Accepted answer
The trade is straightforward once you separate glucagon's hepatic glucose-output effect from its energy-expenditure and hepatic-lipid effects, and notice that GLP-1 co-agonism specifically neutralises the first one.
What glucagon receptor agonism contributes
- Increased energy expenditure. This is the headline rationale. Glucagon raises resting energy expenditure, an effect documented in human infusion studies long before any of these molecules existed. Every GLP-1-based therapy fights the adaptive fall in energy expenditure that accompanies weight loss; glucagon agonism is an attempt to attack the other side of the energy balance equation rather than only suppressing intake.
- Hepatic lipid mobilisation. Glucagon receptor agonism increases hepatic fatty acid oxidation and reduces hepatic steatosis, largely independently of weight change. This is why the glucagon-containing molecules have been pushed hard into metabolic liver disease rather than only obesity.
- Possibly better preservation of the weight-loss trajectory. Speculative, but if a substantial part of the plateau is metabolic adaptation, an expenditure-side mechanism should shift where the plateau sits rather than only how fast you reach it. The phase 2 curves are consistent with this and do not prove it.
What it costs
- Hepatic glucose output. This is the objection in your question and it is real in isolation. The resolution is that GLP-1 receptor agonism is glucose-dependently insulinotropic and glucagonostatic, and in the co-agonist the GLP-1 arm counteracts the glycaemic consequence of the glucagon arm. Empirically the triple agonist improved rather than worsened glycaemic control in type 2 diabetes [1]. So the cost is not realised as hyperglycaemia at the ratios used - but note the phrase "at the ratios used", which is your last paragraph and it is exactly right.
- Heart rate. Dose-dependent increases in heart rate are consistently reported with the glucagon-containing agents, larger in magnitude than with GLP-1 mono-agonists. This is the most concrete price and it is the one to watch in long-term outcome trials, because a sustained heart-rate increase is not obviously benign in a cardiovascular population even when the accompanying weight loss and blood-pressure change are favourable.
- Gastrointestinal burden. Nausea and vomiting rates in the phase 2 programmes are at least as high as the GLP-1 class, and the dose-escalation schedules are correspondingly long. Some of this is GLP-1-attributable rather than glucagon-attributable.
- Lean mass and rate-of-loss questions. Faster and deeper weight loss raises the same questions about body composition that apply across the class, and no glucagon-containing programme has yet published the multi-year body-composition data that would answer them.
The ratio question, which is the real answer
"Triple agonist" is a class label that hides the design. Retatrutide is not an equipotent agonist at its three receptors, and neither is any other molecule here. Relative potency at GLP-1R, GIPR and GCGR is a deliberate engineering choice, and two molecules with the same three targets and different ratios are pharmacologically different drugs. A glucagon-heavy ratio buys more expenditure and more glycaemic risk; a GLP-1-heavy ratio is safer glycaemically and closer in behaviour to a mono-agonist.
Practical consequence: never generalise from one molecule to another on the basis of shared targets. Survodutide and mazdutide are both GLP-1/glucagon duals and their reported weight-loss magnitudes differ noticeably, which could be ratio, could be achievable dose, could be trial population. The published data cannot separate those, so treat each agent as its own entity.
What the evidence actually is
Retatrutide's 48-week phase 2 obesity data reported mean weight reduction around -24.2% at the highest dose, with the curve still descending at the end of the study [2]. Survodutide's 46-week phase 2 reported up to roughly -18.7% [3]. Those are phase 2 numbers in selected populations and they are the weakest kind of evidence for a magnitude claim, for reasons the other answers here go into. The phase 3 TRIUMPH programme is the test that matters for retatrutide, and until it reports in full the phase 2 dataset remains the best-powered public evidence.
edited 13 Jan 2025 by v_ramaswamy — added a caveat about sampling
3Heart rate is the endpoint I would watch hardest in the phase 3 readouts for anything with a glucagon arm. – loss_on_drying 5 months ago 4The framing that GLP-1 co-agonism is what makes the glucagon arm tolerable glycaemically is the key insight. – stopper_core 6 months ago Agreed on treating each molecule separately - "dual agonist" tells you almost nothing without the potency ratio. – Dr_Ilse_Vandenberg 8 months ago add a comment