RetatrutideWeight Loss / GLP-1

Overview

Retatrutide (development code LY3437943) is an investigational, once-weekly, single-molecule peptide developed by Eli Lilly that simultaneously activates three metabolic-hormone receptors: GIP, GLP-1 and glucagon. It is given by subcutaneous injection and has a half-life of roughly 6 days, supporting weekly dosing. As of 2026 it is not approved by the FDA for any use; it remains investigational, with phase 2 randomized trials published and a phase 3 program ongoing. It is sold here as research-use-only and is not a prescription medicine.

Mechanism

Retatrutide is a "triple agonist" engineered from the glucagon/GIP/GLP-1 peptide family, with a fatty-diacid modification that enables albumin binding and prolonged exposure. GLP-1 and GIP receptor activity drive appetite suppression and glucose-dependent insulin secretion, while glucagon-receptor agonism is hypothesized to add increased energy expenditure — a combination intended to produce additive effects on body weight and glycemia. This mechanism was characterized in vitro and in rodent models before first-in-human study (Coskun et al., Cell Metabolism 2022).

Clinical evidence

Human evidence comes from phase 1 and phase 2 randomized controlled trials. In a 48-week phase 2 obesity RCT (Jastreboff et al., NEJM 2023; n=338), the 12 mg dose produced a mean body-weight reduction of −24.2% versus −2.1% for placebo. A phase 2 type-2-diabetes RCT (Rosenstock et al., Lancet 2023) showed dose-dependent reductions in HbA1c and body weight, and a phase 2a MASLD trial (Sanyal et al., Nature Medicine 2024; n=98) reported large relative reductions in liver fat. A 2025 systematic review/meta-analysis pooled the available RCTs. These are mid-stage findings; large-scale phase 3 efficacy and long-term outcome data were not yet established in peer-reviewed pivotal form at this writing.

Safety profile

Across the phase 2 trials, the adverse-event profile was consistent with the incretin (GLP-1) class: gastrointestinal effects (nausea, vomiting, diarrhea, constipation) were most common, generally mild-to-moderate, dose-dependent, and concentrated during dose escalation. Dose-dependent increases in heart rate and transient, dose-related increases in blood glucose at the highest dose have also been reported, the latter attributed to glucagon-receptor activity. Because retatrutide is investigational and not FDA-approved, its long-term safety is unestablished. Research use only; this is not therapeutic or dosing guidance.

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