Phase 2 clinical trial results show that retatrutide, a triple agonist of the GIP, GLP-1 and glucagon receptors, results in up to 82% reduction in liver fat. Nonalcoholic fatty liver disease, now termed metabolic dysfunction-associated steatotic liver disease (MASLD), is one of the most common chronic liver diseases in the world.
In this randomized, double-blind, placebo-controlled trial, participants (n = 98) were randomly assigned to 48 weeks of once-weekly subcutaneous retatrutide (1, 4, 8 or 12 mg dose) or placebo. The mean relative change from baseline in LF at 24 weeks was −42.9% (1 mg), −57.0% (4 mg), −81.4% (8 mg), −82.4% (12 mg) and +0.3% (placebo) (all P < 0.001 versus placebo). At 24 weeks, normal LF (<5%) was achieved by 27% (1 mg), 52% (4 mg), 79% (8 mg), 86% (12 mg) and 0% (placebo) of participants.
Investigators observed a mean relative liver fat change of -81.4% and -82.4% from baseline to 24 weeks with retatrutide 8 mg and 12 mg, respectively—versus a 0.3% increase in placebo. At 48 weeks, the higher-dosage groups reported changes of -81.7% and -86.0%, versus a 4.6% increase with placebo (P <.001). Another 89% and 93% of patients receiving retatrutide 8 mg and 12 mg, respectively, achieved <5% liver fat at 48 weeks (P <.001).
Liver fat: In Phase 2, the 12 mg dose reduced liver fat by 86%, with 93% of participants achieving normal liver fat levels at 48 weeks.
Novel triple agonist therapy retatrutide was associated with steatosis resolution in nearly 9 of 10 treated patients with metabolic dysfunction-associated steatotic liver disease (MASLD).
“At the highest dose of retatrutide, more than 90% of participants with obesity and NAFLD achieved normalization of liver fat. This suggests that the addition of glucagon agonism to GIP and/or GLP agonism may result in greater efficacy in people with NAFLD/NASH.”
These liver fat reductions were the largest ever reported for a pharmacological intervention in MASLD, and they correlated strongly with improvements in insulin sensitivity, liver function markers, and lipid metabolism.
These data suggest that glucagon agonism provides additional liver fat reducing efficacy beyond what is expected from weight loss alone.
“The conventional view of insulin and glucagon has long been seen as an antagonistic one; however, our current understanding of glucagon action is not so glucose-centric, but involves other mechanisms that could conceivably be useful for diabetes treatment. The potential for weight loss is interesting, but I think the most interesting reason to pursue glucagon agonism in a multi-receptor agonist is the possibility that you could alter hepatic liver metabolism and potentially decrease fatty acid accumulation and hypertriglyceridemia.”
The db/db + Reta group demonstrated superior efficacy in reducing alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglyceride, and low-density lipoprotein levels.
Most side effects were mild to moderate gastrointestinal issues, such as nausea, which were more common at higher doses. Importantly, there were no signs of liver toxicity, even in participants with MASLD.
RETA doses ≥ 4mg improved insulin sensitivity, reflected by significant reductions vs PBO for fasting insulin (range -37.3 to -70.9%), HOMA2-IR (insulin; -35.8 to -69.3%), and increases vs PBO for adiponectin (29.8 to 99.3%) at 24 and 48 wks (all p<0.05). By 24 wks, RETA doses ≥4mg significantly changed biomarkers of lipid storage and metabolism vs PBO (p<0.05), including reducing triglycerides (TG; range -35.4 to -40.0%), leptin (-29.0 to -55.8%), and FGF-21 (-52.2 to -65.7%), and increasing beta-hydroxybutyrate (BOHB; 78.0 to 181.2%), a marker of fatty acid oxidation.
The trial also highlighted retatrutide’s ability to improve metabolic markers. Insulin resistance decreased significantly, with fasting insulin levels dropping by up to 71% at higher doses. Triglycerides, a type of fat linked to heart disease, fell by over 40% in participants taking 8 or 12 mg doses. In addition, hormones tied to fat storage and metabolism showed promising changes. Leptin, which reflects fat stores, decreased, while adiponectin, linked to improved insulin sensitivity, increased.
