Ripples of Discovery Created a New Wave of Weight-loss Medications

When it comes to pharmacology, the big story these days is the development of the “glucagon-like peptide-1 (GLP-1) mimics,” the first truly effective medications to treat obesity. It’s a fascinating story to be sure, but get set for a bumpy ride. We are not playing Tiddlywinks here.

The year was 1902. Physiologists William Bayliss and Ernest Starling had just injected an acid extract from the lining of a dog’s duodenum, the first part of the small intestine, into the animal’s bloodstream. To their surprise, the dog’s pancreas began to produce digestive juices. Why the surprise? Because they had carefully cut all nerves surrounding the pancreas.

It was understood at the time that acid secretions triggered by food entering the digestive tract stimulate the pancreas to release digestive juices. The assumption was that the message to the pancreas from the intestine was delivered through nerves. Clearly, with the nerves having been severed, this was not the case. The message must have been delivered by some substance secreted by the intestine that then made its way to the pancreas through the bloodstream.

It was this “secretin,” as Bayliss and Starling called it, that stirred the pancreas into action. Later, Starling would coin the term “hormone” from the Greek for “set in motion” for such chemical messengers. Bayliss and Starling’s landmark experiment also set in motion the research that would eventually lead to today’s most talked-about medications, the GLP-1 mimics, or “GLP-1 agonists,” that would go on not only to battle Type 2 diabetes but also obesity.

Also known in the early 20th century was that food in the intestine, besides triggering the release of digestive juices, can cause the pancreas to release insulin, the hormone cells need to absorb glucose, their main source of energy. In 1932, Belgian physiologist Jean La Barre coined the term “incretin” from “intestine” and “secretion” for gut hormones that stimulate insulin secretion by the pancreas, but the specific nature of these hormones and how they work was a mystery.

A clue came from the “incretin effect,” an observation that the same amount of glucose given to a person orally results in significantly more insulin being released than when glucose is injected directly into the bloodstream. The pancreas must therefore be receiving an extra signal from oral ingestion, and that must come from some substance secreted by the intestine. This was a great stimulant for research because if the identity of that “incretin” were determined, it would offer a potential treatment for diabetes.

Identification of the first incretin occurred in the 1960s when John Brown and colleagues at the University of British Columbia discovered that the duodenal peptide “gastric-inhibitory polypeptide (GIP)” stimulates insulin secretion. Then in the 1980s, researchers discovered that GLP-1 performed even better, paving the way for Ozempic and Mounjaro.

Massachusetts General Hospital researcher Dr. Joel Habener had become interested in glucagon, another pancreatic hormone that behaves in a fashion opposite to insulin, increasing blood glucose when needed. Habener thought that identifying the gene that codes for the production of glucagon could lead to a way of controlling blood sugar. This led to the discovery of a gene that codes for the peptide “proglucagon.” Peptides are chains of amino acids with, in the case of proglucagon, 160 amino acids linked together. Habener and Svetlana Mojsov, also at Mass General, discovered that proglucagon in the body can be broken down into shorter peptides, namely into glucagon in the pancreas and GLP-1 in the lining of the intestine.

In Habener’s lab, Daniel Drucker tested the peptide found by Mojsov and discovered that it stimulates insulin secretion. Independent studies by Danish physiologist Jens Juul Holst demonstrated that GLP-1 was biologically active in animal models, while a group in the UK led by Stephen Bloom demonstrated that GLP-1 stimulates insulin release in humans. This was obviously a candidate for the treatment of diabetes.

There was a problem, though.

When introduced into the body, GLP-1 proved to be impractical as a medication because it was immediately broken down by enzymes. This is when the Gila monster, a lizard that lives in southern climes, came to the rescue. Researchers discovered that its saliva contains a 39-amino acid peptide, eventually named exendin-4, that has an amino acid sequence with some similarity to the incretin GLP-1. Indeed, exendin-4 did stimulate insulin release and was not readily broken down by enzymes. It was a GLP-1 receptor agonist, meaning that it stimulates the same receptors in cells as the GLP-1 produced in the lining of the intestine. Exendin-4 could be produced in the lab readily from amino acids and went on to be marketed as exenatide, trade name Byetta, becoming the first GLP-1 receptor agonist to target Type 2 diabetes. The downside was that it required twice-daily injections.

The challenge was to come up with a version that required fewer frequent injections and ultimately one that would be effective in a pill form. Researchers discovered that if the amino acid sequence of GLP-1 was modified to make it more degradation-resistant, like exendin-4, the ability to stimulate insulin release would be increased. Furthermore, if the molecule could be bound to the blood protein albumin, its likelihood to be broken down by enzymes would be decreased. Fatty acids were found to be appropriate binders, resulting in liraglutide (Victosa), a once-daily injection with fewer gastrointestinal side effects. Further tinkering with the amino acid sequence and strengthening the link to albumin resulted in semaglutide, the drug that rose to fame as Ozempic for the treatment of diabetes.

As early as the 1990s, it was known that GLP-1 reduces food intake in animals, and this was reproduced in humans taking exenatide, and more dramatically with liraglutide. This effect was then exploited, resulting in GLP-1 agonists becoming a treatment for obesity. In 2014, liraglutide under the name Saxenda became the first GLP-1 agonist to be marketed for the treatment of obesity, followed in 2021 by semaglutide as Wegovy, which was just a higher dose of semaglutide than in Ozempic.

While effective for the treatment of obesity, these drugs still require weekly injection, but they turned out to have benefits other than weight loss. Drucker, now at the University of Toronto, continued to make many notable contributions to our understanding of the biological actions of GLP-1, especially its beneficial effects on the heart and kidneys, its role in the brain, and its actions to reduce inflammation in the body.

The era of oral GLP-1 agonists has now arrived, thanks to some ingenious chemistry.

The challenge was to keep the drug from being broken down in the stomach before it could be absorbed into the bloodstream. The key was the discovery that the incorporation into the pill of sodium N-[8-(2-hydroxybenzoyl)amino] caprylate, mercifully abbreviated as SNAC, elevates the pH around the pill and prevents attack by stomach acid, facilitating absorption across the stomach wall.

The development of GLP-1 agonists is definitely Nobel Prize-worthy. Habener recently passed away at age 88. That would seem to leave Drucker, Juul Holst, and Mojsov. That will make for some interesting discussion among selection committee members.

# Reprinted with permission. Dr. Schwarcz’s original article can be found on the OSS website