Arun Sanyal, MD: Retatrutide and GLP-1 Agonists in MASLD

New phase 2 data presented at The Liver Meeting 2023 from the American Association for the Study of Liver Diseases (AASLD) in Boston this weekend showed triple agonist therapy retatrutide resolved early-stage fatty liver disease in nearly 90% of patients with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD).

The findings, presented by Arun J. Sanyal, MD, chair of the division of gastroenterology, hepatology and nutrition at VCU Health, additionally showed correlation between weight loss and liver fat percentage in treated patients. An investigative agent that which targets GLP-1, GIP and glucagon-like receptors, retatrutide represents the latest drug classes emerging in cardiometabolic health—while showing benefit in bariatric, renal and hepatic outcomes.

In the second segment of an interview with HCPLive during The Liver Meeting, Sanyal discussed the pressing need for treatment options that could resolve fatty liver while additionally benefitting comorbidity including excessive weight and cardiometabolic health. Among the global population about three-fourths of overweight and obese individuals carry excess fat in the liver.

“The implication of this is three-fold,” Sanyal said. “One is that just having excess fat in the liver seems to be a risk factor for cardiovascular disease and cardiovascular events. There is also an increase in all-cause cancer mortality and all-cause cancers within this population. And lastly, for those who have significant liver disease, there is an increased risk of liver-related outcomes and mortality.”

The trial participants in the retatrutide study would technically be defined as predominately early-stage liver disease patients due to their weight status.

“If you think about the implications of this trial, it's really for wiping out the liver disease before it becomes a real threat to the liver,” he explained. “And number two, potentially in the long-term, to realize the benefits of weight loss and improve metabolic status from a cardiometabolic perspective.”

Sanyal described the advent of obesity- and metabolic-related research into GLP-1 agonists as a “transformational” trend over the last 5 years. He noted the growing literature of evidence supporting agents like semaglutide in the robust reduction of body weight and benefit for cardiovascular outcomes and events in high-risk patients. Over that time, investigators have additionally considered GLP/GIP agonists, then GLP/glucagon co-agonists. Targeting all 3 receptors with retatrutide clearly indicates more benefit for overweight patients’ hepatic risks.

“Targeting the glucagon receptor allows for some liver targeting, and at least based on preclinical data, one would expect there to be some increase in fat oxidation in the liver, a reduction in mitochondrial injury and oxidative stress, and potentially even less fibrosis, that can be linked to these liver targeted aspects of these triple agonists,” Sanyal said.

Reference

^{Frias JP, Thomas MK, Mather KJ, Wu Q, et al. TRIPLE HORMONE RECEPTOR AGONIST RETATRUTIDE RESOLVES STEATOSIS IN >85 % OF SUBJECTS WITH MASLD AND OBESITY IN ASSOCIATION WITH IMPROVED METABOLIC HEALTH. Paper presented at: The Liver Meeting. Boston, MA. November 10 - 14, 2023}