'Triple G' Agonist Hits New Weight-Loss Heights

Mitchel L. Zoler, PhD

August 09, 2023

A novel triple agonist to receptors for three nutrient-stimulated hormones led to weight loss as high as 24% among people with overweight or obesity but who did not have type 2 diabetes when used at the highest tested dose for 48 weeks. The results are from a phase 2 study of retatrutide that was published in The New England Journal of Medicine on August 9.

This level of weight loss is "unprecedented" for a medication administered for 48 weeks, commented Mary-Elizabeth Patti, MD in an editorial that accompanied the report.

The findings "offer further optimism...that effective pharmacologic management of obesity and related disorders is possible," writes Patti, a principal investigator at the Joslin Diabetes Center in Boston.

The study randomly assigned 338 adults with obesity or overweight ― a body mass index (BMI) of ≥27 kg/m2 ― and at least one weight-related complication to receive either weekly subcutaneous injections of retatrutide in any of six dose regimens or placebo over 48 weeks. The primary outcome was weight change from baseline after 24 weeks.

The highest dose of retatrutide safely produced an average 17.5% drop from baseline weight, compared with an average 1.6% reduction in the placebo group, after 24 weeks, a significant difference.

After 48 weeks, the highest retatrutide dose safely cut baseline weight by an average of 24.2%, compared with an average 2.1% drop among placebo control patients, Ania M. Jastreboff, MD, PhD, and her co-authors say in their report. Weight loss levels after 24 and 48 weeks of retatrutide treatment followed a clear dose-response pattern.

Weight Losses Never Before Seen

"I have never seen weight loss at this level" after nearly 1 year of treatment, said Jastreboff when she discussed these findings in a press conference at the American Diabetes Association (ADA) 83rd Scientific Sessions in San Diego in late June.

A separate presentation at the ADA meeting documented unprecedented weight loss levels in a study of 281 people with obesity or overweight and type 2 diabetes.

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

The mechanism behind retatrutide's potent weight-loss effect seems likely tied to its action on three human receptors that naturally respond to three nutrient-stimulated hormones that control appetite, metabolism, fat mobilization, and related functions.

The three hormones that the retatrutide molecule simultaneously mimics are glucagon-like peptide-1 (GLP-1), such as agents in the class of GLP-1 agonists that includes liraglutide (Victoza/Saxenda) and semaglutide (Ozempic/Wegovy); the glucose-dependent insulinotropic polypeptide (GIP), the receptor that is also activated by tirzepatide (Mounjaro), a dual-incretin receptor agonist that mimics both GLP-1 and GIP; and glucagon. Survodutide is a dual GLP-1 and glucagon receptor agonist in phase 2 development.

Retatrutide is currently unique among agents with reported clinical results by having agonist effects on the receptors for all three of these hormones, a property that led Patti to call retatrutide a "triple G" hormone-receptor agonist in her editorial.

Triple Agonist Has Added Effect on Liver Fat Clearance

The glucagon-receptor agonism appears to give retatrutide added effects beyond those of the GLP-1 agonists or GLP-1/GIP dual agonists that are increasingly used in US practice.

A prespecified subgroup analysis of the no diabetes/Jastreboff study (but that was not included in the NEJM report) 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 whose liver volume was at least 10% fat at study entry).

That percentage increased to about 90% of people receiving these doses after 48 weeks, Lee M. Kaplan, MD, reported during a separate presentation at the ADA meeting.

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

The average age of the participants in the new study of the use of retatrutide for those with obesity/overweight but not diabetes was 48 years. 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.

Treatment with retatrutide was also significantly associated with improvements in several cardiometabolic measures in exploratory analyses, including systolic and diastolic blood pressure, A1c, fasting glucose, insulin, and some (but not all) lipids, reported Jastreboff, director of the Yale Obesity Research Center of Yale University in New Haven, Connecticut, and her co-authors in the NEJM article.

The safety profile of retatrutide was consistent with reported phase 1 findings for the agent among people with type 2 diabetes and resembled the safety profiles of other agents based on GLP-1 or GIP–GLP-1 mimicry for the treatment of type 2 diabetes or obesity.

The most frequently reported adverse events from retatrutide were transient, mostly mild to moderate gastrointestinal events. They occurred primarily during dose escalation. Discontinuation of retatrutide or placebo because of adverse events occurred in 6% to 16% of the participants who received retatrutide and in none of the participants who received placebo.

Lilly, the company developing retatrutide, previously announced the launch of four phase 3 trials to gather further data on retatrutide for use in a marketing-approval application to the US Food and Drug Administration.

The four trials ― TRIUMPH-1, TRIUMPH-2, TRIUMPH-3, and TRIUMPH-4 ― are evaluating the safety and efficacy of retatrutide for chronic weight management for those with obesity or overweight, including those who also have obstructive sleep apnea, knee osteoarthritis, type 2 diabetes, or cardiovascular disease.

The study was sponsored by Lilly, the company developing retatrutide. Patti has been a consultant to AstraZeneca, Dexcom, Hanmi, and MBX. She has received funding from Dexcom and has been a monitor for a trial funded by Fractyl. Jastreboff, Kaplan, and Rosenstock have reported financial relationships with Lilly as well as other companies.

N Engl J Med. Published online August 8, 2023. Abstract, Editorial

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

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