Triple Agonist Retatrutide Hits New Weight-Loss Highs

SAN DIEGO — New designer molecules that target weight loss via multiple mechanisms continue to raise the bar of how many pounds people with overweight or obesity can lose.

Retatrutide (Eli Lilly), an investigational agent that combines agonism to three key hormones that influence eating and metabolism into a single molecule, safely produced weight loss at levels never seen before in a pair of phase 2 studies that together randomized more than 600 people with overweight or obesity, with or without type 2 diabetes.

Among 338 randomized people with overweight or obesity and no type 2 diabetes, 48 weeks of treatment with retatrutide at a 12-mg dose given by weekly subcutaneous injection (the highest dose tested) safely produced an average 24% drop from baseline bodyweight.

Among 281 randomized people with overweight or obesity and type 2 diabetes, the same dose of retatrutide produced a nearly 17% cut in weight from baseline after 36 weeks of treatment.

Never Before Seen Weight Loss

Dr Ania M. Jastreboff

"I have never seen weight loss at this level" after nearly 1 year of treatment, said Ania M. Jastreboff, MD, PhD, who led the obesity study, during a press briefing here at the American Diabetes Association (ADA) 83rd Scientific Sessions.

The average weight loss by study participants taking high-dose retatrutide in the two studies "is really impressive, way beyond my wildest dreams," commented Carel le Roux, MBChB, PhD, an obesity and diabetes researcher at University College Dublin, Ireland, who was not involved with the retatrutide studies.

And Robert Gabbay, MD, chief scientific and medical officer of the ADA, called the results "stunning," and added, "we are now witnessing the first triple-hormone combination being highly effective for not only weight loss but liver disease and diabetes."

A prespecified subgroup analysis of the obesity study showed that at both 8-mg and 12-mg weekly doses, 24 weeks of retatrutide produced complete resolution of excess liver fat (hepatic steatosis) in about 80% of the people eligible for the analysis (those with at least 10% of their liver volume as fat at study entry); that figure increased to about 90% of people on these doses after 48 weeks, Lee M. Kaplan, MD, reported during a separate presentation at the meeting.

Adding Glucagon Agonism Ups Liver-Fat Clearance

"When you add glucagon activity," one of the three agonist actions of retatrutide, "liver-fat clearance goes up tremendously," said Kaplan, who is director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.

"To my knowledge, no mono-agonist of the glucagon-like peptide-1 (GLP-1) receptor [such as semaglutide or liraglutide] produces more than 50% clearance of liver fat," added Kaplan.

Dr Lee M. Kaplan

The separate, randomized study of people with type 2 diabetes showed that in addition to producing an unprecedented average level of weight loss at the highest retatrutide dose, the agent also produced an average reduction from baseline levels of A1c of about 2 percentage points, an efficacy roughly comparable to maximum doses of the most potent GLP-1 mono-agonist semaglutide (Ozempic, Novo Nordisk), as well as by tirzepatide (Mounjaro, Eli Lilly), a dual agonist for the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors.

"No other medication has shown an average 17% reduction from baseline bodyweight after 36 weeks in people with type 2 diabetes," commented Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, Texas, who presented the results from the type 2 diabetes study of retatrutide.

For the obesity study, people with a body mass index (BMI) of 27-50 kg/m² and no diabetes were randomized to placebo or any of four retatrutide target dosages using specified dose-escalation protocols. Participants were an average of 48 years old, and by design, 52% were men. (The study sought to enroll roughly equal numbers of men and women.) Average BMI at study entry was 37 kg/m².

Weight loss levels after 24 and 48 weeks of retatrutide treatment followed a clear dose-related pattern. (Weight loss averaged about 2% among the 70 controls who received placebo.)

26% Without Diabetes Lost ≥ 30% of Bodyweight

Every person who escalated to receive the 8-mg or 12-mg weekly dose of retatrutide lost at least 5% of their bodyweight after 48 weeks, 83% of those taking the 12-mg dose lost at least 15%, 63% of those on the 12-mg dose lost at least 20%, and 26% of those on the highest dose lost at least 30% of their starting bodyweight, reported Jastreboff, director of the Yale Obesity Research Center of Yale University in New Haven, Connecticut.

The highest dose was also associated with an average 40% relative reduction in triglyceride levels from baseline and an average 22% relative drop in low-density lipoprotein cholesterol levels.

The results were simultaneously published online in the New England Journal of Medicine.

The incidence of serious adverse events with retatrutide was low, similar to the rate in those who received placebo, and showed no dose relationship.

The most common adverse events were gastrointestinal, in as many as 16% of those on the highest dose; these were mild to moderate in severity and usually occurred during dose escalation. In general, adverse events were comparable to what is seen with a GLP-1 agonist or the dual agonist tirzepatide, Jastreboff said.

A1c Normalization in 26% at the Highest Dose

Dr Julio Rosenstock

A similar safety pattern occurred in the study of people with type 2 diabetes, which randomized people with an average A1c of 8.3% and an average BMI of 35.0 kg/m². After 36 weeks of treatment, the 12-mg weekly dose of retatrutide led to normalization of A1c < 5.7% in 27% of people and A1c ≤ 6.5% in 77%.

"The number of people we were able to revert to a normal A1c was impressive," said Rosenstock. These results were simultaneously published online in The Lancet.

The additional findings on liver-fat mobilization in people without diabetes enrolled in the obesity study are notable because no agent currently has labeling from the US Food and Drug Administration for the indication of reducing excess liver fat, said Kaplan.

The researchers measured liver fat at baseline and then during treatment using MRI.

"With the level of fat clearance from the liver that we see with retatrutide it is highly likely that we'll also see improvements in liver fibrosis" in retatrutide-treated patients, Kaplan predicted.

Next up for retatrutide is testing in pivotal trials, including the TRIUMPH-3 trial that plans to enroll about 1800 people with severe obesity and cardiovascular disease, with findings expected toward the end of 2025.

The retatrutide studies are sponsored by Eli Lilly. Jastreboff, Rosenstock, Kaplan, and Le Roux have reported financial relationships with Eli Lilly as well as other companies.

ADA Scientific Sessions. Session CT-1.5-SY26. Presented June 26, 2023.

Lancet. Published online June 26, 2023. Full Text

N Engl J Med. Published online June 26, 2023. Full Text

Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler

For more diabetes and endocrinology news, follow us on Twitter and Facebook.

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.