Phase 2 Substudy Shows Retatrutide Use Could Contribute to NAFLD Resolution

Arun Sanyal, MD
Credit: Virginia Commonwealth University

Data from a subgroup analysis of phase 2 retatrutide data suggests use of the GIP/GLP-1/Glucagon receptor agonist could provide additional benefits beyond weight loss and improved glycemic control.

A subgroup analysis of patients with nonalcoholic fatty liver disease (NAFLD) from the landmark obesity trial presented at the 83rd Scientific Sessions of the American Diabetes Association (ADA 2023), results indicate 90% of those using retatrutide at 8 or 12 mg doses achieved resolution of NAFLD.¹

“This study raises the possibility that in the early stages of liver disease, it is possible to ‘de-fat’ the liver, which could in turn help to reduce the long-term cardiac, metabolic, renal, and liver-related harm from obesity. We are encouraged by these results and how they can potentially help tackle a disease that is currently without any approved therapies,” said Arun J. Sanyal, MD, director of the Stravitz Sanyal Institute for Liver Disease and Metabolic Health and professor of medicine, physiology, and molecular pathology at Virginia Commonwealth University.²

Presented on the final day of ADA 2023, the results of a pair of phase 2 trials in patients with overweight or obesity and type 2 diabetes, respectively, captured the attention of both the medical community and the general public. Results of the phase 2 obesity trial suggest use of retatrutide was associated with a least-squares mean percentage change in body weight of -8.7% in the retatrutide 1-mg group, -17.1% in the combined retatrutide 4-mg group, -22.8% in the combined retatrutide 8-mg group, -24.2% in the retatrutide 12-mg group, and -2.1% in the placebo group at 48 weeks.³ The phase 2 trial examining use in people with type 2 diabetes concluded use of retatrutide 12 mg was associated with a mean reduction in HbA1c of –2.02%, with no reports of severe hypoglycemia.⁴

The subgroup analysis of patients with NAFLD, which was presented in the same symposium as the phase 2 obesity and type 2 diabetes trials, included a subset of 98 patients from the obesity trial. The 98-patient subset had comparable baseline characteristics to the full study population, but the NAFLD subset had a greater mean BMI (38.4 vs 37.3 kg/m2) and a lower proportion of African Americans (2% vs 8%). In his presentation, Sanyal noted there were significant differences in baseline hepatic fat fraction among the NAFLD subgroup for the retatrutide 1 mg, 8 mg, and 12 mg groups.¹

The primary and key secondary objective of the subgroup analysis was to assess the relative change in liver fat compared with placebo and the proportion of patients achieving relative liver fat reduction of 30% or greater, 50% or greater, and 70% or greater at week 24. Investigators also planned to assess the proportion of patients achieving resolution of NAFLD, which was defined as a liver fat content less than 5%.¹

Upon analysis, results revealed a stepwise dose-dependent decrease in relative liver fat, with use of retatrutide 8 mg and 12 mg associated with decreases of 81.4% and 82.4%, respectively, at week 24 compared to 0.3% with placebo therapy (P < .001). At week 48, the relative decrease in liver fat was 81.7% with retatrutide 8 mg, 86% with retatrutide 12 mg, and 4.6% with placebo therapy (P < .001).¹

When assessing proportion of patients achieving relative fat reduction at respecified thresholds at week 24, results indicated 100% of the retatrutide 8 mg and 12 mg groups achieved a reduction of 30% or greater, reductions of 50% or greater were achieved by 95% and 100% of the 8 mg and 12 mg groups, respectively, and reductions of 70% or greater were achieved by 86% and 80% of the 8 mg and 12 mg groups, respectively. Sanyal also highlighted resolution of NAFLD was observed in 79% and 86% of the 8 mg and 12 mg groups, respectively, at week 24. This figure increased to 89% of the 8 mg group and 93% of the 12 mg group at week 48.¹

References:

1. Sanyal AJ. Retatrutide NAFLD - Phase 2 Trial Results in Subset of Patients with Obesity and NAFLD. Presentation at the 83rd Scientific Sessions of the American Diabetes Association. June 23 – 26, 2023.
2. American Diabetes Association highlights novel agent RETATRUTIDE which results in substantial weight reduction in people with obesity or type 2 diabetes during late Breaking symposium. American Diabetes Association Highlights Novel Agent Retatrutide which Results in Substantial Weight Reduction in People with Obesity or Type 2 Diabetes During Late Breaking Symposium | ADA. June 26, 2023. Accessed June 28, 2023. https://diabetes.org/newsroom/press-releases/2023/american-diabetes-association-highlights-novel-agent-retatrutide-results-substantial-weight-reduction-people-with-obesity-type-2-diabetes-during-late-breaking-symposium.
3. Rosenstock J, Frias JP, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. The Lancet. Published online June 26, 2023. doi:10.1016/S0140-6736(23)01053-X
4. Jastreboff AM, Kaplan LM, Frias JP, et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. The New England Journal of Medicine. Published online June 26, 2023. doi:10.1056/NEJMoa2301972