MON-702 - Efficacy and Safety of Retatrutide in Obesity, Type 2 Diabetes, and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Systematic Review

Introduction
Retatrutide is a GIP, GLP-1, and glucagon receptor agonist, with higher activity at the human GIP receptor. With few published randomized controlled trials, a comprehensive systematic review of retatrutide's efficacy and safety is needed. We review the efficacy and safety of retatrutide for the management of obesity, type 2 diabetes, and MASLD management.
Methods
We systematically searched PubMed, Cochrane Library, Embase, and clinical trial registries through January 2026 for randomized controlled trials evaluating retatrutide in adults with obesity, T2DM, and/or MASLD. The search strategy combined keywords and Medical Subject Headings terms related to obesity, T2DM, and MASLD.
Studies were screened, and data on percentage body weight change, HbA1c reduction, liver fat content by MRI-PDFF, and adverse events were extracted.
Quality was assessed using standardized criteria for randomization, blinding, missing data, and conflicts of interest. All trials were double-blind, placebo-controlled, with appropriate statistics; generalizability remains limited.
Results
We identified two phase 2 trials: an obesity trial (n=338) and a T2DM trial (n=281), totaling 619 unique participants. A nested MASLD sub-study (n=98) within the obesity trial was analyzed, enrolling participants with baseline liver fat ≥10% by MRI-PDFF. In the obesity trial (48 weeks), retatrutide produced dose-dependent weight reductions ranging from −8.7% to −24.2%, with higher doses achieving progressively greater weight loss compared to placebo, which achieved −2.1%. Body-weight reductions of at least 20% were more common at a dose of at least 4 mg than among those who received a placebo. In the T2DM trial (36 weeks), HbA1c decreased up to -2.16% (12 mg) versus +0.31% (placebo), while 93% of participants receiving 12 mg achieved HbA1c 7.0%. Weight loss in T2DM participants reached -16.3% with 12 mg versus +3.0% with placebo. In the MASLD substudy (24 weeks), retatrutide led to liver fat reduction ranging from -42.9% to -82.4%, compared with +0.3% with placebo. Liver fat normalization was achieved by 86% of participants (12 mg). The most common gastrointestinal (GI) adverse events include nausea, diarrhea, and vomiting in a dose-dependent manner. Adverse events led to treatment discontinuation at rates ranging from 6% to 16%. No severe hypoglycemic events were reported.
Conclusion
Retatrutide shows robust efficacy in obesity, T2DM, and MASLD, achieving weight reductions up to 24.2%, HbA1c reductions up to 2.16%, and liver fat normalization in up to 86% of participants. The safety profile aligns with that of the incretins, primarily involving dose-dependent GI adverse events. Key limitations are small sample sizes, lack of histological liver endpoints, and the nested design of the MASLD substudy. Phase 3 trials are needed to confirm these findings and to establish the long-term effect of retatrutide.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*