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The mystery behind new obesity drugs

The new weight loss drugs taking the world by storm are game changers, say experts, and while they are proving hugely successful, no one is 100% certain of why they work – only that they do.

Although it’s early days, the consensus is that nothing like these drugs – Ozempic, Wegovy, Mounjaro and more that may soon be hitting the market – has existed before.

Obesity affects nearly 42% of American adults, but mounds of research into potential medical treatments for the condition has led to failures. Companies lost interest, with many executives thinking, like most doctors and many of the public, that obesity was a moral failing, not a chronic disease.

The New York Times reports that despite other drugs being discovered in recent decades for diseases like cancer, heart disease and Alzheimer’s, through a logical process leading to clear targets for drug designers, the path to the obesity drugs was different.

In fact, much about them remains shrouded in mystery. Researchers accidentally discovered that exposing the brain to a natural hormone at levels never seen in nature elicited weight loss. They really don’t know why, or if, the drugs may have any long-term side effects.

Although they seem safe, obesity medicine specialists call for caution because – like drugs for high cholesterol levels or high blood pressure – they must be taken indefinitely or patients will regain the weight they lost.

The National Institute of Diabetes and Digestive and Kidney Diseases warns that patients would have to be monitored for rare but serious side effects, especially as scientists still don’t know exactly why the drugs work.

The drugs can cause transient nausea and diarrhoea in some. But their main effect is what matters. Patients lose constant cravings for food, are satisfied with much smaller portions. They lose weight because they naturally eat less – not because they burn more calories.

And results from a recent clinical trial indicate that Wegovy can do more than help people lose weight. It also can protect against cardiac complications, like heart attacks and strokes.

But why that happens remains poorly understood.

“Companies don’t like the term trial and error,” said Dr Daniel Drucker, who studies diabetes and obesity at Toronto’s Lunenfeld-Tanenbaum Research Institute. “They like to say, ‘We were extremely clever in how we designed the molecule.”

But, he said, “They did get lucky.”

In the 1970s, obesity treatments were the last thing on Dr Joel Habener’s mind. An academic endocrinologist starting his own lab at Massachusetts General Hospital, he was looking for a challenging research project.

He chose diabetes. The disease is caused by high blood sugar levels and is typically treated with injections of insulin. But an insulin injection drops the blood sugar, even if levels are already low. Patients have to carefully plan injections because very low blood sugar levels can result in confusion, shakiness and even a loss of consciousness.

Two other hormones also play a role in regulating blood sugar – somatostatin and glucagon – and little was known then about how they are produced. Habener decided to study the genes that direct cells to make glucagon.

In the early 1980s, he discovered a hormone, GLP-1, that exquisitely regulates blood sugar. It acts only on insulin-producing cells of the pancreas, and only when blood sugar rises too high.

Another researcher, Dr Jens Juul Holst at the University of Copenhagen, independently stumbled on the same discovery.

But there was a problem: when GLP-1 was injected, it vanished before reaching the pancreas. It needed to last longer.

Drucker, who led the GLP-1 discovery efforts on Habener’s team, laboured for years on the challenge. It was, he said, “a pretty lonely field”.

Success came from a chance discovery not appreciated at the time.

In 1990, John Eng, a researcher at the Veterans Affairs medical centre in New York, was looking for interesting new hormones in nature that might be useful for medications in people.

He was drawn to the venomous Gila monster – a giant lizard – when he found it kept its blood sugar levels stable if it did not have much to eat. So he decided to search for chemicals in its saliva, and found a variant of GLP-1 that lasted longer.

The VA declined to patent the hormone, so he patented it himself and licensed it to Amylin Pharmaceuticals, which began testing it as a diabetes drug. The drug, exenatide or Byetta, went on sale in the US in 2005.

But Byetta had to be injected twice daily, a disincentive to its use. Drug company chemists sought even longer-lasting versions of GLP-1.

At Novo Nordisk, chemists began by using a well-known trick. They loosely attached GLP-1 to a blood protein that kept it stable enough to remain in circulation for at least 24 hours. But when GLP-1 slips off the protein, enzymes in the blood quickly degrade it. So chemists had to alter the hormone’s building blocks – a chain of amino acids – to find a more durable variant.

After trial and error, Novo Nordisk produced liraglutide, a GLP-1 drug that lasted long enough for daily injections, and named it Victoza. The FDA approved it for diabetes in 2010.

An unexpected side effect was slight weight loss.

Obesity had become a dead end in the industry. No drug worked very well, and every one that led to even modest weight loss had serious side effects.

In the late 1990s, there was brief hope when Dr Jeffrey Friedman at Rockefeller University found a hormone that told the brain how much fat was on the body. Lab mice genetically modified to have none of the hormone ate voraciously and grew enormously fat. Researchers could fine-tune an animal’s weight by altering how much of the hormone it got.

Friedman named the hormone leptin. Amgen bought the rights to leptin and, in 1996, began testing it in people. They did not lose weight.

Dr Matthias Tschöp at Helmholtz Munich in Germany described the frustration. He left academia three decades ago to work at Eli Lilly, excited by leptin, determined to use science to find a weight loss drug.

When leptin failed, he tried a different gut hormone, ghrelin, whose effects were the opposite of leptin’s. The more ghrelin an animal had, the more it ate. Perhaps a drug that blocked ghrelin would make people lose weight.

“Again, it wasn’t that simple,” said Tschöp, who left Lilly in 2002.

The body has so many redundant circuits of interacting nerve impulses and hormones to control weight that tweaking one simply did not make a difference.

Another obstacle was the lack of industry interest. Obesity was seen as a behavioural problem, not a disease.

Starving rats

Novo Nordisk, which today has 45.7% of the global insulin market, thought of itself as a diabetes company. Period.

But one company scientist, Lotte Bjerre Knudsen, was fascinated by results from studies with liraglutide, the GLP-1 drug that lasted long enough to be injected once-daily.

In the early 1990s, Novo researchers, studying rats implanted with tumours of pancreas cells that produced copious amounts of glucagon and GLP-1, noticed the animals had nearly stopped eating.

Knudsen said: “We knew there was something in some of these peptides that was important for appetite regulation.”

Other studies found rats lost their appetites if GLP-1 were injected into their brains. Human subjects who got an intravenous drip of GLP-1 ate 12% less than those who got a placebo.

So why not study liraglutide as both a diabetes drug and an obesity drug, Knudsen asked.

She faced resistance, partly because some company executives believed obesity resulted from a lack of willpower.

Additionally, the company’s business division struggled with the idea of promoting liraglutide for two distinct purposes.

“It’s either diabetes or weight loss,” she recalled.

Finally, after liraglutide was approved in 2010 for diabetes, Knudsen’s proposal to study the drug for weight loss progressed. After clinical trials, the FDA approved it as Saxenda for obesity in 2014. The dose was about twice the diabetes dose. Patients lost about 5% of their weight, a modest amount.

But Dr Martin Holst Lange, executive vice-president of development at Novo Nordisk, said it was at least as good as other weight-loss drugs, without side effects like heart attacks, strokes and death.

However, Novo Nordisk continued to focus on diabetes, seeking ways to make a longer-lasting GLP-1 so patients would not need daily injections.

The result was a different GLP-1 drug, semaglutide, that lasted long enough that patients had to inject themselves only once a week. It was approved in 2017 and is now marketed as Ozempic.

It also caused weight loss – 15%, three times the loss with Saxenda, the once-a-day drug, although there was no obvious reason why. Suddenly, the company had what looked like a revolutionary treatment for obesity.

But Novo Nordisk could not market Ozempic for weight loss without FDA approval for that specific use.

In 2018, a year after Ozempic’s approval for diabetes, the company started a clinical trial. In 2021, Novo Nordisk got approval from to market the same drug for obesity with a weekly injection at a higher maximum dose. It named the drug Wegovy.

But even before Wegovy’s approval, people had begun taking Ozempic for obesity. Novo Nordisk, in Ozempic commercials, mentioned that many taking it lost weight.

Hinting was more than enough.

By 2021, fed by social media, a general frenzy for weight loss and aggressive marketing by Novo Nordisk, the news that Ozempic made people lose weight had reached a tipping point.

Ozempic was on everyone’s lips, even though Wegovy was the drug approved that year for obesity.

But Wegovy caught up.

In July, US doctors wrote about 94 000 weekly prescriptions for Wegovy compared with about 62 000 a week for Ozempic.

Wegovy is in such demand, though, that the company is unable to make enough, so for now, while it ramps up production, the drug is sold only in Norway, Denmark, Germany and the US, where shortages are frequent.

More medicines, more mysteries

Why Ozempic and Wegovy are much more effective than Saxenda remains a mystery.

The drugs, said Randy Seeley, an obesity researcher at the University of Michigan, are not correcting for a lack of GLP-1 in the body – people with obesity make plenty of GLP-1. Instead, they are exposing the brain to hormone levels never seen in nature. Patients on Wegovy get five times the amount of GLP-1 they would produce in response to say a Christmas dinner.

And, he added, in the brain, “the drugs go to unusual places”. They are not just going to areas thought to control overeating.

“If you were designing a drug, you would say that’s a bad idea,” said Seeley. Drug designers try for precision – a drug should go only to the cells where it is needed.

GLP-1, because of its chemical structure, should not even get into some areas of the brain where it slips in.

“Nobody understands that,” Seeley said.

More to come

Lilly’s diabetes drug, tirzepatide or Mounjaro, is expected to get FDA approval for obesity this year. It hooks GLP-1 to another gut hormone, GIP.

GIP, on its own, produces, at best, a modest weight loss. But the two-hormone combination can allow people to lose a median of about 20% of their weight.

“No one fully understands why,” Drucker said.

Lilly has another drug, retatrutide, that, while still in early testing, elicited a median 24% weight loss.

Amgen’s experimental drug, AMG 133, is even more of a puzzle. It hooks GLP-1 to a molecule that blocks GIP.

There is no logical explanation for why seemingly opposite approaches would work.

Researchers continue to marvel at these biochemical mysteries. But doctors and patients have their own takeaway: the drugs work and people lose weight.

 

The New York Times article – We know where these drugs come from but not why they work (Restricted access)

 

See more from MedicalBrief archives:

 

Weight loss drug trial suggests significant heart benefit

 

Global race heats up for weight-loss drug pill

 

Maintenance semaglutide injections led to continued weight loss — STEP 4

 

Obesity drugs may be added

 

Proposed paradigm shift in type 2 diabetes treatment to focus on weight loss

 

Regulatory approval sought for ‘gamechanger’ obesity drug

 

 

 

 

 

 

 

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