What Glucagon Does, and Why Retatrutide and Survodutide Activate Its Receptor

Glucagon has spent most of its scientific life cast as insulin's counterpart: the hormone that pushes blood sugar back up when it falls too low. That reputation makes it a surprising component of the next wave of weight-management drugs. Two of the most advanced investigational candidates, Eli Lilly's retatrutide and Boehringer Ingelheim's survodutide, deliberately activate the glucagon receptor alongside the GLP-1 receptor.

Glucagon is a 29-amino-acid peptide produced by alpha cells in the pancreatic islets, according to the NCBI StatPearls physiology chapter. It is cut from the same precursor protein, proglucagon, that gives rise to GLP-1. Its primary role is to increase glucose output from the liver, by breaking down stored glycogen and by making new glucose. The chapter notes that its receptor is expressed most abundantly in the liver and kidney, with lower levels in tissues including fat, heart and brain, and that elevated glucagon contributes to the high blood sugar seen in diabetes.

A 2025 review in Drugs in Context describes the rationale: GLP-1 receptor activation mainly reduces food intake, while glucagon receptor activation stimulates fat breakdown and may increase energy expenditure. A 2026 IUPHAR review in Pharmacological Research adds that the glucose-lowering effects of GLP-1 and GIP receptor agonism may help mitigate glucagon's tendency to raise blood sugar. The same review cites laboratory data suggesting retatrutide is less potent than the natural hormones at the GLP-1 and glucagon receptors but more potent at the GIP receptor.

That review is also candid about the gaps. Its authors write that mechanistic data come largely from rodent models and that evidence for similar energy-expenditure effects in humans is limited, and they flag open questions about liver glucose output and loss of lean mass.

Retatrutide activates GIP, GLP-1 and glucagon receptors. In the phase 3 TRIUMPH-1 trial, published in the New England Journal of Medicine in 2026, 2,339 adults with obesity and without diabetes were randomized; mean body-weight changes at 80 weeks were -17.6%, -23.7% and -25.0% across the three retatrutide groups, compared with -3.9% with placebo, and the most common adverse events were gastrointestinal. Survodutide activates only the glucagon and GLP-1 receptors. In the 725-participant SYNCHRONIZE-1 trial, also published in NEJM, mean changes at 76 weeks were -12.2% and -13.0% in the two survodutide groups versus -5.4% with placebo under the treatment-regimen estimand, with gastrointestinal symptoms reported in 80.9% and 89.7% of participants versus 47.9% on placebo.

These figures should not be compared directly. The trials enrolled different populations over different durations, and neither was designed to isolate how much of the effect comes from the glucagon component. In the earlier retatrutide phase 2 trial, investigators also reported dose-dependent increases in heart rate that peaked at 24 weeks and declined thereafter.

Glucagon receptor activity is a distinct mechanism rather than a stronger form of GLP-1, and its human benefits and trade-offs are still being characterized. Both drugs remain investigational; Lilly said in July 2026 that it plans to submit retatrutide for U.S. approval in the first quarter of 2027. Until a regulator reviews these products, anything sold online under their names has not been through that process, and treatment decisions should rest on approved labeling and a licensed clinician.