Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial

Literature - Jastreboff AM, Kaplan LM, Frías JP, et al. - N Engl J Med. 2023 Jun 26 [Online ahead of print]. doi: 10.1056/NEJMoa2301972

Introduction and methods

Background

To find an effective obesity therapy, several nutrient-stimulated hormone-based therapeutics directed at the neuroendocrine mechanisms underlying the disease are currently being developed [1-6]. Retatrutide (LY3437943) is a triple agonist targeting the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon receptors. A recent phase 1b trial showed T2DM patients treated with retatrutide 12 mg lost ~10% more body weight than those receiving placebo [7].

Aim of the study

The authors investigated the efficacy, side effects, and safety of subcutaneous retatrutide at various doses and dose-escalation regimens in patients with obesity but no T2DM.

Methods

In this multicenter, double-blind, placebo-controlled, phase 2 RCT conducted in the US, 338 adults with either a BMI of 30–50 kg/m² or a BMI of 27–29 kg/m² plus ≥1 weight-related conditions , but no T2DM, were enrolled. Participants were randomized in a 2:1:1:1:1:2:2 ratio to subcutaneous retatrutide 1 mg, 4 mg (initial dose: 2 mg), 4 mg (initial dose: 4 mg), 8 mg (initial dose: 2 mg), 8 mg (initial dose: 4 mg), or 12 mg (initial dose: 2 mg), or placebo once weekly for 48 weeks. Thereafter, patients proceeded to a 4-week safety follow-up period.

Outcomes

The primary endpoint was the percentage change in body weight from baseline to 24 weeks. Secondary endpoints included percentage change in body weight from baseline to 48 weeks; weight reduction of ≥5%, ≥10%, or ≥15% at 24 and 48 weeks; and change in weight, BMI, and waist circumference from baseline to 24 and 48 weeks.

Safety assessments included adverse events and serious adverse events.

Main results

Efficacy

• The least-squares (LS) mean percentage change in body weight at 24 weeks (primary endpoint) was –7.2% in the retatrutide 1-mg group (n=69), –12.9% in the combined retatrutide 4-mg group (n=67), –17.3% in the combined retatrutide 8-mg group (n=70), and –17.5% in the retatrutide 12-mg group (n=62), compared with –1.6% in the placebo group (n=70).
• The LS mean percentage change at 48 weeks (secondary endpoint) was –8.7% in the retatrutide 1-mg group, –17.1% in the combined retatrutide 4-mg group, –22.8% in the combined retatrutide 8-mg group, and –24.2% in the retatrutide 12-mg group, compared with –2.1% in the placebo group.
• At 48 weeks, a weight reduction of ≥5%, ≥10%, and ≥15% was observed in 92%, 75%, and 60%, respectively, of the participants who received retatrutide 4 mg (at either starting dose); in 100%, 91%, and 75% of those who were on retatrutide 8 mg (at either starting dose); in 100%, 93%, and 83% of those who received retatrutide 12 mg; and in 27%, 9%, and 2% of those who received placebo.
• The LS mean reduction in waist circumference at 48 weeks ranged from 6.5 to 19.6 cm in the retatrutide groups, compared with 2.6 cm in the placebo group.

Safety

• During the treatment period, adverse events were reported in 73%–94% of the patients in the retatrutide groups (highest incidence in 8-mg and 12-mg groups) and 70% of those in the placebo group.
• The most frequently reported adverse events were gastrointestinal (nausea, diarrhea, vomiting, and constipation) and occurred more often with retatrutide than with placebo. These events were dose-related and mostly mild to moderate in severity and could be partially mitigated with a lower starting dose (2 mg vs. 4 mg).
• Adverse events leading to discontinuation of the study drug occurred in 6%–16% of the patients who received retatrutide and in none of the participants taking placebo.
• The incidence of serious adverse events was 4% in the placebo group and ranged from 0% to 6% in the retatrutide groups.
• Up to 24 weeks, the heart rate increased in a dose-dependent with retatrutide and declined in the weeks thereafter.

Conclusion

References

Find this article online at N Engl J Med.