Glucagon antagonists, a story of failure

(Ant)agonizing over glucose, and the next medical revolution

Author

David W
May 31, 2025

Welcome to whatever this space ends up being! I’m hoping it is focused mostly on obesity, diabetes and incretins, but it may diverge from time to time. I wanted to start writing long form articles with the topic I’m most passionate.

Glucagon.

The hormone that has for decades been sort of a red-headed stepchild. Mostly viewed as the counter-regulatory hormone to insulin thanks mostly to Roger Unger and his bi-hormonal hypothesis of diabetes. But glucagon is so much more than that, and from a pharmacology standpoint, we have tried glucagon antagonists, which failed in clinical trials, and now glucagon agonists are in trials. Let’s review these two mechanisms, part one is why one failed and part two will be why the other appears ready to usher in a new revolution in medicine and may perhaps shed glucagon’s status as a pariah hormone.

Glucagon (GCG) was discovered only a year after insulin in 1922, it’s a portmanteau of two words GLUcose AGONist, which is a perfect name as it stimulates glucose release from the liver. Because it raised glucose, it took a backseat to insulin, since in the 1920s, the goal was to find a treatment for diabetes, not make it worse. GCG then wasn’t purified chemically until the 1950s(!!) and hasn’t been studied nearly as much as insulin, a simple search on PubMed will confirm this, with roughly 500,000 studies on insulin and only about 34,000 on glucagon (as long as you exclude the term glucagon-like peptide). As I said in the opening, GCG is viewed more for its negative implications in diabetes and most teaching about glucagon is focused on its role of raising glucose. 

This brings us to the topic at hand, if glucagon is such a problem why are many multi-agonist peptides choosing to add glucagon as an agonist? Why aren’t glucagon antagonists available? Let's review the risks, and major benefits of each, starting with glucagon antagonists and review how glucagon works in the body.

This first illustration shows the classic understanding of glucagon. The pancreas releases both insulin and glucagon; insulin lowers glucose and also signals the liver to store excess glucose as glycogen in the liver after a meal. Glucagon meanwhile is stimulated with low glucose or during periods of fasting, causing the liver to breakdown glycogen and stimulating gluconeogenesis, raising & maintaining blood glucose. This is the hepatic glucose effect of glucagon and where most teaching about glucagon stops.

In more detail, glucagon acts primarily in the liver, stimulates glycogenolysis & gluconeogenesis, freeing glucose into the bloodstream, pausing glycogenesis, raising blood glucose. It also increases hepatic fatty acid oxidation for energy for gluconeogenesis (spoiler alert for part 2!) Glucagon also plays an important role in protein and amino acid metabolism in the liver as well.

So, we know GCG raises glucose through the liver, so it would seem simple enough to create a glucagon antagonist drug. Block the action, and glucose should drop. 

Right? 

Well yes and no. Let's review some data from failed clinical trials and see where things went wrong, and why only focusing on the hepatic action of glucagon was shortsighted.

Let’s start with the good, in this trial data from Merck there was large drop in A1c, about 1.5% in 12 weeks, lowered fasting insulin, blocked hepatic glucose release, which then lowered fasting glucose, but in a warning shot, it did nothing to slow the rise of glucose after a meal.  So that’s the good part with a caveat. And truthfully, that’s the ONLY good thing about the glucagon antagonists. I wish there was more. 

Source: Drucker YouTube Lecture https://youtu.be/4U0OorK9Gb4?si=-tOvNWp7SlnXuH-R 

On the other hand, the bad is quite bad. Across multiple drugs and trials, a combination of effects was noted: increased body weight, increased blood pressure, increased liver enzymes, increased liver fat amount, increased LDL cholesterol(!!), pancreatic alpha cell hyperplasia, increased glucagon levels, hyperaminoacidemia and it even caused a DELAYED recovery from hypoglycemic events. 

Source: Drucker YouTube Lecture https://youtu.be/4U0OorK9Gb4?si=-tOvNWp7SlnXuH-R 

In plain English, increased risk of liver issues, potential increased risk of pancreatic cancer, increased risk of cardiovascular disease via elevated lipids, increased risk of kidney disease. Without surprise, all development of these drugs was stopped, for a really good reason. The safety signals we build into clinical trials worked.

So why did these medications fail when the mechanism of action seems so obvious as a drug target? From a biology standpoint, it really is quite simple. Glucagon does far more than just act through the liver to raise glucose and these drugs showed that. It controls protein and lipid flux in the liver. The glucagon receptor is present in the liver, kidney, pancreas and brain just to name a few. As noted in these trial results, which I’ve linked at the end of the article, it seemed the drugs worsened the classic metabolic syndrome symptoms. There was also the fact that glucagon as a peptide has an extremely short half life, so while there was some data about these other effects of glucagon, many of these studies were decades old, hadn't been repeated and given medical dogma around it, were seemingly forgotten.

But then again when you think through the mechanism, blocking the glucagon receptor makes the body think there’s not enough glucagon, so it should be no surprise that glucagon levels then rose in response and as we are classically taught, elevated glucagon levels are practically diagnostic for a type 2 diabetic. In essence these drugs just exacerbated this fact AND as if that wasn’t enough, because of the similarities between the glucagon receptor and the glucagon-like peptide 1(GLP-1) receptor, the glucagon antagonists were blocking both receptor sites which probably explains why this class of drugs couldn’t lower post-prandial glucose, GLP-1 was blocked and insulin levels could not rise in response to a meal.

At this point, glucagon receptor antagonists have been mostly forgotten, even finding data for this has been difficult. But, if blocking glucagon failed, what would happen if we did the opposite? Would all these metabolic derangements reverse? And importantly, if you countered the hepatic glucose rise, say, by using a GLP-1 agonist at the same time, could we finally target glucagon in such a manner to benefit from it? Enter glucagon agonists, which I will explore in part 2 of this series.

Some selected references: