Retatrutide Treatment Resulted in Weight Loss Compared to Placebo

Results from the new trial of retatrutide (LY3437943; Eli Lilly) found that participants experienced appreciable weight loss at week 48, although this was dose-dependent and varied because of the heterogeneity of obesity.

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

The study authors conducted a 52-week, multi-center, double-blind, randomized, placebo-controlled, phase 2 trial to investigate the efficacy, adverse effects (AEs), and safety of retatrutide at various doses and dose escalation procedures in patients. with obesity. Previous phase 1b trials involved patients with type 2 diabetes; However, this phase 2 trial was not successful.

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 plus 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 (starting dose, 4 mg), 8 mg (starting dose, 4 mg), or 12 mg (starting dose, 2 mg), or placebo once every week for 48 weeks.

Those who have diabetes, have had or have undergone surgical treatment for obesity, and those who are receiving treatment with drugs to lose or gain more than 5 kg within 3 months of the trial’s start are not eligible to participate. After a 48-week trial period, participants were included in a 4-week safety follow-up.

Findings indicated that retatrutide treatment resulted in appreciable weight loss at week 48 depending on the dose; However, the variability arises because of the heterogeneity of obesity. Women showed greater average weight loss than men (28.5% and 26.6% vs. 19.8% and 21.9%), although the study authors were unable to determine whether these differences were due to body composition, distribution fat, or hormonal differences.

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

At week 48, weight loss of 5% or more, 10% or more, and 15% or more occurred in 27%, 9%, and 2% of participants who received placebo, respectively, compared with 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 participants in the retatrutide group reported AEs, the most common of which were dose-related gastrointestinal symptoms (eg, nausea, diarrhea, vomiting, and constipation), most of which were mild to moderate in severity. , was more common in the high-dose group (eg, the 8 mg and 12 mg groups), and was partially relieved by the use of a lower initial dose. Furthermore, 15 serious AEs had occurred in 13 participants (4% in the retatrutide and placebo groups).

Limitations of the trial included the lack of participants with overweight BMI, which in this trial was defined as a BMI of 27 to <30. Furthermore, this group (4% of participants) had conditions associated with obesity, therefore the results to this population may not be generalizable. The study authors recommend that additional research is needed to further investigate the efficacy and safety of retatrutide in treating obesity.

Reference

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