The Phase 2 Retatrutide Obesity Trial

• Study Objective: To determine the efficacy, safety, and dose-response relationship of once-weekly subcutaneous Retatrutide across various doses and escalation regimens in adults with obesity or overweight (Jastreboff et al., 2023).

• Methodology: A 48-week, double-blind, randomized, placebo-controlled human trial (Jastreboff et al., 2023). The study evaluated 338 adult participants with a body-mass index (BMI) of 30 or higher, or a BMI of 27 to less than 30 with at least one weight-related condition (excluding type 2 diabetes) (Jastreboff et al., 2023). Participants were randomized to receive a weekly placebo or varying maintenance doses of Retatrutide ($1\text{ mg}$, $4\text{ mg}$, $8\text{ mg}$, or $12\text{ mg}$) utilizing different starting escalation doses ($2\text{ mg}$ vs. $4\text{ mg}$) to check for tolerability (Jastreboff et al., 2023).

• Primary Weight Loss Outcomes:

  • At 24 Weeks (Primary Endpoint): The average change in body weight was $-7.2\%$ in the $1\text{ mg}$ group, $-12.9\%$ in the $4\text{ mg}$ group, $-17.3\%$ in the $8\text{ mg}$ group, and $-17.5\%$ in the maximum $12\text{ mg}$ group (compared to just $-1.6\%$ in the placebo group) (Jastreboff et al., 2023).

  • At 48 Weeks (Sustained Efficacy): Weight reduction continued progressively to $-8.7\%$ ($1\text{ mg}$ group), $-17.1\%$ ($4\text{ mg}$ group), $-22.8\%$ ($8\text{ mg}$ group), and a striking $-24.2\%$ in the $12\text{ mg}$ group, compared to a baseline loss of $-2.1\%$ in the placebo group (Jastreboff et al., 2023).

• Success Rate Thresholds (At 48 Weeks):

  • Among the participants who received the maximum $12\text{ mg}$ dose of Retatrutide, $100\%$ achieved a weight loss of $\ge 5\%$, $93\%$ achieved a loss of $\ge 10\%$, and $83\%$ achieved a total body weight reduction of $\ge 15\%$ (Jastreboff et al., 2023).

• Adverse Events & Mitigation Findings: The most common adverse events were gastrointestinal (nausea, diarrhea, vomiting, and constipation) (Jastreboff et al., 2023). These events were strictly dose-related and mostly mild-to-moderate in severity (Jastreboff et al., 2023).

  • The Escalation Dynamic: The data uniquely showed that gastrointestinal side effects were significantly mitigated when participants utilized a lower initial starting dose of $2\text{ mg}$ before stepping up to higher target doses, rather than starting directly at $4\text{ mg}$ (Jastreboff et al., 2023).

  • Heart Rate Observations: Dose-dependent increases in heart rate were noted, which peaked at week 24 and gradually declined as the trial progressed (Jastreboff et al., 2023).

References

Jastreboff, A. M., Kaplan, L. M., Frías, 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. New England Journal of Medicine, 389(6), 514–526. https://doi.org/10.1056/nejmoa2301972

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