Abstract

Background: Retatrutide (RETA; LY3437943) is a novel triple agonist of the GIP, GLP-1 and glucagon receptors under investigation for obesity treatment. A 48-week phase 2 obesity study demonstrated weight loss of −22.8% and −24.2% with RETA 8 and 12 mg. We report effects of RETA on liver fat (LF) and correlations with metabolic measures in subjects with MASLD included in this trial.

Methods: Adults aged 18-75 yr with BMI ≥30 or ≥27 kg/m² and ≥1 weight-related condition (T2D excluded) were randomly assigned to 48 wk of QW sc RETA (1, 4, 8 or 12 mg) or PBO. The MASLD substudy included subjects with ≥10% LF (MRI-PDFF). The primary outcome was relative LF change from baseline (CFB) at 24 wks. Additional outcomes included relative LF CFB at 48 wks and proportion of subjects achieving LF <5%. Relationships between relative LF CFB and changes in body weight (BW), waist circumference (WC) and fasting metabolic biomarkers were explored.

Results: Of 338 subjects enrolled in the trial, 98 (46.9% female) participated in the substudy with mean age 46.6 yrs, BMI 38.4 kg/m², WC 118.3 cm, ALT 35.9 IU/L, AST 25.4 IU/L, FIB4 0.79 and ELF 8.1. Mean LF at baseline ranged from 15.6 to 21.0% across treatment groups. The mean relative LF CFB (%) at 24 wks was −42.9 (RETA 1 mg), −57.0 (4 mg), −81.4 (8 mg), -82.4 (12 mg) and +0.3 (PBO), and at 48 wks was −51.3 (1 mg), −59.0 (4 mg), −81.7 (8 mg), −86.0 (12 mg) and −4.6 (PBO) (all p<0.001 vs PBO). At 48 wks, LF <5% was achieved by 57% (1 mg), 29% (4 mg), 89% (8 mg), 93% (12 mg) and 0% (PBO) of subjects (all p<0.001 vs PBO). ALT and AST did not change consistently versus PBO. At 48 wks, relative LF reduction was significantly correlated with %CFB in BW and WC (r=0.774 and 0.588, respectively; both p<0.001); a nonlinear relationship with BW %CFB was demonstrated, with near-maximal LF reduction achieved at ~20% BW loss (p=0.002; Figure). 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. At 24 and 48 wks, significant (p<0.05) linear correlations were observed between relative LF reduction and % CFB in liver volume, TG, insulin, HOMA2-IR, adiponectin, leptin and FGF-21, but not BOHB.

Conclusion: In subjects with MASLD, RETA 8 and 12 mg resolved steatosis in >85% of subjects. Near-maximal LF reductions were achieved at ~20% reductions in BW. LF reductions were linearly related with metabolic measures associated with improved insulin sensitivity and lipid metabolism.