In May 2023, Novo Nordisk decided to stop all TV advertising for semaglutide. Not because of any adverse news or anything like that, but because the drug’s popularity was so high advertising was no longer necessary.
Semaglutide represents the global acclaim of GLP-1 drugs, which were initially made as diabetes treatment, but have now been used in weight loss and even in the management of alcohol addiction. These drugs have been considered a breakthrough in the pharmaceutical industry. Some even view them as Nobel Prize-worthy.
However, the development of GLP-1 drugs was neither quick nor simple. The discovery and evolution of the GLP-1 spanned 40+ years. So, to honor the people who discovered and conducted extensive GLP-1 research, let us revisit its history, particularly the discovery and evolution of GLP-1 research.
How GLP-1 was Discovered
Svetlana Mojsov, Dan Drucker and Joel Habener at the Massachusetts General Hospital, along with Jens Juul Holst at the University of Copenhagen, were instrumental in the early understanding of GLP-1’s structure and function.
It was in the 1970s when Boston and California-based researchers developed pioneering technology that separated genes and provided insights into their functions.
With this new technology, they could convert mRNA (used by cells to produce proteins) into DNA, sequence it, or insert it into bacteria to create “biomolecular factories.”
What once took six months to accomplish could now be achieved in half a day.
Recombinant DNA technology, which brought physiological processes to molecular detail, became widespread in biomedical research labs across the country and internationally. One prominent lab that used this technology to study hormones was at the Massachusetts General Hospital. In 1979, researcher Richard Goodman extracted small tissue samples from the intestines of fish which contained cells with DNA instructions for producing metabolic hormones.
P. Kay Lund, who has extensive experience with gut peptides, identified the genetic sequence of a glucagon precursor (a hormone that increases blood glucose) using Goodman’s bacterial library which contained the fish DNA. In a paper they published in 1982, they revealed that the glucagon precursor gene encoded three peptides: 2 new hormones from the gut and glucagon.
In 1983, Graeme Bell’s team at Chiron Corporation in California cloned and sequenced versions in humans naming them GLP-1 and GLP-2 (glucagon-like peptides 1 and 2).
A Danish team later attempted to synthesize GLP-1 and inject it into pigs’ pancreas to observe its effects. But it wasn’t successful.
After encountering setbacks, researchers turned to their colleague Thue Schwartz, who had experience with peptide synthesis from his postdoctoral work in Donald Steiner’s lab at the University of Chicago, USA.
Collaborating with Schwartz, they discovered a hormone known as pancreatic polypeptide which exhibited a distinct breakdown pattern. They hypothesized that a similar pattern might exist for GLP-1. So, with data from two groups of scientists, GLP-1 began to emerge as a potential treatment for diabetes.
They conducted further tests such as applications of GLP-1 in human trials. In the summer of 1987, Danish team leaders attended a gathering with renowned endocrinologist Stephen Bloom and during the event, they discussed the therapeutic promise of GLP-1.
However, they soon encountered a major challenge: GLP-1 had a very short lifespan in the body. Enzymes in the blood rapidly broke it down within minutes. This means large doses of GLP-1 were needed to treat diabetes.
But the problem is, excessive amounts could cause nausea and vomiting in patients. So to address this issue, researchers needed to develop molecules that resembled GLP-1 but lasted longer than the natural hormone.
Exendin-4 A More Durable GLP-1 Analog
Rosalyn Sussman Yalow was awarded the Nobel Prize in 1977 for her pioneering work in developing radioimmunoassay techniques, which revolutionized peptide measurement in the blood.
Her lab included a talented researcher named John Eng, who excelled at using new technology to separate and determine peptide structures. In 1983, gastroenterologist Jean-Pierre Raufman and Eng collaborated to extract a 39-amino acid peptide from the venom of Gila monsters and named it exendin-4.
Exendin-4 was nearly identical to GLP-1 in structure but while the latter could only stay active for a minute, the exendin-4 remained active for more than two hours. Raufman’s team saw this as a potential diabetes treatment.
Unfortunately, their discovery was way ahead of its time.
“When we presented it at conferences, it garnered little interest,” Raufman recalled. Even the Department of Veterans Affairs – where Eng worked – was hesitant to use resources to patent exendin-4. Eng completed the patent paperwork himself and approached major diabetes drug companies, but all of them turned down his offer.
The main reason was that no one wanted to inject a substance derived from a venomous lizard into patients. Raufman noted, “Pharmaceutical companies need to take risks and recognize the therapeutic potential in venom-derived substances.”
In 2005, the FDA approved exenatide, marketed as Byetta, for diabetes treatment. It became a major success and was affectionately nicknamed “Lizzie” or “Gilly” by some users. Time would prove Raufman correct.
Using GLP-1 Drugs as Obesity Treatment
Meanwhile, Novo Nordisk a Danish pharmaceutical company was also working on its own GLP-1 receptor agonist, which they called Liraglutide, intended as treatment for obesity.
After extensive research, the company developed a successful drug design by adding a long fatty acid chain to GLP-1-like molecules. This increased their duration and allowed them to bind reversibly to GLP-1 receptors.
Liraglutide entered clinical trials in 2000 as an injectable treatment for diabetes. It increased insulin production while at the same time reduced appetite, so it works as both diabetes treatment and weight loss treatment. The team created an improved version known as Semaglutide. Liraglutide was found to lower food intake by 15%, while Semaglutide could reduce it by as much as 35%.
In 2010, the FDA approved Liraglutide and was marketed as Victoza. In 2021, Semaglutide was also approved under the name Wegovy. The latter’s exact mechanism is not fully understood, however its weight loss effects are well-documented. So it didn’t take long before the rest of the world found out about it and created a huge demand.