Retatrutide Showcases Historic Weight-Lowering, Glycemic Control Benefits in Phase 2 Data

Ania Jastreboff, MD, PhD
Credit: Yale School of Medicine

The future appears bright for Eli Lilly and Company’s novel GIP/GLP-1/Glucagon triagonist, retatrutide, based on phase 2 data presented at the 83rd Scientific Sessions of the American Diabetes Association (ADA 2023).

Results of the trials, which were simultaneously published in the New England Journal of Medicine and The Lancet, suggest use of retatrutide was associated with a mean body weight reduction of 17.5% at 24 weeks and 24.2% at the end of the 48-week treatment duration, with phase 2 data in type 2 diabetes indicating use was associated with a reduction in mean HbA1c of –2.02% and no reports of severe hypoglycemia.

"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 Yale School of Medicine; Director, Yale Obesity Research Center and co-Director of the Yale Center for Weight Management.³ "Participants treated with the highest dose of retatrutide achieved a mean weight reduction of 24.2%; this translates to an average absolute weight reduction of about 58 pounds over 11 months of the study. Given that participants had not yet reached a weight plateau at the time the study ended, it appears that full weight reduction efficacy was not yet attained. Longer duration phase 3 trials will enable comprehensive evaluation of efficacy and tolerability of this potential pharmacotherapeutic for the treatment of obesity."

Retatrutide in Overweight/Obesity¹

A phase 2, double-blind, randomized, placebo-controlled trial, the retatrutide phase 2 obesity trial was launched to assess the dose-response relationship of retatrutide as it pertains to the agent’s safety and efficacy profile. Per trial protocol, patients underwent randomization in a 2:1:1:1:1:2:2 ratio to receive subcutaneous retatrutide 1 mg, 4 mg, 4 mg, 8 mg, 8 mg, or 12 mg or placebo for 48 weeks. Investigators pointed out multiple 4, 8, and 12 mg groups were included to assess the safety and efficacy of different dose escalation strategies.

For inclusion in the trial, patients were required to have a BMI of 30 kg/m2 or greater or a BMI of 27 kg/m2 and at least 1 weight-related condition. In total, 338 adults underwent randomization in the trial. This cohort had a mean age of 48.2 (SD, 12.7) years, a mean BMI of 37.3 (SD, 5.7) kg/m2, and 51.8% were men. Of the 338 participants, 81% completed the 52-week trial.

The primary outcome of interest for the trial was he percentage change in body weight from baseline to 24 weeks. The trial included multiple secondary outcomes of interest, including 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, or 15% or more.

Upon analysis, results of the study suggested there was a least-squares mean percentage change in body weight at week 24 of -7.2% in the retatrutide 1-mg group, -12.9% in the combined retatrutide 4-mg group, -17.3% in the combined retatrutide 8-mg group, -17.5% in the retatrutide 12-mg group, and -1.6% in the placebo group. Analysis of secondary endpoints of interest revealed a least-squares mean percentage change of -8.7% in the retatrutide 1-mg group, -17.1% in the combined retatrutide 4-mg group, -22.8% in the combined retatrutide 8-mg group, -24.2% in the retatrutide 12-mg group, and -2.1% in the placebo group.

Further analysis indicated weight reductions of 15% or more were achieved by 60% of the retatrutide 4-mg group, 75% of the retatrutide 8-mg group, 83% of the retatrutide 12-mg group, and 2% of the placebo group. In a safety analysis, investigators found most adverse events were dose-related and partially mitigated with a lower starting dose.

Retatrutide in Type 2 Diabetes²

The phase 2 trial of retatrutide in in type 2 diabetes was designed as a randomized, double-blind, double-dummy, placebo-controlled and active comparator-controlled, parallel-group and conducted across 42 sites in the US. The trial enrolled adult patients aged 18-75 years with type 2 diabetes, an HbA1c of 7.0 to 10.5%, and a BMI of 25-50 kg/m2. Investigators noted participants were required to have received treatment with diet and exercise alone or with a stable dose of metformin for at least 3 months prior to the screening visit.

Overall, 281 patients underwent randomization in 2:2:2:1:1:1:1:2 to placebo, dulaglutide 1.5 mg, retatrutide 1 mg, retatrutide 4 mg, retatrutide 4 mg, retatrutide 8 mg, retatrutide 8 mg, retatrutide 12 mg or placebo for 48 weeks. Similar to the obesity trial, trial protocol called for multiple 4, 8, and 12 mg groups to be included to assess the safety and efficacy of different dose escalation strategies. This patient population had a mean age of 56.2 (SD, 9.7) years, a mean duration of diabetes of 8.1 (SD, 7.0) years, 56% were female, and 84% were White.

The primary outcome of interest for the trial was change in HbA1c from baseline to 24 weeks. The secondary outcome of interest was the change in HbA1c and body weight at 36 weeks.

Results of the investigators’ primary outcome analysis pointed to least-squares mean changes in HbA1c from baseline to week 24 of -0.43% (SE, 0.20) for the retatrutide 0.5 mg group, -1.39% (SE, 0.14) for the retatrutide 4 mg escalation group, -1.30% (SE, 0.22) for the retatrutide 4 mg group, -1.99% (SE, 0.15) for the retatrutide 8 mg slow escalation group, -1.88% (SE, 0.21)for the 8 mg fast escalation group, -2.02% (SE, 0.11) for the 12 mg group, and -0.01% (SE, 0.21) in the placebo group. Further analysis suggested HbA1c reductions achieved with retatrutide were significantly greater than placebo in all but the 0.5 mg group and greater than 1.5 mg dulaglutide in the 8 mg slow escalation group (P = .0019) and retatrutide 12 mg escalation group (P = .0002).

When assessing the safety of the agent, results suggested mild-to-moderate gastrointestinal adverse events, occurred 35% of participants in the retatrutide groups, 13% of participants in the placebo group, and 35% of participants in the 1.5 mg dulaglutide group.

In their release, Eli Lilly and Company noted plans to further explore the potential of retatrutide in the TRIUMPH phase 3 development program, which will evaluate the safety and efficacy of retatrutide for chronic weight management, obstructive sleep apnea (OSA), and knee osteoarthritis (OA) in people with obesity and overweight. According to the release, the TRIUMPH 1, 2, 3, and 4 trials will examine the agent in patient populations with OSA and OA, OSA, obesity and established cardiovascular, and obesity or overweight with OA, respectively.³

"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."

References:

1. Rosenstock J, Frias JP, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. The Lancet. Published online June 26, 2023. doi:10.1016/S0140-6736(23)01053-X
2. Jastreboff AM, Kaplan LM, Frias JP, et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial List of authors. The New England Journal of Medicine. Published online June 26, 2023. doi:10.1056/NEJMoa2301972
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. https://investor.lilly.com/news-releases/news-release-details/lillys-phase-2-retatrutide-results-published-new-england-journal.