Sat, May-18-24, 01:23
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Plan: Muscle Centric
Stats: 238/153/160
BF:
Progress: 109%
Location: UK
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The lizard, the wonder drug — and how it will change the world
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The lizard, the wonder drug — and how it will change the world
Developed to treat diabetes, Ozempic and Wegovy have revolutionised weight loss — and Denmark’s economy. But the benefits of this medication do not stop there
It hadn’t been easy to source a Gila monster. “You know,” says Daniel Drucker, “you can’t go to a pet store and ask for a poisonous lizard.” The countryside around his office in Toronto University was not overburdened, either, with desert reptiles.
Eventually, in this pre-internet age, he rang round and found a supplier. “Remarkably, a zoo in Utah had a bunch of these and was willing to sell. I was both excited and a bit taken aback.” He had carefully explained to the zoo what he had planned for the Gila monster. The lizard would definitely not be leaving his lab alive. Were they bothered? They were not.
“I had a very simplistic view of zoos as places where you protected the animals.” Not this one. The zoo had just said, fine — that’ll be $250. So, that day in the mid 1990s, the doomed lizard sat there in his laboratory, unaware it was about to become among the most significant lizards in the history of medical science.
Drucker is not a herpetologist. He is not even a zoologist. He is an endocrinologist. In his pre-lizard career his particular achievement had been to identify a hormone our body makes called GLP-1, and work out that, among other things, it promotes insulin production, helping to reduce blood sugar levels. But research can take you to odd and unexpected places — such as the salivary glands of North America’s only venomous lizard. Tipped off by other research, Drucker knew that inside this lizard was something he needed to see: a peptide similar to GLP-1, but also different. He went in to get it.
It would be distorting a nice tale too much to attribute the recovery of the Danish economy, the future salvation of the NHS and, quite possibly, your own future good health to what he found inside that lizard. But in the story of how weight loss drugs changed the world, of how a synthetic hormone became the world’s willpower substitute, the Gila monster will certainly deserve a mention.
GLP-1, the hormone Drucker uncovered, was scientifically fascinating. It had, up until then, proved useless, medically. After Drucker helped work out what GLP-1 did, the hope had been to use it to combat diabetes. Scientists wanted to inject it to help control blood sugar. When you put GLP-1 in the body, though, it just broke down, disappearing in minutes. Which was what made the lizard intriguing.
Other researchers, notably a scientist called John Eng, from the Bronx Veterans Affairs Medical Center in New York, had found it made something that looked like GLP-1 but which wasn’t GLP-1 — and seemed to be longer lasting. What did it do?
“We can’t ask the lizard god why he designed its venom this way,” says Drucker. We can make a guess, though. The thing about a Gila monster is when it eats, it binges. It feeds infrequently, and needs to smooth out its digestion over a period of time.
The thing about a human is, just very recently in our evolution, we also started bingeing — and unlike a lizard, we did not do so infrequently. Humans, too, growing corpulent in our unaccustomed world of plenty, could benefit from a little digestional smoothing.
That was why, since the 1980s, pharmaceutical companies around the world had been seeking a form of GLP-1 that disappeared slowly — that controlled blood sugar over a long period of time. “And it turned out,” says Drucker, “the lizard had won the race.”
That lizard allowed Eng, the researcher, in 2005 to develop exenatide, the first slow-release GLP-1 mimic to find its way to the market. After that proof of concept, others would follow, synthesised in laboratories. One, arrived at by a different route, did better than others. It was called semaglutide. It was made by the Danish pharmaceutical company Novo Nordisk and was marketed as Ozempic.
It was, as Novo had hoped, an effective treatment for type 2 diabetes. Not by making people thinner, but by controlling blood sugar. Then researchers noticed something else. It did make people thinner too — and did so at a rate never before seen with a drug: around 15 per cent over two years. Patients told the scientists that, after taking it, food just wasn’t that big a thing for them. They still ate, they still got hungry. Just not as hungry as before and not as often. The same signals that modulated blood sugar seemed to modulate appetite.
Just getting an effective diabetes drug through clinical trials was the sort of achievement that spiced up a pharmaceutical company’s annual report. In Britain alone more than four million people have type 2 diabetes and they will likely be a source of revenue for the rest of their lives. Diabetes drugs are big business.
Weight, though? Weight was bigger still. Weight was involved in diabetes. It was also involved in heart disease, stroke, dodgy hips, cancer, dementia — and self-image. It was that uniquely profitable mix of a health concern, covered by insurance, and a vanity concern, so in demand. What would it mean to have a drug that defeated it? For already excited pharma execs, there was only one appropriate comparison. This was Viagra levels of excitement.
Three decades after Drucker looked up the best way to transport a venomous lizard in a plane, and a few months after Ozempic was rebranded as Wegovy (remarketed for weight loss and promptly sold out globally), a senior employee at the Novo Nordisk Foundation sat down for lunch with journalists in Copenhagen.
The foundation, a non-profit, gains much of its revenue from its pharmaceutical namesake. This particular employee was responsible for investing that revenue in other companies. He was asked a question. “Are there even enough companies out there”, to put the money in? He smiled, the smile of a contented man. It had been, he conceded, a challenge.
In March this year, Novo Nordisk overtook Tesla to become the world’s 12th biggest company. Its valuation, of about $600 billion, is comfortably higher than the annual GDP of Denmark. On Monday, Rishi Sunak referred to the drug, for the benefits it might bring to patients but also as a sign of the benefits that innovation brings to a country.
“You can see the opportunity in healthcare, giving people longer, healthier lives,” he said. “In Denmark, Novo Nordisk created the Ozempic drug which is not only helping to tackle chronic disease globally but singlehandedly grew Denmark’s economy last year.”
And it doesn’t look like its contribution will cease any time soon. Because there have been other anecdotes, other reports, of people who take the drug for one thing finding themselves being cured of another. This week, a study found that it cuts the risk of heart disease, independent of the weight you also lose. Probably, it’s because it also lowers inflammation. If so, many other patients could benefit.
“We have trials under way in people with kidney disease, Parkinson’s disease, liver disease,” says Drucker. This month, a trial began to see if it reduces — as some users consistently claim — appetite for alcohol, in the same way as it reduces appetite for food.
Then there’s the biggie. “The tallest mountain to climb, the most exciting, is in Alzheimer’s disease.” There is a trial in that too. It too is linked to inflammation. “We will learn over the next two or three years how broadly the benefits extend,” says Drucker.
What started as a diabetes drug became a weight-loss drug, and could become an all-sorts-of-things drug. And, whether we ourselves use it or not, whether we like it or not, it will change all our lives.
This week in Venice, a particular phrase was used a lot. A disconcerting amount, in fact. At the 2024 European Congress on Obesity, Professor Donna Ryan beamed as she announced the results of a trial of 17,000 people taking semaglutide.
“Everybody knows it’s a game-changer in the field of medicine,” she said. Then up stood Professor John Deanfield, from UCL, who had analysed the bit of the study that found people’s heart disease risk dropped, independently of their weight. “This fantastic trial really is a game-changer,” he said.
Later, speaking as the conference came to an end, how did Professor Jason Halford, president of the European Association for the Study of Obesity, sum up what we had learnt? “The arrival of Ozempic,” he said, “has been a game-changer.” And, he said, more game-changers, or at least game-modifiers, are on their way.
Other companies are keen to get in with their versions too, tweaked to be better, to last longer, and, most of all, to be taken as pills rather than injections. Administration is set to get easier, supply more plentiful and, inevitably, costs lower. (A four-week supply of Wegovy at the standard 2.4mg dose is £175.80 in the UK. The price the NHS will pay is not disclosed.)
Given the circumstances, obesity researchers are allowed a little bit of hyperbole. It used to be difficult to get pharmaceutical companies to take an interest in obesity. Now, they cannot get enough of it. What used to be an underfunded and deeply unsexy area of medical research is gaining billions of pounds with the same ease the population gains billions of lbs. Walking round the conference centre in Venice, the logos of the two main players, Novo Nordisk and Eli Lilly, were on display at every turn. (Even the wifi code for the conference was EliLilly). Eli Lilly is the first company to get its own Ozempic-imitator, Mounjaro.
Their excitement, though, is less about the unaccustomed arrival of funding than something even more unaccustomed: hope. For decades, there have been three ways to defeat obesity: get people to exercise more; get people to eat less; stomach surgery. The third approach is extreme and dangerous. The first two approaches are not at all extreme, and in one sense are highly effective. There is a massive evidence base to show diet and exercise work.
There is also a massive evidence base to show people don’t do them. Or rather, they do, then stop. From the 5:2 to the Caveman to the Atkins to the Keto, almost everyone who loses weight on a diet puts it right back on again. Defeating obesity, until now, has been hard, grinding, and — given the statistics on what obesity is doing — deeply depressing.
Today, a quarter of us in Britain are obese. Obesity is the second biggest preventable cause of cancer and costs the NHS £6.5 billion a year. The cost to wider society is ten times that or more. For so long, says Halford, obesity seemed unstoppable. “I worked on some of the drugs 20, 30 years ago. The best we could do was 5 to 10 per cent weight loss, but the drugs would always be withdrawn eventually because of side effects, or they wouldn’t get approved because there wasn’t enough cost-benefit.”
The thing about Ozempic was, it had already been used at scale for diabetes. A lot of the unknowns, including long-term safety, were now known. There have been signals, disputed, that it might raise the risk of thyroid cancer — but on a cost-benefit analysis it didn’t come close to outweighing the positives.
Not everyone will benefit, warns Halford. Some people don’t respond, or react badly. Short-term side effects include nausea and vomiting. Even so, “For some people, these will be the management tool they’d be waiting for their whole lives.” What these drugs do, in effect, is make diets work. They do so by making dieting something you want to do, short-cutting the need for willpower. Should we, though, be short-cutting willpower?
Simon remembers the first time he started taking semaglutide. “It was like a switch.” An article he read described the idea of “food noise”, how there’s this constant rolling noise in our brain: “When is lunch, should I have a snack, what’s for dinner?” He said: “Ozempic is like noise-cancelling headphones. It goes silent. It wasn’t that I found food unpleasant. I had no difference in the taste. I just wasn’t that hungry. I wouldn’t graze on a bunch of crap in the day.”
For all of the record profits made by Novo Nordisk, for all of the talk of a weight loss revolution, most of the people who will one day take these drugs haven’t yet done so. The NHS is still introducing them and there are still shortages around the world. Even when they do arrive properly, it’s unlikely Simon will be eligible. When he started he wasn’t obese, not even close. But, he still wasn’t happy.
“I do lots of Zoom calls. I could see I was chunky. So I thought, well, I could go on a diet.” But he has a PhD in a medical research discipline. He had read the dieting literature. He knew he’d probably fail. He had also read the Ozempic literature. He decided to go for that instead. First, he had to pretend to be obese.
He signed up to a website. Some online pharmacists require you to upload a picture. This one didn’t. It relied on self-reports. “You just underestimate your height a bit, overestimate your weight a bit, and they’re only too happy to sell you their products. Presumably there’s a doctor prescribing it, but I’ve never talked to anyone. It’s all filling in forms on the internet: ‘I do solemnly swear I’m fat.’”
When he started, he lost 10kg in a month. When he stopped, he put it back on again. So, like a yo-yo dieter but without the effort or guilt, he restarted. Sometimes he is on, sometimes he is off. “I lazily now think to myself, if I eat a bunch of crap now I can probably go back on Ozempic. I know that’s not great. But I’m busy. I’ve lost the internal impetus to go on a diet. Maybe in the long term that’s bad. Maybe in the long term we’ll have even better drugs to take, so what’s the big deal?”
Simon (not his real name) is, of course, the embodiment of the public health nightmare around these drugs. He’s taking a medicine as a lifestyle choice. To get it, he’s bypassing traditional medical gatekeepers. What if he was doing it because he had an eating disorder? Worse, in some sense he is bypassing traditional morality. Food-and-fatness is so hard to talk about because, in the modern world, food does not merely exist on a nutritional spectrum but a moral one. From virtuous to vice, from pine nuts to doughnuts, soy beans to jelly beans.
Simon should be, metaphorically and literally, eating his greens. Yet instead of making sensible choices, eating healthily and exercising, he just injects himself. He has substituted pharmacy for celery. And it looks like many millions of us will follow: voluntarily injecting one substance into our veins to counteract another we put in our mouths. It is entirely possible that he, and many of us, will be doing so for decades. It’s not ideal. To which Simon says, neither is the world. “If people who are obese can lose 10 per cent of their weight with little side effects, it’s an incredible, amazing thing. It’s just going to free up people from this constant background noise of food desire.”
The Venice obesity conference has packed up. The posters have been dismantled, the Novo Nordisk sponsorship removed. The delegates have taken their water taxis across the lagoon, to the airport. There, perhaps allowing themselves an extra croissant, they have flown home — to a world that doesn’t yet know quite how much it is going to change. As scientists who have spent their lives working to combat obesity, this is an exciting time. As scientists who know just how big that change will be — medically, societally, economically — it would be odd to not be just a little trepidatious.
“These drugs are very, very powerful,” says Halford. “That’s not an endorsement, it’s actually a warning.”
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https://www.thetimes.co.uk/article/...world-zjlxj6zc6 |
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The ease with which someone not even close to obese can obtain these drugs, to use them to mimic an eating disorder, decide food does not exist on a nutritional spectrum, but a moral one. A woman who "doesn’t like meat" can enjoy jelly beans and smoothies until the lack of protein destroys her muscles and bones. A warning indeed.
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