Findings from two related phase 2 clinical trials looking at the novel triple-hormone receptor agonist retatrutide were presented during a late-breaking symposium at the 83rd Scientific Sessions. Investigators shared new data on retatrutide, an investigational, once-weekly injectable glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1)/glucagon (GCG) receptor agonist, and its effects on obesity, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). 

The session, Retatrutide (LY3437943), a Novel GIP/GLP-1/Glucagon Receptor Triagonist—Obesity, NAFLD, and T2D Phase 2 Trial Results, can be viewed on-demand by registered meeting participants at ADA2023.org. If you haven’t registered for the 83rd Scientific Sessions, register today to access the valuable meeting content through August 28.  

The Triple–Hormone-Receptor Agonist Retatrutide for Obesity Phase 2 Trial studied the efficacy and safety of retatrutide for the treatment of obesity.

“Retatrutide was well tolerated and provided substantial and clinically meaningful reductions in body weight at 48 weeks of treatment,” said Ania M. Jastreboff, MD, PhD, Associate Professor of Medicine, Director of Weight Management & Obesity Prevention, and Medical Director of the Yale Stress Center, Yale School of Medicine.

The study evaluated 338 participants with obesity who did not have type 2 diabetes. They were randomized to receive 1 mg, 4, mg, 8 mg, or 12 mg doses of retatrutide or to placebo for 48 weeks. 

“The highest dose of retatrutide led to an average 24.2% in weight reduction at 11 months, and the weight reduction threshold of greater than or equal to 5% was reached in all participants who received 8 mg or 12 mg of retatrutide,” Dr. Jastreboff said. “Additionally, there were improvements in various cardiometabolic markers.”

The most common side effects were gastrointestinal, she reported, and occurred primarily during dose escalation.

“The safety and tolerability profile of retatrutide was comparable to that observed with GLP-1 and GIP/GLP-1-based therapies for the treatment of type 2 diabetes or obesity,” Dr. Jastreboff said. “Overall, these findings support moving retatrutide into phase 3 trials.”

Findings from this study were published simultaneously in the New England Journal of Medicine.

Arun J. Sanyal, MD, Professor of Medicine, Physiology, and Molecular Pathology and Interim-Chair of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, discussed results from a substudy of the obesity trial that looked at patients who also had non-alcoholic fatty liver disease (NAFLD).

“All doses of retatrutide showed significantly greater reductions in liver fat content versus placebo through week 24 and week 48 in the NAFLD subset,” Dr. Sanyal said. “Mean relative liver fat reduction was greater than 80% with retatrutide 8 mg and 12 mg, and 80% or more of participants on retatrutide 8 mg and 12 mg had a 70% or more relative reduction in liver fat. And hepatic steatosis resolved in greater than 85% of participants with retatrutide 8 mg and 12 mg at week 48.”

The safety profile of retatrutide in the NAFLD subset was similar to that in the obesity population, and no hepatotoxicity signals in obesity or NAFLD was seen through week 48. 

“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,” Dr. Sanyal said. “The current pilot data, along with the weight loss findings from the main phase two trial, further support the use of retatrutide in people with NASH.”

Julio Rosenstock, MD, Principal Investigator and Director of Velocity Clinical Research at Medical City and Clinical Professor of Medicine at the University of Texas (UT) Southwestern, discussed the efficacy and safety results from the Retatrutide for People with Type 2 Diabetes Phase 2 Study.

The trial enrolled 281 participants with type 2 diabetes who were randomized to receive 0.5 mg, 4 mg, 8 mg, or 12 mg doses of retatrutide, 1.5 mg of dulaglutide, or placebo for 36 weeks. The study’s main goal was to determine if retatrutide helps people with type 2 diabetes lower their blood sugar and to evaluate its impact on body weight changes and safety. 

“Clinically meaningful reductions in A1C and body weight were achieved with retatrutide 4 mg-12 mg compared with placebo and dulaglutide 1.5 mg,” Dr. Rosenstock said. “A1C less than 6.5% was achieved in up to 82% of the participants, and A1C of less than 5.7% was achieved up to 31% of the participants.”

In terms of the effect of retatrutide on body weight, Dr. Rosenstock reported that body weight loss of almost 17% was achieved with the 8 mg and 12 mg doses at week 36, without showing a plateau.

“When I look at this data, I can summarize it by saying that retatrutide demonstrated significant, meaningful improvements in glycemic control—up to normoglycemia—that were associated with robust body weight reductions of a magnitude not previously shown with any of the medications previously tested in type 2 diabetes,” Dr. Rosenstock said.

David A. D’Alessio, MD, the James B. Wyngaarden Distinguished Professor of Medicine and Chief of the Division of Endocrinology and Metabolism at Duke University Medical Center, reviewed studies from the past few years that have increased understanding of the metabolic action of glucagon and contributed to the development of retatrutide.

“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,” Dr. D’Alessio said. “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.”