Without the influence of a Gila monster, semaglutide – better known as Ozempic and Wegovy – may never have been possible.
The Gila monster is not an obvious answer to the question “how do we solve the worldwide obesity epidemic?” but science is seldom short of surprises.
Big, ugly and highly venomous, the sluggish lizard is more than a little terrifying. Telegraph reporters came face to face with one a few years back at a little known herpetarium in Liverpool, which is home to more than 100 of the most venomous animals on the planet.
Most were snakes but the Liverpool School of Tropical Medicine also keeps a Gila monster, an animal which is bizarrely (but correctly) credited with being instrumental in the development of Ozempic and Wegovy, two of the new class of fat-busting drugs that are selling almost as fast as fizzy drinks and burgers across the world.
Deftly taking the lizard from its cage, lead herpetologist Paul Rowley warned us to stand back. The Gila monster has the most agonising venom. “It won’t kill but there are people who have cut off their hands after being bitten because of the pain,” he said.
It is a synthetic variation of a hormone found in the saliva of these animals that some experts, and many drug companies, now believe could “cure” obesity and many of the nasties that flow from it – most notably diabetes, heart disease and several cancers.
Sir John Bell, the UK’s life sciences champion, says they are likely to become “the new statins”, the cholesterol-lowering medicines that have done so much to reduce stroke and heart attack among those with an elevated risk of cardiovascular disease.
On the surface at least, there’s good evidence to support this optimism.
For the past year or two, the pounds have been mysteriously falling off Hollywood celebrities. Next in line were buxom reality stars and tubby talk show hosts. And now, as the new drugs have started to flow into private clinics, even office colleagues are being transformed.
“You look terrific, have you been working out?,” I asked a slender-looking editor on The Telegraph’s op-ed desk last week. “No, it’s Ozempic. This is the only exercise required!”, he said, making a jabbing movement to the injection site on his upper left thigh.
Wealthy elites have struggled with obesity since time immemorial. Hippocrates wrote that “corpulence is not only a disease itself, but the harbinger of others”.
Yet for much of history, treatments have been crude. The monks of Portugal’s Golden Age resorted to narrowing the doors to the communal dining areas of their monasteries in a bid to deal with corpulent colleagues, to give just one example.
Today obesity is much more widespread and solutions of the type that Ozempic and Wegovy promise are desperately needed. But are they really the answer or is the very idea that a simple pill or injection could solve the obesity crisis just too good to be true?
Might rare but lethal side effects still emerge? Will the pounds simply pile back on when the medication stops? And perhaps most intriguing of all, how is it that even the scientists who created these new wonder drugs do not understand how they really work?
A lonely field
It has long been known that hormones produced by the gut and pancreas modulate blood sugar levels.
Injected insulin has been used by doctors to help control diabetes since the 1920s. It’s a somewhat crude intervention, cutting blood sugar levels when they climb too high, but for the best part of a century it’s been a lifeline for millions across the globe.
But insulin is not the only hormone that helps regulate blood sugar and in the 1980s, two groups of academics – one in the US, one in Denmark – independently stumbled across a new one: glucagon-like peptide 1 or GLP-1.
Using pigs as a model, Jens Juul Holst, a professor in the Department of Biomedical Sciences at the University of Copenhagen in Denmark, found the hormone was a much more subtle regulator of blood sugar than insulin. It was a “particularly powerful hormone”, he noted, and would normalise blood sugar levels – moving them up or down – within minutes.
Dr Joel Habener and Dr Daniel Drucker, working at Massachusetts General Hospital in the US, independently came across GLP-1 at about the same time. Like Holst, they recognised it held the potential to regulate diabetes much better than the one-way battering ram that was insulin, but there was a problem: it didn’t survive long enough in the blood.
There was another thing. Drucker and Habener were running experiments in which diabetics were given GLP-1 and then asked to eat ahead of their blood sugar levels being checked. However, many of the test subjects complained they couldn’t finish their food. They simply felt too full to manage another mouthful, they said.
Drucker worked on GLP-1 for years, telling The New York Times recently that, for a long time, it was “a pretty lonely field”. At conferences, his talks were always scheduled right at the end. “Everyone had left for the airport – people were taking down the exhibits,” he recalled.
In Europe, it was much the same story. Holst had taken his findings “just up the street” to the Danish pharmaceutical giant Novo Nordisk, one of the world’s biggest producers of insulin, only to find that they weren’t very interested either.
‘Those rats simply starved themselves to death’
Enter the Gila monster and Dr John Eng, a researcher at the Veterans Affairs Medical Centre in New York. Eng had spent nearly 25 years searching for peptide hormones that might be useful to medical science and had run tests on hundreds of animals including guinea pigs and chinchillas, but all without much luck.
Then, in 1990, he came across studies done in the early 1980s which noted that the bite of some venomous snakes and lizards caused inflammation of the pancreas. Of particular interest, he thought, was the Gila monster which appeared to be able to maintain its own blood sugar levels at a constant even when it was very hungry.
With nothing to lose, Eng ordered some dried Gila venom from a serpentarium in Utah and began testing it. In 1992, his work revealed the venom contained two compounds, including one he called Exendin-4. It’s essentially a Gila monster version of GLP-1, but one which survives much longer in the blood.
Eng realised immediately the significance of what he had found and urged the Veterans Centre to patent the new hormone. But they refused. The discovery did not address a “veteran-specific ailment, such as spinal cord damage or some other combat injury” so they didn’t think it was worth pursuing, he told the Diabetes in Control journal in 2007.
Dispirited but not broken, Eng – who is now a multimillionaire – eventually patented the hormone himself and licensed it to Amylin Pharmaceuticals. After successful trials, it was finally launched as a treatment for type 2 diabetes under the name exenatide or Byetta in 2005. It had to be injected twice a day – a significant drawback – but it worked.
Back in Denmark, Novo Nordisk was now showing interest in GLP-1 as a treatment for diabetes. Early efforts came to nothing but eventually a long-lasting version of the hormone was created by a young researcher called Lotte Bjerre Knudsen. Called liraglutide, it also showed striking weight loss in rats.
“It was always the idea to develop liraglutide as a diabetes drug as well as an anti-obesity drug,” wrote Knudsen. “We started addressing weight loss in rodent studies back in 1995… Those rats simply starved themselves to death.”
Liraglutide was first approved for the treatment of type 2 diabetes in 2010 and initially marketed under the brand name Victoza. Then in 2020, under the brand name Saxenda, it was approved for use in the NHS for weight loss in those with a BMI of 35 or over and a risk of both diabetes and heart disease.
Novo Nordisk wasn’t satisfied and felt it could go further. Indeed Mads Tang-Christensen, head of obesity research at the pharma giant, was getting very excited indeed.
A second version of their weight loss drug called semaglutide not only lasted longer in the bloodstream but was found to cause twice as much weight loss in human trials. Better still, it only needed to be injected once a week. It was given the brand name Wegovy for the treatment of obesity and Ozempic for diabetes.
“The magical barrier” to creating a revolution in the treatment of obesity was a drug that could cause 10-15 per cent weight loss, Tang-Christensen told journalists in 2021. “All of a sudden the magical barrier was gone.” The “holy grail” had been found.
A medicinal mystery
Novo Nordisk has certainly hit the financial jackpot.
In the first six months of this year, the company’s sales increased by 30 per cent to DKK 107.7 billion ($26.24 billion). Sales within their diabetes and obesity care alone accounted for DKK99.0 billion.
And that’s only the beginning. The global market for weight-loss drugs will, by some estimates, be worth US$100 billion ($169.6 billion) a year by the mid-2030s.
Serendipity in the promotion of the new drugs has also played its part.
Although Wegovy is only approved for use in the United Kingdom on the NHS for those with a BMI of 35 or more and Ozempic for the treatment of type 2 diabetes, private clinics across the US and UK got the ball rolling early by prescribing pretty much any GLP-1 meds they could get their hands on to social media-friendly celebrities for aesthetic weight loss.
The subsequent media frenzy has pushed demand through the roof – so much so that the Department of Health in the UK has had to issue edicts restricting its private use.
There remain worries, too, about the drugs themselves. New classes of “miracle drugs” are not unheard of – antibiotics, for instance – but they are rare and can take decades to fully understand.
Like all drugs, the new GLP-1 products have side effects and are not well-tolerated by everyone.
The most common side effects include nausea, diarrhoea, vomiting, constipation, stomach pain, headache, tiredness, dizziness, feeling bloated, belching, gas and heartburn.
More worrying, perhaps, is what may emerge as more data comes in. Possible serious side effects clinicians and regulators are looking out for include thyroid cancer, which was seen in some animal studies.
“Tell your healthcare provider if you get a lump or swelling in your neck, hoarseness, trouble swallowing, or shortness of breath. These may be symptoms of thyroid cancer,” the Novo Nordisk packaging warns.
More mundane is the worry that the new fat busters may end up having the same problem as every fat diet or exercise regime ever created: it works well for a brief and joyous moment but when you stop, the fat piles back on.
Already there are studies showing that when people stop taking GLP-1 medications they start to regain weight. One study found patients who stopped taking semaglutide put back on two-thirds of their body weight within a year.
Carel Le Roux, professor of metabolic medicine at Ulster University and professor of experimental pathology at University College Dublin, does not see the drugs as a “cure” for obesity. “The minute you stop them, the disease relapses. One of the most important questions we now ask our patients is, ‘Are you prepared to take this treatment for the rest of your life?’.”
There is also the not insignificant matter of no one knowing how the new GLP-1 drugs actually work.
Most modern drugs are painstakingly designed to hit a specific and closely defined target. The hunger quashing effect of GLP-1 medications, on the other hand, remains a mystery. They somehow impact the brain but no one knows exactly how.
Dr Drucker, who now consults for Novo Nordisk and other companies, told The New York Times. “They like to say, ‘We were extremely clever in the way we designed the molecule’,” But, he added, “They did get lucky.”
Prof Le Roux believes the new drugs will have a profound impact on health outcomes for many obese people but warns against thinking they will necessarily get you to the weight you want.
We need to be “clear and honest with patients”, he says. “People will go from 100kg to 80kg. Their diabetes is reversed, their heart attack risk is down, yet they are bitterly unhappy because they wanted to be 70kg.”
Evidence from studies into bariatric surgery suggests the new drugs “won’t change body image”, he notes.
“We’re not going to tell patients that this medication is going to make them thin and happy, because that’s not true – we’re going to tell patients it’ll make them healthier and more functional,” he says.