Triple Agonist Retatrutide Associated with Weight Loss of up to 24% in 48-Week Phase 2 Trial

Treatment with the novel triple-hormone agonist retatrutide was associated with a mean body weight reduction of 17.5% at the 24-week point in a new landmark study and with mean reduction of 24.2% at the end of the 48-week treatment duration, according to phase 2 data¹ presented at the 83rd Scientific Sessions of the American Diabetes Association (ADA). Participants in the study had overweight or obesity and did not have type 2 diabetes (T2D).

Retatrutide, dubbed a “triagonist,” combines a glucagon-like peptide 1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, and a glucagon receptor agonist. The agent was described in an earlier ADA statement as "the next in the string of game-changing metabolic agents" that began with the GLP-1 receptor agonist semaglutide and continued with tirzepatide, a dual GLP-1/GIP receptor agonist.²

"Obesity is a treatable chronic disease with a complex underlying biology. We are now in the midst of a rapidly expanding therapeutic landscape of potential highly effective treatment options for individuals with obesity," said principal investigator Ania Jastreboff, MD, PhD, associate professor of medicine & pediatrics, endocrinology & metabolism at the Yale School of Medicine in an Eli Lilly press statement.³ The mean weight reduction of 24.2% observed among study participants treated with the highest dose of retratudide (12 mg) translates to an average absolute weight loss of approximately 58 pounds over 11 months, she added.³ The full efficacy of retatrutide for weight loss was probably not realized during the study because participants’ weight had not plateaued at the study’s end, Jastreboff emphasized. She noted that longer phase 3 trials will allow comprehensive evaluation of efficacy and tolerability of retatrutide.³ Astreboff is also director of the Yale Obesity Research Center and co-director of the Yale Center for Weight Management.

Methods

The purpose of the phase 2, double-blind, randomized, placebo-controlled trial as described by the research team in the study's simultaneous publication in the New England Journal of Medicine, was to evaluate the efficacy, tolerability, and safety of retatrutide across investigational doses and titration schedules. Study participants were randomly assigned in a 2:1:1:1:1:2:2 ratio to receive subcutaneous retatrutide 1 mg, 4 mg (starting dose 2 mg), 4 mg (starting dose 4 mg), 8 mg (starting dose 2 mg), 8 mg (starting dose 4 mg), 12 mg (starting dose 2 mg) or placebo once weekly for 48 weeks. To evaluate dose escalation strategies, Jastreboff et al randomly assigned participants in the cohorts receiving the 4-, 8-, and 12-mg doses to different starting doses.¹

Eligible participants for the study had a body mass index (BMI) of 30 kg/m² or greater or a BMI of 27 kg/m² to less than 30 and at least 1 weight-related condition. The final cohort numbered 338 adults with a mean age of 48.2 years, mean baseline body weight of approximately 107.7 kg and mean BMI of 37.3 kg/m². Half the group were men (51.8%), and the majority White. The average duration of obesity was approximately 13 years. Of the full cohort, 81% completed the 52-week trial.

The study’s primary outcome of interest was the percentage change in body weight from baseline to 24 weeks. The secondary end points were the percentage change in body weight from baseline to 48 weeks and the proportion of patients achieving weight reductions of 5% or more, 10% or more, and 15% or more.

FINDINGS

24-week outcomes. Analyzed in terms of least-squares mean percentage, the change in body weight after 24 weeks was -7.2% in the retatrutide 1-mg group, -12.9% in the combined 4-mg group, -17.3% in the combined 8-mg group, -17.5% in the 12-mg group, and -1.6% in the placebo group.

48-week outcomes. When recorded at 48 weeks, least-squares mean percentage change of body weight was -8.7% in the retatrutide 1-mg group, -17.1% in the combined 4-mg group, -22.8% in the combined 8-mg group, -24.2% in the 12-mg group, and -2.1% in the placebo group.

Weight reductions of equal to or greater than 5%, 10%, and 15% were (below):

Jastreboff and colleagues also reported that reductions in weight of 20% or more and 25% or more were more common among participants who received retatrutide doses of at least 4 mg. Among those in the 12-mg dose group, 26% of participants experienced body weight reduction of 30% or more.

In 2 of several prespecified analyses, the investigators reported that weight loss while recieving retatrutide was greater among participants with BMI of 35 or higher than among those with BMI of lower than 35 and greater for women than for men.

Safety analysis

Findings from the safety analysis for retatrutide reflect profiles of other incretin-based therapies, ie, gastrointestinal side effects were the most commonly reported adverse events and were mild-to-moderate in severity, according to the study. Most adverse events occurred during the dose escalation period, were transient, and resolved without discontinuation of the study drug or placebo.

Particular strengths of the study cited by the authors include its long duration as a phase 2 study, the balance of men and women in the trial cohort, sample size large enough to allow exploration of cardiovascular outcomes, and a population with 35% self-identifying as Hispanic or Latino. Limitations they note are the homogeneity of the sample (White, US only) and the small proportion of participants with overweight vs obesity.

"We believe that combining glucagon receptor agonism with GIP and GLP-1 receptor agonism may be one of the reasons retatrutide showed this level of weight reduction," said Dan Skovronsky, MD, PhD, Lilly's chief scientific and medical officer, and president of Lilly Research Laboratories.³ "These phase 2 data have given us confidence to further explore the potential of retatrutide in phase 3 trials that will look beyond weight reduction and focus on treating obesity and its complications comprehensively."

The company’s TRIUMPH phase 3 development program will evaluate the safety and efficacy of retatrutide for chronic weight management, obstructive sleep apnea, and knee osteoarthritis in people with obesity and overweight.³

References

1. Jastreboff AM, Kaplan LM, Frias JP, et al. Triple–hormone-receptor agonist retatrutide for obesity— a phase 2 trial. New Engl J Med. Published online June 26, 2023. doi:10.1056/NEJMoa2301972
2. Halsey G. "Triagonist” therapy for type 2 diabetes and comorbidities to be previewed at 2023 ADA scientific sessions. Patient Care Online. June 23, 2023. Accessed June 27, 2023.
3. Lilly’s Phase 2 retatrutide results published in the New England Journal of Medicine show the investigational molecule achieved up to 17.5% mean weight reduction at 24 weeks in adults with obesity and overweight. Eli Lilly and Company. June 26, 2023. Accessed June 26, 2023.