Glucagon renaissance — from diabetes scare hormone to multi-target partner
Glucagon has been known for nearly 100 years as the hormone that raises hepatic glucose production — exactly what one does not want in diabetes. Nevertheless in 2024-2026 it has returned, as a component of retatrutide and survodutide, to the most advanced obesity/diabetes trials. A story about a hormone whose clinical value changes when seen in a new combination.
A substance with a problematic reputation
Already in 1923 — barely two years after the Banting/Best insulin isolation in Toronto (see separate article) — John Murlin in Rochester described a second pancreatic factor that did exactly the opposite of insulin: it raised blood glucose. Murlin named the factor 'glucagon' (from 'glucose agonist'). Sequence elucidation took until the 1950s; human glucagon is a 29-amino-acid peptide formed in the α-cells of the islets of Langerhans, closely related to GLP-1 (both arise from the proglucagon precursor).
From a pharmacological view, glucagon had a clear but narrow clinical place: as emergency therapy for severe hypoglycaemia. A glucagon injection mobilises hepatic glucose via cAMP-mediated glycogenolysis and can save the lives of unconscious diabetes patients. This use — as a 1 mg emergency kit — has been standard for decades and was iterated in 2019 with nasal glucagon (Baqsimi). Outside hypoglycaemia emergency care, glucagon had practically no clinical position. In diabetes pharmacology it was what one wanted to inhibit or bypass — not stimulate.
An old observation with new meaning
In the 1980s it was documented that chronic glucagon receptor activation in animals raises energy expenditure: stimulation of hepatic lipid oxidation, activation of brown adipose tissue, increased thermogenesis. Under a high-calorie diet, glucagon infusions reduced weight gain. This observation remained a curiosity for 30 years: nobody wanted to give a diabetes patient glucagon, so the thermogenic effect was not clinically followed up.
Rehabilitation began with the tirzepatide hypothesis (see separate multi-target article). If a peptide simultaneously activates GLP-1 and GIP receptors and thereby adds the metabolic effects, why not also include the glucagon receptor? The GLP-1 component normalises glucose; the glucagon component adds an energetic burning effect desirable in obesity; the counter-intuitive hyperglycaemic action of glucagon is compensated by concurrent GLP-1 activation. Eli Lilly developed retatrutide as the first triple-agonist peptide (GLP-1 + GIP + glucagon); Boehringer Ingelheim followed with survodutide (dual GLP-1/glucagon, without GIP).
What the first trials show
Retatrutide phase 2 (Jastreboff et al., NEJM 2023) showed weight losses of 24.2% at the highest dose over 48 weeks in obesity — a step up from tirzepatide. Disentangling the effect components is, however, difficult: from clinical data alone one cannot separate which proportion of the effect comes from the GLP-1, GIP or glucagon component. Mechanistic studies suggest that the glucagon component contributes above all to hepatic lipid reduction and to energy balance — i.e. amplifies the 'metabolic' part, while the GLP-1 component carries the 'appetite' part.
Survodutide phase 2 showed similar weight effects in obesity; in non-alcoholic fatty liver disease (NASH/MASH) the hepatic lipid reduction is particularly pronounced — positioning the glucagon component as a key driver in this indication. Phase 3 programmes for both substances are running 2024-2026; approvals are expected 2027-2028.
„Glucagon was for 100 years the hormone one avoided. In combination with GLP-1 it becomes the hormone that extends the GLP-1 effect. Pharmacology is more contextual than our clinical prejudices."
What the glucagon story methodologically shows
Three structural lessons are valuable. First: a hormone with a clearly negative clinical profile in isolation can become productive in combination. The GLP-1 component buffers the undesired glucagon effects (hyperglycaemia) while the desired effects (thermogenesis, hepatic lipid reduction) are preserved. This combination logic is not accessible through additive pharmacology; it requires a balanced activation architecture.
Second: the clinical judgement criterion for a hormone depends on the indication. Glucagon activation is counter-intuitive in the diabetes indication; potentially valuable in the obesity indication; possibly central in the NASH/MASH indication. The same hormone has three different pharmacological valuations in three different indication contexts. Third: the mechanistic disentangling of multi-target substances is methodologically demanding. For retatrutide or survodutide it is not definitively clear which component carries which effect share — which complicates clinical optimisation (selective agonists? other affinity ratios?).
Open questions
- Which affinity ratios between GLP-1, GIP and glucagon activation optimise the therapeutic profile — and do the optimal ratios differ by indication (diabetes vs. obesity vs. NASH)?
- Can the glucagon component be individually titrated to selectively amplify specific effects (thermogenesis, hepatic lipid reduction)?
- Which other 'historically problematic' hormones (e.g. catecholamines) could become productive in multi-target constructs?
- How does the glucagon renaissance change the regulatory assessment of substances with counter-intuitive components — will multi-target logic become the standard?