Century-Long Quest: Unraveling GLP-1 and Obesity Treatment

Today, I want to take you on a fascinating journey, a scientific detective story that spans over two centuries and culminates in a revolution in treating diseases like diabetes and, more recently, obesity. It's the story of GLP-1, a humble peptide that went from a scientific curiosity to a groundbreaking therapeutic.

Our story actually begins much earlier than you might expect, even before the concept of hormones was fully understood. As far back as 

1785, scientists like Lavoisier and de La Place were building the first calorimeters, laying foundational work for understanding energy balance. In 

1902, the first gastrointestinal hormone, secretin, was identified by Bayliss and Starling, who also coined the term "hormone".

Then, in 1906, a group in Liverpool made a remarkable observation: an extract from the intestine could actually lower blood glucose. They called this mysterious factor "incretin," hinting at its ability to increase insulin secretion. However, the excitement around incretin soon waned with the groundbreaking discovery of insulin in 

1921 by Banting and Best, which offered a direct treatment for diabetes. Shortly after, in 

1923, glucagon, another pancreatic hormone, was isolated. For decades, the focus remained on the pancreas, and the potential role of incretins lay dormant.

The scientific flame was rekindled in the 1960s. Observations by independent research groups revealed something peculiar: if you gave glucose orally, it led to a greater increase in insulin concentrations and a more significant drop in blood glucose compared to giving glucose intravenously. This strongly suggested that the gut was producing a hormone – or hormones – that helped regulate insulin levels. The search for these "incretins" was officially on, with the hope that they could offer a novel treatment for diabetes.

The first incretin to be identified was in 

1970, when J.C. Brown and colleagues identified gastric inhibitory polypeptide (GIP). GIP was shown to potently stimulate insulin secretion in humans and animals in 

1973. While initially promising, GIP did not show efficacy in diabetic patients, and interest waned because its insulin-stimulatory effect was not evident in those with type 2 diabetes. This led the scientific community, particularly Creutzfeldt, to conclude around 

1979 that "GIP is not the only incretin".

The real breakthrough for GLP-1 came in 1981 and 1982. This is where our first key player enters the scene: Joel Habener, an endocrinologist and molecular biologist. While studying how hormones are produced, he looked at fish glucagon precursors and in 

1981, he and his colleagues cloned a glucagon cDNA from anglerfish. In 

1982, they reported that glucagon was a cleavage product of a larger precursor protein that also encoded a previously unknown 34-amino acid peptide. They named it "glucagon-related peptide" and noted its similarities to glucagon and GIP.

Then, in 

1983, a crucial piece of the puzzle emerged when the hamster glucagon precursor was cloned by Graeme Bell and colleagues. This revealed an important difference: the hamster's version of this glucagon-related peptide, now renamed 

Glucagon-Like Peptide 1, or GLP-1, was 37 amino acids long, with an additional 6 amino acids at its beginning not seen in the fish version. The scientific community suspected this 37-amino acid peptide held a biological function.

Around this time, in 

1983, a brilliant peptide chemist, Svetlana Mojsov, joined the scene. She was a pioneer in synthesizing peptides, having developed innovative chemical methods for synthesizing glucagon variants. She became intrigued by the possibility of GLP-1 having biological effects.

The pivotal year was 1986. Through their collaborative efforts, Habener and Mojsov identified 

GLP-1(7-37) in the intestine, confirming it as a cleavage product from the glucagon precursor. Mojsov's meticulous work showed that this specific form, GLP-1(7-37), was the predominant molecular form in the intestine. This finding was a major leap forward, suggesting that GLP-1(1-37) was a "prohormone" or precursor for the active GLP-1(7-37).

The confirmation of GLP-1(7-37)'s power came swiftly in early 1987. Mojsov, alongside Weir and Habener, tested it in isolated rat pancreas and found it potently stimulated insulin secretion, even at very low, physiological concentrations. Importantly, the longer GLP-1(1-37) had no such effect. This strongly suggested that GLP-1(7-37) was indeed an incretin. Similar findings were quickly corroborated by other groups, including Holst et al., also in 

1987, who confirmed GLP-1(7-37) was present in pig intestine and potently stimulated insulin secretion. Later in 

1987, Bloom et al. provided human evidence, showing that GLP-1(7-36) infusions increased insulin and reduced glucose in patients who had received a glucose load. With these cumulative findings, GLP-1(7-37) finally satisfied all the criteria to be recognized as a true incretin.

By 1992 and 1993, the clinical potential became clearer. Studies, including one by David Nathan, Mojsov, and Habener, demonstrated that GLP-1 infusions significantly increased insulin levels and lowered glucose in diabetic patients. This was a pivotal moment, establishing GLP-1's potential as a diabetes therapy.

However, there was a significant challenge: native GLP-1(7-37) had an incredibly short half-life in the bloodstream, only 1 to 2 minutes. This meant it would need continuous infusion to be effective – not a practical solution for patients. This is precisely when our third key figure, 

Lotte Knudsen, a young pharmaceutical scientist from Novo Nordisk, entered the picture in the early 1990s.

Knudsen, who would soon lead Novo's innovation team by 

1995, had a visionary belief from the outset: GLP-1 wouldn't just be a treatment for diabetes, but also for obesity. This idea was supported by earlier research showing that certain glucagon-producing tumors caused severe appetite loss in animals, and that GLP-1 itself could profoundly reduce food intake. The formidable challenge was to engineer a stable, long-acting version of GLP-1. Knudsen's team pioneered a novel approach: attaching a fatty acid to the GLP-1 molecule, which was first developed by other Novo chemists in 

1995. This clever modification allowed the drug to bind to albumin in the blood, protecting it from breakdown and extending its half-life.

In 

2000, their efforts bore fruit with the reporting of liraglutide. This modified GLP-1 derivative, with a C16 fatty acid, achieved a half-life of 13 hours, making daily administration feasible. Clinical studies soon began.

While Novo Nordisk was working on liraglutide, other companies were also making strides. In the 

mid-1980s, John Eng identified Exendin-4 from Gila monster venom, a peptide remarkably similar to GLP-1 but with a longer half-life. This led to the approval of 

exenatide for diabetes in 2004, which also showed modest weight loss. Then, in 

2006, sitagliptin, the first DPP-4 inhibitor (an enzyme that breaks down GLP-1), was approved. While effective for diabetes, DPP-4 inhibitors had little to no effect on body weight.

Despite the competition and initial hurdles like nausea with liraglutide, Knudsen's team persevered. By gradually increasing the dose, they found that once-daily liraglutide (Victoza) significantly decreased HbA1c and, crucially, caused significant weight loss of 5% or more in over half of diabetic patients. This led to its approval in 

2010. Furthermore, Knudsen bravely pushed for trials using a higher dose of liraglutide (

Saxenda) specifically for obesity, resulting in an average of 5 kg weight loss.

But the story didn't end there. To improve patient convenience even further, Knudsen and her team set out to create a GLP-1 receptor agonist that could be administered 

once weekly. After testing thousands of modifications, they developed 

semaglutide, an "ultrastable" receptor agonist reported in 2015. This version, with its unique fatty acid attachment and a mutation preventing DPP-4 cleavage, extended its half-life to an incredible 7 days.

The results of semaglutide were truly astonishing. In diabetic patients, semaglutide (Ozempic) showed dose-dependent weight loss, with an average of 6 kg lost. It also significantly reduced cardiovascular events by 26%, with results published in 

2016. Then came the trials for obesity at even higher doses (

Wegovy), and the findings were "stunning". Patients lost an average of 12.4% of their initial body weight, with profound health implications. Weekly semaglutide was also shown to reduce cardiovascular events in overweight and obese patients without diabetes but with pre-existing cardiovascular disease, with results published in 

2023. Semaglutide, including its oral form, was approved in 

2022.

The impact of GLP-1 receptor agonists like liraglutide and semaglutide has been transformative, revolutionizing the treatment of metabolic disease. Their success has also spurred the development of even more potent agents, including oral GLP-1 agonists and "dual" and "triple" agonists that activate other gut hormone receptors alongside GLP-1. For instance, 

tirzepatide (a GLP-1/GIP dual agonist) was approved in 2022 , and induced an average weight loss of 21% in people with obesity. And even more recently, 

retatrutide (a triple agonist), whose development was reported in 2018/2019, has shown a remarkable 24% weight loss after just 48 weeks, without even reaching a plateau.

This incredible journey, from a mysterious intestinal extract in 

1906 to highly effective, once-weekly injections and even oral medications, is a testament to persistent scientific inquiry. The cloning of the glucagon gene, the identification of GLP-1(7-37) as a key incretin, and its development into these powerful drugs represent a true milestone in medicine. It has solved a century-old mystery about the gut's role in glucose metabolism, uncovered a new endocrine mechanism for insulin regulation, and, for the first time, provided highly effective treatments for obesity, with profound implications for human health.

This monumental achievement was recognized just this year, in 

2024, with the Lasker-DeBakey Clinical Medical Research Award being jointly given to Joel Habener, Svetlana Mojsov, and Lotte Knudsen for their essential and distinct roles in making this revolution possible. Their collective efforts have truly changed what we thought was possible in medicine.