The Gila monster gave the weight-loss revolution its bite

It’s currently estimated that over one-half of the adult US population is either overweight or obese. Being overweight means having a Body Mass Index (BMI) between 25 and 30. Obese means a BMI higher than 30. This statistic shouldn’t be taken to indicate neglect by the healthcare, research, or pharmaceutical industry. In reality, enormous attention has been paid to the problem for decades. But by a strange twist of fate, one unusual feature of a small lizard called the Gila monster gave the world a much-needed revolution in weight loss treatments that we have been benefiting from for the past seven or so years.

Introducing the Gila monster (Heloderma suspectum)

The Gila monster isn’t much of a monster. According to Wikipedia, “The Gila monster is a species of venomous lizard native to the Southwestern United States and the northwestern Mexican state of Sonora. It is a heavy, slow-moving reptile, up to 56 centimeters (21 inches) long and the only venomous lizard native to the United States.” It’s also not much of a poisoner, because only one fatality from a Gila bite has been recorded in the US in nearly 100 years, and that was delivered to a person who was keeping a Gila monster as a pet.

What brought the monster to the attention of scientists in the mid-1990s was the presence in the lizard’s venom of a hormone (exendin-4) that closely resembled a hormone in the human body called GLP-1. Both of these have a role in stimulating insulin production, which is the main controller of sugar levels in the blood. What made exendin-4 so interesting was that it has a half-life that is more than double that of GLP-1. 

The importance of half-life when it comes to any chemical activity can be explained this way. Imagine it as if you have a bowl containing 100 molecules of GLP-1, with a half-life of two minutes, and another bowl with 100 molecules of extendin-4, which has a half-life of 4 minutes. The table below shows the remaining number of active molecules after each “half-life” has passed:

Beyond 12 minutes, there would be hardly any GLP-1 molecules left, whereas a fair number of active extendin-4 molecules are available that stayed active for longer.

Bringing the monster molecule into the laboratories.

One of the problems scientists had up to that point when trying to create a synthetic version of GLP-1 to treat diabetes was that its half-life was so short that it had run out of power almost immediately after getting into the bloodstream. It barely had any effect in stimulating insulin production in the pancreas, where insulin is manufactured. Trying to overcome this by increasing the up-front strength so that enough GLP-1 remained in a person’s blood created too many risks of negative side effects. Right up front, the extra duration of exendin-4 meant that there was enough concentration in the bloodstream, even at low starting dosages, to kick the pancreas into action and pump out the necessary volume of insulin.

In the earlier years of this century, scientists like Drs. Daniel Drucker, working at the Lunenfeld-Tanenbaum Research Institute at the Mount Sinai Hospital in Toronto, and John Eng and Jean-Pierre Raufman, working for the US Veteran Affairs Office of Research, began to focus on finding ways to extend the half-life of the Gila-derived molecules even further. Using the new techniques of gene manipulation that were being developed in parallel in those years, the half-life was doubled and doubled again. The first medical use of this new technology came in 2005, when a synthetic version of exendin-4, called exenatide, was approved for medical use by the FDA. It was sold in the form of a twice-daily self-administered injection under the name Byetta.

Synthetic GLP-1 beats the Gila monster

Synthetic GLP-1 receptor agonists mimic the action of the naturally occurring hormone GLP-1, which helps regulate glucose metabolism. These drugs enhance insulin secretion and suppress unwanted glucagon release.

The process of extending the life of the GLP-1 agonist molecules continued through the following ten years, and steady progress was made. This is illustrated by the cascade of medications that came out of the laboratories of major pharmaceutical companies in the US and Europe. Byetta (exenatide) itself was extended to become a once-a-week version (Bydureon), along with competing versions like Victoza and Saxenda (both based on liraglutide.) Victoza was approved for type 2 diabetes in 2010 and has been shown to reduce cardiovascular events. Saxenda is a higher-concentration version of Victoza, and was the first major diabetes drug that was approved for chronic weight management in 2014.

Then in 2017, the first version of the hyper-performing Gila-derived molecules, called semaglutide, was released to the public, under the brand name Ozempic. Semaglutide has a half-life of nearly five days! This once-weekly injectable has better control over blood sugar levels than the earlier versions like Victoza and Bydureon.  Against Victoza, perhaps its greatest benefit is that it does not require daily administration, ensuring a much higher degree of adherence to the required dosing regime. Against Bydureon (withdrawn from the market in 2021), it proved to be much more effective in controlling blood sugar levels, achieving an average reduction of HbA1c of 1.8%, compared to 1.4% by Bydureon.

Scaling up (pun intended) the use of GLP-1

Wholly unforeseen at the time of the development of all these versions of the Gila-derived drugs was its impact on appetite and digestion. In its native form in the human body, GLP-1 degrades so quickly that there’s too little left to have any effect other than promoting insulin output. However, once the synthetic versions with 100+ times the half-life started to reach the gut of patients in trials, a remarkable effect was noticed in the early studies of Ozempic as a treatment for diabetes (the SUSTAIN studies). 

One of the findings was that diabetics taking the weekly injection were losing substantial amounts of weight (even those who were not clinically obese). This led to a new round of trials of people without diabetes who were overweight or obese (STEP trials), which combined Ozempic at a higher concentration with moderate exercise and diet control. The results were even more impressive, with average weight losses between 14.9% and 17.4% after treatment.

Ozempic had a head start of three years and came to dominate the market. It was followed by a similar drug called Mounjaro (tirzepatide), which has a slightly different molecular structure. It combines GLP-1 agonists with another natural hormone known as glucose-dependent insulinotropic polypeptide (GIP). Combining these two hormones has a synergistic effect, creating what’s come to be called a ‘twincretin’. The SURMOUNT studies found that tirzepatide was slightly more effective at helping participants lose weight. About four out of five of the participants taking tirzepatide experienced 5% or greater weight loss. In comparison, about two-thirds of participants taking semaglutide achieved this level of weight loss. In both trials, slightly lower percentages of the participants went on to lose substantially more weight, reaching an average of around 22% of starting body mass for tirzepatide and 18% for semaglutide.

The effectiveness of semaglutide in promoting weight loss was maximized only with higher dosages than were FBI-approved for treating type 2 diabetes. Initially, the highest dose of semaglutide that was available in Ozempic was 1 mg per week. The SUSTAIN studies were based on two higher dosages – either 1.7 mg or 2.4 mg. In 2021, the FDA approved semaglutide as a weight-loss medication, with the brand name Wegovy.  Doctors now prescribe Wegovy for weight loss, whereas Ozempic and Mounjaro are only for diabetic patients.

Wegovy promotes weight loss by slowing gastric emptying and increasing feelings of fullness, leading to reduced food intake and less hunger. This dual benefit of glycemic control and weight reduction is particularly advantageous for patients with type 2 diabetes, who often struggle with obesity.

Improved heart health, thanks to Gila’s venom!

Some GLP-1 receptor agonists have demonstrated marked cardiovascular benefits, reducing the risk of major adverse heart outcomes in patients with type 2 diabetes and established cardiovascular disease. A trial of semaglutide (Ozempic) showed that it reduced the risk of a combination of stroke, heart attack, and death from cardiovascular causes by 20%.

Summary

Who would have imagined that a bite from a small lizard could possibly have had such a phenomenal effect on nearly half of the US population and countless billions of others around the world? It’s almost like a fairytale come true!