It is the story of a lot of effort. And of a few coincidences too, there are so many in medical research. Without this element of chance, there would be no Saxenda, Wegovy (Novo Nordisk) or Mounjaro (Eli Lilly), these drugs prescribed for about ten years against diabetes, and which have recently proven effective in combating obesity. They could allow millions of people to “live better” and “longer”, by helping to regulate their appetite.
Already authorized in the United States, and currently being evaluated in Europe for this indication, these treatments could make patients lose around ten kilos in a few months, thanks to simple injections. Enough to avoid them major surgical operations, subject to complications. Better still: recent studies, the latest of which were published no later than the beginning of the month, indicate that these drugs could also have a protective action against certain cancers, as well as several neurodegenerative diseases, from Alzheimer’s to Parkinson’s.
Research into these unexpected benefits is still ongoing. And like any medication, these molecules are obviously not without side effects, and must be used with caution. But, in the eyes of many specialists, these substances already present all the hallmarks of a new medical revolution, due to the many benefits they seem to bring, and the perspectives thus opened up. An important scientific achievement, the first stones of which were laid nearly forty years ago, and which has continued to grow since then.
The scientific epic behind these new drugs began in the 1980s, in a laboratory in Massachusetts, General Hospital, a prestigious American medical establishment. At the time, disco was dying and biochemistry was being reborn all over the country. New analysis techniques were stirring up research. Based on recombinant DNA, they made it possible to isolate many molecular processes that were previously unknown. A young and ambitious endocrinologist, Joel Habener, who had just started work, took advantage of this to choose a new subject for study. It would be glucagon, a hormone that regulates insulin, and therefore diabetes.
A molecule found without wanting it
Luck came into play for the first time in 1982: while researching how the substance is produced by the body, Joel Habener and his team stumbled upon two other molecules that had never been seen before. From test tubes to test tubes, the endocrinologist noticed that they resembled glucagon. He called them “glucagon-like peptide” (GLP). All the new “anti-obesity” drugs today were based on this family of hormones. But the scientists at the time knew nothing of the importance of this discovery.
The discovery even seems relatively banal: new molecules secreted by the body were scribbled down every day in the experimental reports of the time. “No one could have predicted such success for these substances,” smiles Richard Goodman, American biologist and co-author of the first study mentioning GLPs, alongside Joel Habener. The story could therefore have ended there, with this simple publication serving as an inventory, which can be read in the archives of the scientific journal PNAS.
But instead of putting these substances away, a handful of die-hard curious people, Joel Habener, of course, but also scientists like Svetlana Mojsov, Daniel Drucker or Jens Juul Holst in Denmark decided to analyze them. They injected them into cells, then into animals. A first study was published, then a second. The researchers understood that GLPs are produced by cells of the pancreas and the intestine. And that in addition to playing a role in diabetes, like glucagon, they also regulate digestion and satiety, mechanisms that were until now very mysterious. At the end of the meal, the body secretes them, which pushes you to stop eating and facilitates the efforts of the intestines.
Enough to give this research a completely different twist. Regulating the feeling of being full, acting on the absorption of food, these are interesting effects, say the specialists. At the same time, work on its interest in the fight against diabetes continues. In 1992, a clinical trial showed the effectiveness of GLP on this pathology. In 2014, then in 2017, two molecules similar to GLP-1, liraglutide (Saxenda) and semaglutide (Ozempic), specially developed against diabetes, were finally authorized in the United States. The scientific saga against obesity, however, has not really begun.
“Everyone started throwing up”
The first marketing as “anti-obesity” of a GLP-1 derivative was only authorized by the FDA, the American agency, in 2021. Three decades after the discovery of the role of this family of molecules. Why did it take so long? “While the appetite suppressant effect of GLP-1 had been known to specialists for a long time, its pharmaceutical use was not at all self-evident,” recalls with a fit of laughter Jens Juul Holstresearcher at the University of Copenhagen, specialist in GLP.
Jens Juul Hoslt was one of the first to prove that GLP could be injected into humans, and that the effects observed so far in the laboratory on the digestive organs also worked inclinical trials, which he organized since 1998. But nothing went as planned: “We did have an effect on appetite, but the weight loss observed was small. And above all, the volunteers started vomiting everywhere, as if they had eaten too much,” recalls Jens Juul Holst, now an employee of the Danish pharmaceutical laboratory Novo Nordisk. What’s more, at the time, obesity was not entirely considered a disease. The trail ended in a dead end.
A new coincidence will revive the “appetite suppressant” trail. In the 2000s, manufacturers tried to optimize the effects of GLP-1 on diabetes, without worrying too much about the aspects related to appetite regulation. The teams at Novo Nordisk, to name just the manufacturer that arrived first on the market, manipulated the structure of the molecule, its composition, its shape. Until they managed to modify the way it was absorbed. Surprise: when the molecule took a long time to be consumed, the weight loss observed increased, and nausea diminished. “This is the real contribution of the company and the scientist Lotte Bjerre Knudsen, then responsible for these products: having managed to find the right formulas and the right dosages,” continues Jens Juul Holst.
What was then only a laboratory observation was confirmed a few years later by data collected on diabetic patients who had been consuming it since 2014 and many of whom reported to their doctors a loss of weight and a reduced appetite for food. Manufacturers, first Novo Nordisk, then Ely Lily, also at the forefront in this field, are conducting additional trials on obese people. The first results confirm a real benefit on weight, but also on pathologies associated with obesity. There are of course side effects. But they are mostly limited to nausea, diarrhea or inflammation of the pancreas, if the product is used under the right conditions.
From obesity to Alzheimer’s?
Today, GLP-1 derivatives are still being examined by French institutions. Questions remain, particularly regarding the reimbursement that patients could claim. Their effectiveness, however, no longer seems to be in doubt. But the authorities hesitated for a long time before paying such close attention to this type of product. The sector is still haunted by the Mediator scandal, this appetite suppressant also presented as revolutionary, and whose high toxicity on the heart was hidden by Servier laboratories. Before this affair, other pills of this type, from the amphetamine derivative to Sanofi’s Acomplia, were also abandoned because they were too dangerous.
To be effective, GLP-1 must be consumed for years. As soon as treatment is stopped, the pounds come back, as indicated by a study published in 2023 in Journal of the American Medical Association (JAMA). It is difficult to know what consequences such long treatments could have on the body. But they do not seem to disrupt the heart, unlike their predecessors that have fallen into disgrace. On the contrary: “The molecule reduces the risk of having a heart attack or stroke by up to 20%,” says Dan Drucker, another GLP-1 pioneer, also a Novo Nordisk collaborator. This is what the scientist observed, on mice in 2009and more recently on humans. A powerful argument for drug safety agencies.
Dan Drucker and Joel Habener, the discoverer of GLP-1, both attended Massachusetts General Hospital during the early discoveries in the 1980s. Then they lost touch, each working in their own way. They reunited at the Warren Alpert Foundation Prize in 2020, along with Jens Juul Holst, to receive a shared award. The trio is now a contender for the Nobel Prize in Medicine. They are convinced: the adventure is only just beginning. And they are not the only ones who think so: in biochemistry laboratories, more and more scientists are convinced that GLP-1 has not given up all its secrets.
“We are only at the beginning of a new era”
Recent developments may prove them right. In March 2024, the United States approved Wegovy to prevent cardiovascular accidents in overweight people, completing its recognition of its benefits against heart disease. In March, scientists presented preliminary results on AIDS patients and the side effects of triple therapy at a conference. In April, a team announced in The New England Journal of Medicine a beneficial action against Parkinson’s. In July, work published in JAMA reported a protective effect on about ten cancers. And many experiences suggest that an effect against Alzheimer’s is possible. Enough to reinforce the expectation around these molecules.
Enough, also, to cut short the emergence of concerns about potential new adverse effects, ranging from the increase in suicidal thoughts to an impact on vision. These conditions, although rare, are the subject of investigations, in particular by the National Agency for the Safety of Medicines and Health Products, which indicated that it was increasing its “vigilance” in a press release published on July 5. Precautionary measures above all, because at this stage there is no indication that these manifestations are directly attributable to taking GLP-1, nor that they are frequent enough to make these drugs more harmful than beneficial.
Scientists do not yet know all the mechanisms behind these protective effects. Losing weight certainly helps the body function properly, in general. But the molecule also seems to act directly on pathologies. At the beginning of 2024, Dan Drucker and his team made a new discovery in this direction. GLP-1 limits inflammatory reactions by modulating the brain activity responsible for it. This gives rise to a lot of hope, since inflammation is the cause of many diseases. “We are only at the beginning of a new era,” enthuses the specialist. The scientific adventure has only just begun.
.