How triple agonists differ: adding glucagon to GIP and GLP-1

Dual agonists reduce how much you eat. Triple agonists also try to change how much you burn. That is the whole difference, and it comes from the least intuitive receptor to put in a metabolic drug.

The glucagon receptor's other job

Glucagon is known as the hormone that raises blood glucose by telling the liver to release it. It also does three other things at pharmacological doses: raises energy expenditure, increases fat oxidation in the liver and reduces food intake. Tan and colleagues infused glucagon into healthy volunteers and measured a rise in energy expenditure; when they co-infused GLP-1, the expenditure rise stayed and the rise in glucose was blunted (PubMed 23248172). That experiment is the human proof of principle for the whole class: the incretin arms cover glucagon's liability and keep its asset.

Finan and colleagues built the first single-molecule triagonist in 2015 and showed in obese rodents that adding glucagon receptor activity to a GIP/GLP-1 dual agonist produced greater weight loss than the dual agonist alone, with improved rather than worsened glucose control (PubMed 25485909).

Retatrutide

Retatrutide (LY3437943) is a 39-amino-acid peptide with a C20 fatty diacid, engineered from the GIP backbone with activity at all three receptors. Coskun and colleagues describe it as having less than native potency at the GLP-1 receptor, roughly native potency at GIP and a fraction of native potency at glucagon, a deliberate imbalance that keeps the glucagon component from dominating (PubMed 35985340).

In the phase 2 obesity trial, 338 adults without diabetes were randomised to retatrutide 1, 4, 8 or 12 mg or placebo for 48 weeks. Mean weight change was -8.7%, -17.1%, -22.8% and -24.2% respectively, versus -2.1% on placebo, and the 8 and 12 mg curves were still falling at week 48 (PubMed 37366315). Gastrointestinal adverse events were dose-related and mostly mild to moderate, concentrated during escalation, as with the dual and single agonists.

Two signals in that trial are worth watching. Heart rate rose more than is typical for GLP-1 receptor agonists, peaking around week 24 and declining toward baseline by week 48 (PubMed 37366315); glucagon receptor activation is the likely contributor. And the energy-expenditure mechanism, while established for glucagon infusion, has not been directly measured for retatrutide in people at the doses used.

What it changes conceptually

Every approved GLP-1 medicine works by reducing intake. The body responds to reduced intake with adaptive thermogenesis, covered on the why weight returns page. A drug that raises expenditure while lowering intake is in principle pushing on both sides of the balance. Whether that translates into a different plateau, different body composition or different regain after stopping is exactly what phase 3 and withdrawal studies will have to show; none of it can be assumed from the mechanism.

What is debated

Whether the glucagon component's liver effects (fat oxidation, reduced liver fat) are large enough to matter clinically, and whether the same benefit is available from dual agonists through weight loss alone, is unresolved. Hammoud and Drucker's review is careful on this point: the tissue-level actions of GIP and glucagon are established in animals and only partly in humans (PubMed 36509857). Other glucagon-containing agents, including GLP-1/glucagon dual agonists, are in development; this page covers the mechanism, not the pipeline.

Retatrutide is not FDA approved. No compounded version can legally be marketed for human use as an approved drug, and any product sold under that name outside a clinical trial has not been through FDA review.

Where to go next

• The phase 2 digest with confidence intervals and adverse event tables is at FormBlends Research.
• Every agent in the class, with status: GLP-1s Explained.
• The dual-agonist logic this builds on: GIP and dual agonism.