Background:

Obesity, a chronic neurometabolic disease, is anticipated to impact nearly 25% of the global population by 2035. Recent breakthroughs in pharmacotherapy, such as semaglutide and tirzepatide, are revolutionizing obesity treatment by targeting neuroendocrine mechanisms involving G-protein–coupled receptor targets, including GLP-1, GIP, GCG, amylin, oxyntomodulin, and peptide YY receptors. Retatrutide (LY3437943), a novel single peptide conjugated to a fatty diacid moiety, demonstrates agonism towards GIP, GLP-1, and GCG receptors, offering a potential avenue for effective obesity management.

Summary:

The phase 2 trial investigated retatrutide’s efficacy, safety, and side effects at various doses in individuals with obesity without type 2 diabetes. In 48 weeks, participants receiving retatrutide experienced substantial weight reductions, with the 12-mg dose group achieving an impressive 24.2% mean weight reduction. Notably, participants continued to lose weight beyond 48 weeks, indicating a sustained effect. Secondary endpoints, including reductions of 5% or more, 10% or more, and 15% or more in body weight, were consistently higher in the retatrutide groups compared to placebo. Moreover, retatrutide demonstrated positive effects on cardiometabolic risk factors and participant-reported outcomes, including improvements in blood pressure, glycated hemoglobin levels, and lipid profiles. Noteworthy is the potential reversal of prediabetes in 72% of participants receiving retatrutide.

Endpoints:

• Primary Endpoint: Percentage change in weight from baseline to 24 weeks.
• Secondary Endpoints: Percentage change in weight from baseline to 48 weeks, weight reduction thresholds, and changes in BMI and waist circumference.
• Exploratory Endpoints: Various cardiometabolic measures, including glycated hemoglobin, fasting glucose, insulin, and lipid levels.

Statistical Analysis:

The study, involving 338 participants, demonstrated the superiority of retatrutide over placebo in achieving weight reduction. The statistical power, assuming an 8-percentage-point difference in mean percentage weight change, was estimated at 97% with a significance level of 0.05. The analysis included data from all randomized participants, and various estimands were utilized to assess treatment efficacy, ensuring robust statistical scrutiny.

Critical Analysis:

Methodology:

The trial employed a robust design, being a phase 2, multicenter, randomized, double-blind, placebo-controlled study. However, potential biases, such as the role of lifestyle interventions and counseling sessions, should be considered in interpreting results.

Statistical Values:

The statistical analysis demonstrated a significant and dose-dependent efficacy of retatrutide. However, potential confounders, such as individual variability and the impact of lifestyle interventions, should be carefully evaluated in interpreting the outcomes.

Implications for Medical Practice:

The results suggest that retatrutide, particularly at higher doses, holds promise as a potent anti-obesity agent. The observed weight reductions and improvements in cardiometabolic parameters underscore its potential impact on obesity-related comorbidities. Further, the study prompts a reevaluation of treatment goals, considering the magnitude and quality of weight reduction, specific BMI targets, and health effects.

Limitations:

• The study population excluded individuals with diabetes, potentially limiting generalizability to this subgroup.
• The gastrointestinal adverse events, predominantly during dose escalation, indicate potential tolerability challenges that need further investigation.
• The trial’s duration may not fully capture long-term effects, and results from the ongoing phase 3 trial may provide additional insights.

Keywords:

Retatrutide, Obesity, GIP, GLP-1, GCG receptors, Phase 2 trial, Weight reduction, Cardiometabolic risk factors.

Reference:

Jastreboff, A. M., Kaplan, L. M., Frías, J. P., Wu, Q., Du, Y., Gurbuz, S., Coskun, T., Haupt, A., Milicevic, Z., Hartman, M. L., et al. (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