Retatrutide

This 48-week Phase 2, double-blind, randomized, placebo-controlled trial enrolled 338 adults with a BMI of 30 or higher (or 27 with a weight-related comorbidity) and randomized them to subcutaneous retatrutide (1, 4, 8, or 12 mg weekly) or placebo. Least-squares mean percentage change in body weight at week 48 was -8.7%, -17.1%, -22.8%, and -24.2% for the 1, 4, 8, and 12 mg arms versus -2.1% for placebo. A weight reduction of 15% or greater occurred in 60%, 75%, and 83% of participants in the 4, 8, and 12 mg arms, compared with 2% in placebo. The adverse-event profile was dominated by dose-related gastrointestinal events that were typically mild-to-moderate and concentrated during the dose-escalation period.

In a 48-week study of about 340 adults with overweight or obesity, weekly retatrutide injections produced average body-weight reductions ranging from roughly 9% at the lowest tested dose to about 24% at the highest. Eight in ten participants on the highest dose lost at least 15% of their starting weight. Side effects were mostly stomach-related — nausea, diarrhea, and vomiting — and tended to occur during dose increases.

Coskun and colleagues describe the discovery, in vitro pharmacology, preclinical pharmacology, and first-in-human Phase 1 results for LY3437943, the molecule subsequently known as retatrutide. The peptide is engineered for balanced agonism at the glucagon and GLP-1 receptors with stronger activity at the GIP receptor, anchored to a C20 fatty-diacid side chain for albumin binding and extended exposure. In diet-induced obese mice, weekly LY3437943 reduced body weight and improved glycemic indices to a degree exceeding matched GLP-1 mono-agonist comparators. The Phase 1 single- and multiple-ascending-dose data in healthy and obese participants supported a once-weekly dosing schedule with a half-life of roughly six days and a dose-dependent reduction in body weight at four weeks.

This is the original paper that introduced retatrutide to the scientific literature. The authors explain how the molecule was designed to activate three different hormone receptors at once, show that it produces larger weight and blood-sugar reductions than single-receptor analogs in obese mice, and report early human results consistent with a once-weekly dosing schedule. It is the foundational reference for understanding why a triple agonist might behave differently from GLP-1-only or GLP-1/GIP molecules.