Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a prevalent chronic liver disease with a dramatically increasing global prevalence (25% in 1990–2006 to 38% in 2016–2019). Obesity is a major contributor, with at least half of MASLD patients being obese. Insulin resistance is a key pathophysiological driver, leading to dysregulated lipolysis, excessive fatty acid delivery to the liver, hepatic de novo lipogenesis, and inflammation. This can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and liver failure. Currently, no treatments for NASH are approved in the US or Europe. Several pharmacological therapies are under development, including incretin-based therapies targeting glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. Semaglutide (a GLP-1 receptor mono-agonist), and tirzepatide (a GIP/GLP-1 dual agonist) have shown promise, but adding glucagon (GCG) agonist activity may offer greater hepatic fat reduction. Retatrutide, a novel triple GLP-1/GIP/GCG receptor agonist, is being investigated for its potential in treating MASLD.

Existing literature highlights the increasing global burden of MASLD and the critical role of insulin resistance in its pathogenesis. Studies on GLP-1 receptor agonists, such as semaglutide, and GIP/GLP-1 dual agonists, such as tirzepatide, have demonstrated efficacy in reducing liver fat and improving biomarkers of MASLD. However, these studies suggest that the addition of glucagon agonism might further enhance these effects. Preclinical and early clinical data on other triple agonists, like efinopegdutide, have indicated significant liver fat reduction. This study builds upon this foundation to investigate retatrutide's efficacy and safety profile in reducing liver fat content in patients with MASLD.

This randomized, double-blind, placebo-controlled phase 2a trial (NCT04881760) enrolled 98 participants with MASLD and ≥10% liver fat (identified by MRI-PDFF) from a larger phase 2 obesity study. Participants were randomized to receive once-weekly subcutaneous retatrutide (1, 4, 8, or 12 mg) or placebo for 48 weeks. The primary objective was to assess the mean relative change from baseline in liver fat at 24 weeks. Secondary objectives included changes in liver fat at 48 weeks and other relevant parameters. MRI-PDFF was used to measure liver fat content at baseline, week 24, and week 48. Body composition (VAT and ASAT) was assessed using AMRA Profiler Research. Serum biomarkers of MASLD, fibrosis, insulin sensitivity, and lipid metabolism were also collected. Statistical analyses included mixed models for repeated measures and logistic regression.

Retatrutide significantly reduced liver fat at all doses compared to placebo at 24 weeks (*P* < 0.001 for all doses). The LSM relative liver fat changes at 24 weeks were -42.9% (1 mg), -57.0% (4 mg), -81.4% (8 mg), and -82.4% (12 mg) versus +0.3% for placebo. At 24 weeks, normal liver fat (<5%) was achieved by 27% (1 mg), 52% (4 mg), 79% (8 mg), and 86% (12 mg) of participants compared to 0% in the placebo group. At 48 weeks, similar trends persisted, with further reductions in liver fat. Retatrutide also significantly reduced body weight and waist circumference at both 24 and 48 weeks (*P* < 0.001 for all doses). Reductions in liver fat were strongly correlated with changes in body weight (*r* = 0.800, *P* < 0.001 at 24 weeks) and waist circumference (*r* = 0.652, *P* < 0.001 at 24 weeks). Significant improvements in markers of insulin sensitivity (fasting insulin, C-peptide, HOMA2-IR) and lipid metabolism (adiponectin, leptin, triglycerides) were observed. K-18 and pro-C3, markers of liver injury and fibrosis, showed significant reductions with higher doses of retatrutide. The safety profile was similar to previous reports in obesity trials, with the most common adverse events being gastrointestinal events.

This study demonstrates that retatrutide, a triple hormone receptor agonist, effectively reduces liver fat in individuals with MASLD. The magnitude of liver fat reduction observed with retatrutide surpasses that reported for GLP-1 mono-agonists and the GIP/GLP-1 dual agonist tirzepatide. The superior efficacy might be attributed to greater weight reduction, direct hepatic effects of glucagon receptor agonism, or a combination of both. Improvements in insulin sensitivity and lipid metabolism further support the beneficial effects of retatrutide. While reductions in K-18 and pro-C3 suggest a potential impact on liver injury and fibrosis, the absence of histological data necessitates further investigation. The strong correlation between liver fat reduction and improvements in other metabolic parameters highlights the multifaceted impact of retatrutide on metabolic health.

This phase 2a trial provides compelling evidence for retatrutide's efficacy in reducing liver fat in patients with MASLD. The high rates of steatosis resolution observed with the higher doses are encouraging. Further studies, including those with histological assessment and longer durations, are warranted to determine retatrutide's impact on fibrosis progression and major adverse liver outcomes in a broader patient population.

The relatively small sample size, the lack of liver histology, the exclusion of patients with T2D, and the lack of 48-week MRI data for all participants limit the generalizability of the findings. The geographic and racial homogeneity of the sample also warrants caution in extrapolating the results to diverse populations. The lack of multiplicity control due to the large number of statistical tests is also a limitation. The study primarily focuses on liver fat reduction; long-term effects on fibrosis and clinical outcomes require further investigation.