Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial.

Retatrutide is a novel triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptors. A 48-week phase 2 obesity study demonstrated weight reductions of 22.8% and 24.2% with retatrutide 8 and 12&#x2009;mg, respectively. The primary objective of this substudy was to assess mean relative change from baseline in liver fat (LF) at 24&#x2009;weeks in participants from that study with metabolic dysfunction-associated steatotic liver disease and &#x2265;10% of LF. Here, in this randomized, double-blind, placebo-controlled trial, participants (n&#x2009;=&#x2009;98) were randomly assigned to 48&#x2009;weeks of once-weekly subcutaneous retatrutide (1, 4, 8 or 12&#x2009;mg dose) or placebo. The mean relative change from baseline in LF at 24&#x2009;weeks was -42.9% (1&#x2009;mg), -57.0% (4&#x2009;mg), -81.4% (8&#x2009;mg), -82.4% (12&#x2009;mg) and +0.3% (placebo) (all P&#x2009;<&#x2009;0.001 versus placebo). At 24&#x2009;weeks, normal LF (<5%) was achieved by 27% (1&#x2009;mg), 52% (4&#x2009;mg), 79% (8&#x2009;mg), 86% (12&#x2009;mg) and 0% (placebo) of participants. LF reductions were significantly related to changes in body weight, abdominal fat and metabolic measures associated with improved insulin sensitivity and lipid metabolism. The ClinicalTrials.gov registration is NCT04881760 .