Retatrutide Treatment Results in Reductions in Body Weight Compared to Placebo

Results from a new trial of retatrutide (LY3437943; Eli Lilly) found that participants had considerable decreases in body weight at week 48, although this depended on the dose and varied due to the heterogeneity of obesity.

Retatrutide is a single peptide coupled to a fatty diacid moiety and has agonism toward the GIP, GLP-1, and GCG receptors. Retatrutide is less effective at the human GCG and GLP-1 receptors and more effective at the human GIP receptor, compared to the endogenous receptor ligands. It is dose-proportional and has a half-life of approximately 6 days, making it suitable for weekly administration.

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Study authors conducted a phase 2, multi-center, double-blind, randomized, placebo-controlled, 52-week trial to investigate the efficacy, adverse effects (AEs), and safety of retatrutide at various doses and dose-escalation procedures in patients with obesity. A previous phase 1b trial had included patients with type 2 diabetes; however, this phase 2 trial did not.

A total of 338 adults aged 18 to 75 years with a body mass index (BMI) of 30 to 50, or a BMI of 27 to less than 30 in addition to at least 1 weight-related condition, were studied. These participants were randomly assigned in a 2:1:1:1:1:2:2 ratio to receive subcutaneous retatrutide (1 mg, 4 mg [treatment initiated with 2 mg dose and increased gradually until week 12]), 4 mg (initial dose, 4 mg), 8 mg (initial dose, 4 mg), or 12 mg (initial dose, 2 mg), or placebo once every week for 48 weeks.

Those with diabetes, previous or planned surgical treatment for obesity, and those receiving treatment with medication to promote weight loss or gain of more than 5 kg within 3 months of the trial beginning were not eligible to participate. Following the 48-week trial period, participants were involved in a 4-week safety follow-up period.

The findings indicated that retatrutide treatment resulted in considerable decreases in body weight at week 48 depending on the dose; however, variability was present due to the heterogeneity of obesity. Women had presented greater mean weight reductions than men (28.5% and 26.6% versus 19.8% and 21.9%), although the study authors were unable to determine whether these differences were a result of body composition, adipose distribution, or differing hormones.

Those with a BMI of 35 or higher had a greater mean percentage weight reduction with retatrutide than those with a BMI less than 35. Those with a BMI of 35 or higher in the 8-mg and 12-mg dose groups had weight reductions of 26.5% and 26.4%, respectively (compared to 21.3% and 21.5%, respectively, among those with a BMI of less than 35).

At week 48, a weight reduction of 5% or more, 10% or more, and 15% or more had occurred in a respective 27%, 9%, and 2% of participants who received placebo, compared to 92%, 75%, and 60% of participants who received 4 mg of retatrutide; 100%, 91%, and 75% of participants who received 8 mg; and 100%, 93%, and 83% of participants who received 12 mg.

Approximately 70% of participants in the placebo group and 73% to 94% of those in the retatrutide groups had reported AEs, the most common being gastrointestinal (e.g., nausea, diarrhea, vomiting, and constipation) symptoms that were dose-related, mostly mild to moderate in severity, were more frequent in higher-dose groups (e.g., 8-mg and 12-mg groups), and were partially mitigated by the use of a lower starting dose. Further, 15 serious AEs had occurred in 13 participants (4% in both the retatrutide and placebo groups).

Trial limitations include the lack of participants with an overweight BMI, which in this trial was defined as a BMI of 27 to <30. Further, this group (4% of participants) had an obesity-related condition, therefore the results for this population may not be generalizable. The study authors recommend that additional research performed is needed to further investigate the efficacy and safety of retatrutide when treating obesity.

Reference

Jastreboff A, Kaplan L, Frías J, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. doi:10.1056/NEJMoa2301972.