AA Jastreboff et al. NEJM 2026; DOI: 10.1056/NEJMoa2604169.
Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity

Background: Retatrutide (LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors.

In 2023, “a phase 2 trial involving participants with obesity, once-weekly subcutaneous retatrutide (at a dose of 12 mg) resulted in a mean weight reduction of 24.2% at 48 weeks²⁴ and improved multiple cardiometabolic measures, including waist circumference, systolic and diastolic blood pressure, glycated hemoglobin, and lipid levels.” This randomized, double-blind phase 3 trial examined a larger cohort (n=2339) with respect to obesity as well as knee osteoarthritis and obstructive sleep apnea in participants with obesity without diabetes.

Key findings:

• Obesity at 80 weeks: The mean percent change in body weight in the retatrutide groups at 80 weeks was −17.6% (4-mg dose), −23.7% (9-mg dose), and −25.0% (12-mg dose) versus −3.9% in the placebo group. The 12 mg dose resulted in a mean change of -28.3% (according to the efficacy estimand) at 80 weeks
• Obesity at 104 weeks: In the extension phase of the trial, retatrutide treatment was associated with a mean weight reduction of up to 29.9% (treatment-regimen estimand) and 30.3% (efficacy estimand) at 104 weeks
• Osteoarthritis: the mean change in the WOMAC pain subscale score (in points) at week 80 for the knee osteoarthritis basket was −3.5 and −3.6 with retatrutide 9 mg and 12 mg, respectively, and −1.9 with placebo. Treatment with retatrutide resulted in a reduction in pain of up to 61.6%
• Obstructive sleep apnea: the mean change in the AHI events per hour at week 80 was −34.3 and −31.7 with retatrutide 9 mg and 12 mg, respectively, and −9.9 with placebo; this resulted in a mean decrease in AHI events per hour of up to 57.3% (hybrid-treatment estimand)
• Limitations of the trial include the absence of an active comparator, which may have contributed to greater attrition in the placebo group,

My take: Retatrutide was so effective, even at lower doses, that use of the lowest effective dose to achieve treatment goals may be a useful strategy rather than expecting to maximize the dose in all individuals. While the results are terrific, access and affordability remain important issues with these newer obesity medications.

• Related blog posts:
• Another Promising Medication (Retatrutide) for Obesity
• GLP-1 Receptor Agonists vs. Bariatric Surgery in Youth
• “GLP-1 Receptor Agonists and Eating Disorders — Cause for Concern”
• Reduced Dosing of GLP-1 RAs May Work for Maintenance Treatment of Obesity
• GLP-1 Use Associated with Lower Risk of Colon Cancer
• Beneficial GI Effect of GLP-1 Receptor Agonists: Lower Risk of Peptic Ulcer Disease
• More Pediatric Data Supporting GLP-1 RA Efficacy for MASLD
• Two Pediatric MASLD Publications: Call for Action and Use of GLP-1 RAs
• The Risks and Absolute Risks of GLP-1 RAs and Gastrointestinal Adverse Events

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