Retatrutide (development code LY3437943) is an investigational single-molecule peptide that acts as a triple receptor agonist: it activates the receptors for three metabolic hormones at once, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon. This sets it apart from the dual GIP/GLP-1 agonist tirzepatide and from semaglutide, which works on the GLP-1 receptor only. Retatrutide is one of the most studied «unimolecular» multi-agonists to emerge from research on incretin biology [3].
The three receptor arms
The GLP-1 and GIP arms are shared with the incretin compounds already familiar from diabetes and obesity research: together they enhance glucose-dependent insulin secretion and act on central pathways that reduce food intake. The novel element is the third arm, glucagon-receptor agonism. Although glucagon is best known for raising blood glucose, sustained signalling at its receptor also increases energy expenditure and promotes hepatic fat oxidation. The design goal of a triple agonist is to combine the appetite- and glucose-lowering effects of GIP/GLP-1 with the additional energy-expenditure component contributed by glucagon, while the GLP-1 and GIP activity offsets glucagon’s tendency to raise glucose [3]. Early first-in-human work (a phase 1b multiple-ascending-dose study) characterised the compound’s pharmacology and supported once-weekly subcutaneous dosing with gradual dose escalation [4].
What the phase 2 obesity trial showed
In a double-blind, randomised phase 2 trial in 338 adults with obesity (and without diabetes), participants received once-weekly subcutaneous retatrutide (1, 4, 8 or 12 mg, reached by titration) or placebo for 48 weeks. The least-squares mean change in body weight at 48 weeks was −8.7% in the 1 mg group, −17.1% at 4 mg, −22.8% at 8 mg and −24.2% in the 12 mg group, versus −2.1% for placebo; by 24 weeks the highest doses had already reduced weight by up to about −17.5% [1]. These are among the largest weight reductions reported for an investigational compound in an obesity trial of this length, though the data come from a phase 2 study and await confirmation in larger phase 3 trials.
What the phase 2 type 2 diabetes trial showed
A separate phase 2 trial randomised 281 adults with type 2 diabetes (mean baseline HbA1c about 8.3%) to placebo, the GLP-1 agonist dulaglutide 1.5 mg, or retatrutide (0.5 to 12 mg once weekly) for 36 weeks. At 24 weeks the least-squares mean reduction in HbA1c reached about −2.02% in the 12 mg group (and roughly −1.9% at 8 mg), versus −0.01% for placebo and −1.41% for dulaglutide. Body weight fell by up to about −16.9% at 36 weeks in the 12 mg group, compared with −3.0% for placebo and −2.0% for dulaglutide [2]. In other words, the higher retatrutide doses lowered glucose at least as much as the active comparator while producing substantially greater weight loss.
Tolerability reported in the trials
Across both phase 2 trials the most common adverse events were gastrointestinal, nausea, diarrhoea, vomiting and constipation, mostly mild to moderate and dose-dependent, becoming more frequent at higher doses and with faster escalation. In the type 2 diabetes trial, gastrointestinal events ranged from roughly 13% at the lowest dose to about 50% at the highest [1][2]. These figures describe what was observed in controlled clinical trials under gradual titration; they are reported here as trial findings, not as guidance for use.
Dosing in the studies
The phase 2 programme used once-weekly subcutaneous administration with stepwise titration over several weeks up to target doses as high as 12 mg, an approach intended to improve gastrointestinal tolerability. We do not restate the full escalation table here: for the week-by-week schedule used in the published research, see our dedicated reference page, retatrutide dosing schedule.
Research-use-only note
This article is compiled from publicly available sources (peer-reviewed publications and clinical-trial reports) and is provided for reference and informational purposes only. It is not medical advice and not a recommendation for use. Retatrutide is an investigational compound that is not an approved medicine. Any products referenced on this site are supplied strictly for laboratory research purposes only, they are not for human consumption and not for diagnostic or therapeutic use. All doses and results described above come from controlled research settings and must not be interpreted as instructions.
The full list of sources with links, is in the monograph: Retatrutide.
