What Is Retatrutide? How the GIP, GLP-1 and Glucagon Triple Agonist Works

Retatrutide is a synthetic peptide, described from discovery to first clinical proof of concept in Coskun et al., Cell Metabolism 2022. Like tirzepatide, it carries a fatty-acid side chain that binds serum albumin. That binding slows clearance: Lilly reports a mean half-life of about 6 days in a Phase 1 study of healthy participants (BMI 19 to 40), which is what supports once-weekly dosing in its trials.

Published sources disagree on the side chain’s exact length and on the molecular weight, so we quote neither. Any CoA you rely on should state the theoretical mass and how it was calculated.

The three targets are not hit equally. Lilly’s medical information, citing the discovery paper, compares retatrutide with the native human hormones:

Supplier datasheets citing the same paper list EC50 values of roughly 0.064 nM (GIPR), 0.78 nM (GLP-1R) and 5.8 nM (glucagon receptor). Check these against the original paper before using them to design an assay.

GLP-1 receptor. The best-characterised arm. It is the sole target of semaglutide and the foundation the other two build on.

GIP receptor. Tirzepatide showed that adding GIP receptor agonism to GLP-1 receptor agonism raises weight loss, and retatrutide’s strongest activity is here.

Glucagon receptor. The arm that sets retatrutide apart, and the least settled in humans. Glucagon raises blood glucose, so the design question is whether GLP-1 and GIP activity offsets it. In Lilly’s TRIUMPH-3 trial, hyperglycaemia was reported by 3.9% and 3.1% of retatrutide participants versus 13.4% on placebo, which suggests it does. The proposed benefit of the glucagon arm is higher energy expenditure, but analyses of the programme still describe that contribution as not fully characterised in humans. Treat any measured metabolic-rate claim with caution.

The clearest glucagon-linked signal is in the liver. In a Phase 2 substudy of 98 people with at least 10% liver fat, relative liver fat fell by 81.4% (8 mg) and 82.4% (12 mg) at 24 weeks versus a 0.3% rise on placebo, and 89% and 93% were below 5% liver fat at 48 weeks. That substudy measured liver fat by MRI, not biopsy outcomes, and its participants were mostly early-stage disease.

The argument is cumulative. Semaglutide (GLP-1 only) produced 14.9% mean weight loss at 68 weeks in STEP-1. Tirzepatide (GIP and GLP-1) reached up to 22.5% at 72 weeks in SURMOUNT-1 on the efficacy estimand. Retatrutide (all three) produced 24.2% at 48 weeks in Phase 2 and 28.3% at 80 weeks in TRIUMPH-1 on the efficacy estimand. These come from different trials, populations and durations, so they show direction, not the measured effect of each receptor. The tirzepatide and semaglutide comparison article in this series sets out the caveats.

The Phase 2 obesity trial reported dose-dependent increases in heart rate that peaked at 24 weeks and declined afterwards (NEJM). The trial reports the pattern, not its cause.

The GLP-1, GIP and glucagon receptors are class B G protein-coupled receptors that signal mainly through Gαs and cAMP. Semaglutide (GLP-1R), tirzepatide (GIPR and GLP-1R) and retatrutide (all three) differ in receptor profile, so researchers can use them together as a comparison set to work out which receptor drives a given readout in cell-based assays.

Nordapep supplies retatrutide for laboratory research use only. It is not a medicine and is not for human or veterinary use.