Retatrutide was found to be effective for reducing body weight in obese adults in a phase 2 trial.
Recent years have witnessed rapid advancements in the development of pharmacotherapeutic agents for treating obesity, especially with the introduction of hormone-based agents. Retatrutide is a single peptide that is an agonist of glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors.
A phase 2 randomized controlled trial published in The New England Journal of Medicine evaluated the efficacy and safety of subcutaneous retatrutide in obese adults without type 2 diabetes.
Study Design and Population
In this study, 338 participants were enrolled, 51.8% of whom were male. Demographic and baseline clinical characteristics of the participants were similar among the treatment groups. Participants were randomly assigned to the following groups: 1mg; 4mg, with an initial dose of 2 mg; 4 mg, with an initial dose of 4 mg; 8 mg, with an initial dose of 2 mg; 8 mg, with an initial dose of 4 mg; 12 mg, with an initial dose of 2 mg; or placebo. Seventy-eight percent of the participants completed the 48-week treatment period.
Remarkable Weight Loss Results With Retatrutide in Obesity Management
Most participants who received retatrutide experienced substantial weight loss, although there was individual variability due to the heterogeneity of obesity. The least-squares mean percentage change in body weight at 24 weeks in retatrutide groups was −7.2% in the 1 mg group, −12.9% in the combined 4 mg group, −17.3% in the combined 8 mg group, and −17.5% in the 12 mg group, compared to −1.6% in the placebo group.
The least-squares mean percentage change at 48 weeks in the retatrutide groups was −8.7% in the 1 mg group, −17.1% in the combined 4mg group, −22.8% in the combined 8 mg group, and −24.2% in the 12mg group, compared to −2.1% in the placebo group.
At 48 weeks, a weight reduction of ≥5%, ≥10%, and ≥15% had occurred in 92%, 75%, and 60%, respectively, of the participants on 4 mg retatrutide; 100%, 91%, and 75% of those on 8 mg; 100%, 93%, and 83% of those on 12 mg; and 27%, 9%, and 2% of those who received placebo. In the 12 mg retatrutide group, 26% of the participants had a ≥30% body weight reduction.
Higher BMI and Female Patients Lose More Weight With Retatrutide
Greater percentage reductions in weight with retatrutide were achieved among participants with a body mass index of ≥35 than those with a BMI <35 and in female participants than male participants.
Cardiometabolic Risk Factors
Retatrutide therapy was associated with improvements in cardiometabolic risk factors, including blood pressure, glycated hemoglobin, fasting glucose, insulin, and lipids (except high-density lipoprotein) at weeks 24 and 48.
Adverse events were reported in 73–94% of participants in the retatrutide groups (highest incidence in the 8 and 12 mg groups) and 70% of placebo group participants. The most common adverse events were gastrointestinal, including nausea, vomiting, diarrhea, and constipation, in the retatrutide groups. These were dose-related, mostly mild to moderate, and partially mitigated with a lower initial dose. Dose-dependent increases in heart rate were noted until 24 weeks and declined thereafter.
Jastreboff, A. M., Kaplan, L. M., Frias, J. P., Wu, Q., Du, Y., Gurbuz, S., Coskun, T., Haupt, A., Milicevic, Z., & Hartman, M. L. (2023). Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. The New England Journal of Medicine, 389(6), 514–526. https://doi.org/10.1056/nejmoa2301972