, and meta-analyses were also consulted. Data extraction was performed independently by two authors with blinded verification by a third.
**Key Results:** A total of 32 studies were identified: eight with exenatide, sixteen with liraglutide, six with semaglutide, and two with dulaglutide. No studies with efpeglenatide, lixisenatide, or albiglutide were found. All studies reported positive results in improving NAFLD. Liraglutide was the most investigated agent. Key findings include: (1) Liver enzymes—A meta-analysis of the LEAD program (4442 patients) showed liraglutide 1.8 mg/day improved liver enzymes after 26 weeks. A post hoc analysis of AWARD trials (1499 subjects) showed dulaglutide 1.5 mg/week decreased serum aminotransferases vs. placebo (−8.8 IU/L vs. −6.7 IU/L). (2) Composite indices—Gameil et al. found liraglutide and dulaglutide significantly improved Fatty Liver Index (FLI) and FIB-4 index, with greater changes in the liraglutide group. (3) Imaging—Liraglutide reduced intrahepatic fat content by approximately 60% from baseline. Semaglutide reduced controlled attenuation parameter (CAP) values from 344 to 279 dB/m at 24 weeks. (4) Histology—The 48-week LEAN trial showed liraglutide delayed fibrosis progression vs. placebo (39% vs. 9%, p = 0.019). A 72-week RCT of semaglutide showed NASH resolution in 59% of the 0.4 mg/day group vs. 17% in placebo (p < 0.001), with slower fibrosis progression (4.9% vs. 18.8%) but no significant improvement in fibrosis severity. (5) Meta-analyses—Kumar et al. (26 studies) found significant ALT reduction (MD −27.98, p = 0.04) and GGT reduction (MD −40.65, p = 0.03), with significant improvement in liver steatosis (standard MD −2.53, p = 0.03) but insufficient data on inflammation and fibrosis.
**Clinical Implications:** Current evidence supports that GLP-1RAs improve liver enzymes, reduce hepatic steatosis, and achieve NASH resolution in 40–60% of patients with T2DM and NAFLD. However, no consistent improvement in fibrosis has been demonstrated. Major guidelines (including US guidelines) have begun recommending GLP-1RAs in patients with T2DM and NASH. The review notes that GLP-1RAs' hepatic benefits likely arise from systemic metabolic effects—including weight loss, glycemic control, insulin sensitization, anti-inflammatory and antioxidant properties, and gut microbiome modulation—rather than direct hepatic GLP-1 receptor activation, as these receptors are not significantly expressed in liver tissue. The authors emphasize that larger RCTs with biopsy-assessed outcomes are needed. Emerging therapies such as tirzepatide (dual GLP-1/GIP agonist) and cotadutide (dual GLP-1/glucagon agonist) show promise, with tirzepatide demonstrating significant decreases in NASH-related biomarkers and weight loss of up to 20.9% in obese patients without diabetes. The ongoing ESSENCE trial and other studies will further clarify the role of GLP-1-based therapies in NAFLD management.