Physicians' Academy for Cardiovascular Education

Results of phase 2 trial with GIP, GLP-1, and glucagon receptor agonist to treat obesity

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


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.


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.


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




This phase 2 trial in adult patients with obesity but no T2DM showed that treatment with subcutaneous retatrutide 12 mg once weekly resulted in a placebo-adjusted LS mean weight reduction of 16% at 24 weeks and 22% at 48 weeks. The safety profile of retatrutide was similar to that seen previously with GLP-1RAs and GIP–GLP-1 receptor agonists. A longer-duration phase 3 trial is currently ongoing.


Show references

Find this article online at N Engl J Med.

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