“Triagonist” Therapy for Type 2 Diabetes and Comorbidities to be Previewed at 2023 ADA Scientific Sessions

Retatrutide, a novel triple therapy that combines a glucagon-like peptide 1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, and a glucagon agonist, will be introduced to the diabetes and metabolic disease community when phase 2 trial results are presented on Monday, June 26, at the 83rd Scientific Sessions of the American Diabetes Association (ADA).

Arun J Sanyal, MD

Courtesy American Diabetes Association

Described in a statement from the ADA as the next agent in “the string of game-changing metabolic agents that began with semaglutide, a GLP-1 receptor agonist for type 2 diabetes (T2D) and obesity, and continued with tirzepatide, a dual GLP-1/GIP receptor agonist, retatrutide may also be the first medication to treat diabetes that also targets hepatic disease.

“Traditionally, we have employed glycemic-focused approaches to diabetes,” said Arun J Sanyal, MD, professor of medicine, physiology, and molecular pathology and interim chair of gastroenterology, hepatology, and nutrition at Virginia Commonwealth University, in the ADA release. “With GLP-1, GIP, and now glucagon receptor agonists, we may finally be able to holistically manage the multiple morbidities we see in type 2 diabetes.”

Dr. Sanyal will discuss retatrutide and nonalcoholic steatohepatitis (NASH) during the symposium titled, Retatrutide (LY3437943), a Novel GIP/GLP-1/Glucagon Receptor Triagonist—Obesity, NAFLD, and T2D Phase 2 Trial Results on Monday, June 26, 2023, at 1:30 PM PST.

Among individuals with T2D, between 5% and 7% will develop hepatic fibrosis and NASH, noted Sanyal. The burden of cost on patients and families as well as on the US health care system is significant. Both GLP-1 and GIP receptor agonists temper appetite and modulate glucose regulation and have also proven beneficial in NASH. But none have demonstrated a direct effect on the liver fibrosis seen in more advanced disease.

Triagonist targets: NASH, obesity

The glucagon-receptor agonism observed with retatrutide may find favor among nephrologists. The mechanism of action appears to ease oxidative stress in liver mitochondria, which is a major driver of NASH progression, Sanyal explained.

Preclinical data have shown that improved fat oxidation can improve mitochondria function and has antifibrotic benefits as well. Improved bile acid profiles, seen in animal models, also reduces fibrosis.

“There are multiple ways one would expect the addition of a glucagon receptor agonist to translate into a more aggressive benefit than just GLP-1/GIP,” Sanyal said. “Adding glucagon to the target mix will promote antifibrotic benefits, at least that’s the hope.”

Another and significant outcome observed in initial retatrutide findings was weight loss superior to that of tirzepatide, which showed a 20% weight loss in 72 weeks.

“The medical community and society as a whole are finally moving away from the idea that obesity is just too many calories and accepting the reality that obesity is a medical problem that needs a holistic approach, not just dieting,” Sanyal observed. “There is tremendous excitement that triple therapy may finally allow us to address the multiple metabolic factors that affect people who are obese whether or not they have type 2 diabetes. That’s really what is driving this research program.”

Retatrutide principal investigator Ania 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, will discuss obesity results. Julio Rosenstock, MD, principal investigator and director of Velocity Clinical Research at Medical City and clinical professor of medicine at the University of Texas Southwestern, will discuss T2D results.

Reference: Investigators to share new data on retatrutide triple therapy. News release. American Diabetes Association. ADA Meeting News. June 20, 2023. Accessed on June 22, 2023.