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.

Related Speaker and Session

Arun J. Sanyal, Virginia Commonwealth University
Novel Therapeutic Approaches for MASH

Date: Monday, November 13th

Time: 8:30 - 10:00 AM EST