Why a Weight-Loss Drug Would Add Glucagon, of All Things

Glucagon is the hormone your body uses to raise your blood sugar. When you have not eaten for a while, the pancreas releases it, the liver breaks down its stored glycogen, and glucose goes back into the blood. That is roughly the opposite of what a diabetes drug is for. Several of the most closely watched weight-loss drugs in development include glucagon activity anyway, on purpose, and it seems to help.

A glucagon receptor agonist is a molecule that switches on the glucagon receptor (GCGR), which, in the words of a structural biology paper on this receptor family, “responds to glucagon by increasing blood glucose levels and promoting the breakdown of liver glycogen.” The receptor sits mostly in the liver and kidney, and to a lesser extent in other tissues. In obesity drugs it never shows up alone. It gets bolted onto GLP-1 activity, and sometimes GIP activity too, in molecules like mazdutide, survodutide and retatrutide. The short version of why: glucagon appears to make the body burn more energy and pull fat out of the liver, and the incretin parts of the molecule are there to clean up its blood-sugar mess.

What the other drugs were doing before glucagon showed up

Most weight-loss drugs work on the eating side of the ledger. A 2026 review says traditional ones “primarily act by centrally suppressing appetite” through circuits in places like the hypothalamus. GLP-1 drugs reduce appetite, slow gastric emptying and boost insulin secretion when glucose is high. They get approximately 6 to 15% weight loss in trials. Add GIP, as tirzepatide does, and you get approximately 15 to 20%. In the SURMOUNT-1 phase 3 trial, tirzepatide produced mean weight reductions of 19.5% at 10 mg and 20.9% at 15 mg.

That is a lot of eating less. At some point you run out of less.

So the obvious next thing is the other side of the ledger: energy out. This is where glucagon comes in, and where I should admit that I write about this for a living and still sometimes have to stop and remember which direction glucagon pushes blood sugar. (Up. It pushes it up, which is the one direction a diabetes drug would prefer it did not go.)

There are three ways to read the glucagon receptor agonist bet

There are, roughly, three ways to read this. The first is that glucagon makes you burn more. The second is that it is really a liver drug that happens to cause weight loss. The third is that the industry is deliberately buying a side effect and paying for its removal, and the price of removal is a lot of the result. They are not mutually exclusive. I feel like the third one gets less airtime than it deserves.

Reading one: the drug turns up the furnace

Here is the cheerful version. One review of next-generation multi-agonists says dual GLP-1/glucagon agonism “increases energy expenditure by stimulating fat oxidation and glucose production,” which it describes as distinguishing it from the appetite-focused GLP-1/GIP approach. An industry article lists glucagon’s effects as stimulating energy expenditure, increasing fat oxidation and thermogenesis, triggering lipid breakdown and also reducing food intake. So it does a bit of the eating thing too. That’s fine.

The mechanism stuff gets weirder the closer you look. One line of research proposes that dual and triple agonists trigger heat production in brown and beige fat by changing amino acid metabolism there. Another, in mice, found that glucagon receptor agonism regulates bile acid metabolism, and that adding bile acid binding resins (an old class of cholesterol drug) made glucagon-driven weight loss bigger. Its authors suggest bile acid signaling is “a key component” of how glucagon causes weight loss. In mice. Also, GLP-1 drugs alone may do some heat production of their own: liraglutide has been proposed to activate brown fat partly through thyroid hormone activation inside cells. So the furnace story is real but not tidy.

There is a reason the furnace matters. A review on what happens after GLP-1/GIP treatment notes that weight loss often comes with a loss of fat-free mass, which “further lowers energy expenditure” and makes regaining weight easier after stopping. The body, having lost weight, quietly turns its own thermostat down. A drug that turns it back up is attacking that directly, at least in theory.

Here is a made-up scenario to show the appeal. Imagine a household budget where the only lever is spending less on groceries. You cut groceries by a fifth. Then a fourth. Then the household starts eating the curtains. At some point a sensible financial adviser says “hey, have we considered earning more,” and everyone stares at him, because nobody had, and then they hire a second job that also, for some reason, sets the kitchen on fire a little. The fire is the blood sugar. We will get to the fire.

Reading two: it is mostly a liver drug that also causes weight loss

The glucagon receptor lives mostly in the liver, so in some sense the liver is where you would expect the action. A review of glucagon signalling says that in early trials, mazdutide, survodutide and retatrutide each produced substantial weight loss while “improving liver health in those with MASLD.”

The official name is metabolic dysfunction-associated steatotic liver disease (a name that, I assume, took a committee several meetings). Translated: the liver has too much fat in it, for reasons tied to the rest of your metabolism. Glucagon tells the liver to burn its fuel rather than store it, so a drug that does this is chewing on the problem from the inside. (The site has a separate piece on survodutide, which is the one most openly aimed at the liver.) There are also early data on cotadutide, a GLP-1/glucagon dual, suggesting benefits on albuminuria and cardiorenal risk markers, which fits a receptor that also lives in the kidney.

On this reading, the weight loss is almost a pleasant side benefit of a molecule designed to drain a fatty liver. I suppose that would be a dumb way to describe something that produced double-digit weight loss, but drug development has done stranger things with its marketing.

Reading three: buy a problem, pay to cancel it

The glucagon signalling review states the design rule flatly: mazdutide, survodutide and retatrutide all incorporate GLP-1 receptor-activating parts “to counteract glucagon’s hyperglycaemic effects.” Put plainly, the molecule contains one piece that raises blood sugar and another piece whose job is to lower it back down (a product spec that would get you laughed out of most engineering reviews outside pharmacology). The industry article says the GLP-1 and GIP activity in triple agonists “offsets” glucagon’s effect on blood sugar while keeping the energy-expenditure benefit.

It is a bit like a basketball team signing a player who is incredibly fast and occasionally shoots at his own basket, and then signing two more players whose whole role is to block him. If it works, it works.

And it does work, by the numbers. A network meta-analysis of 14 randomized trials of glucagon receptor agonists found retatrutide produced the largest weight reduction versus placebo: a mean difference of 13.44 kg. Look at that number for a second. Thirteen and forty-four hundredths of a kilogram, pooled across trials, with a 95% confidence interval running from 8.51 to 18.38. That is a range of almost ten kilograms, and the bottom of it is still more than eight kilograms. Statisticians call that a wide interval. Anyone else would call it a person’s worth of carry-on luggage, at minimum.

Then look down the table. Survodutide: 10.74 kg. Mazdutide: 6.47 kg. Cotadutide: 3.41 kg, and not statistically significant, with a confidence interval that crosses zero. Retatrutide was also the only one whose blood sugar effect (HbA1c) reached statistical significance. Retatrutide, notably, is the one with the most incretin machinery attached, the one that adds GIP on top of GLP-1. Separately, an Annals of Internal Medicine review of 26 trials and 15,491 adults without diabetes found retatrutide at 12 mg weekly led with 24.2% weight loss, versus 17.8% for tirzepatide and 13.9% for subcutaneous semaglutide.

Other triples are arriving too. UBT251, another GLP-1/GIP/glucagon peptide, produced 13.6% to 19.7% weight loss versus 2.0% on placebo over 24 weeks in a 205-person phase 2 trial (an article on it led with “up to 19.7%,” which is a perfectly normal way to write a headline, and also the most flattering one).

That leaves the matter of which part is doing the work, and the uncomfortable reading is that the facts do not cleanly separate them. The glucagon parts that perform best are the ones most heavily wrapped in incretin activity, the meta-analysis found retatrutide and cotadutide less well tolerated than mazdutide, and the mechanism research is a pile of mouse bile acids and brown-fat amino acids. Nobody has settled what fraction of retatrutide’s result is glucagon burning fuel and what fraction is GLP-1 and GIP doing what they already did, plus mopping up after glucagon. Longer-term questions about lean mass, regain and safety, which reviews list as still open for the whole class, are not settled either. lol, it’s medicine.

Glucagon is still the hormone that raises your blood sugar. It just turns out that, if you surround it with enough other hormones, it also makes you lose weight.