We know where new weight loss drugs come from, but not why they work (2023)

We know where new weight loss drugs come from, but not why they work (1)

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The empty auditoriums, Gila monsters, drug-resistant pharmaceutical executives, and mysteries that led to Ozempic and other drugs that could change the way society thinks about obesity.

Credit...Ryan David Brown for the New York Times

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TypeGina Kolata

For more than 25 years, Gina Kolata has reported on obesity research, which until recently found that medications and changes in diet or exercise had little lasting effect on weight.

Every now and then a drug comes along that has the potential to change the world. Medical experts say the latest drugs to treat obesity -- Ozempic, Wegovy, Mounjaro and more -- offer that opportunity and could hit the market soon.

It's still early days, but there hasn't been anything quite like these drugs yet.

"Game changers," says Jonathan Engel, historian of medicine and health policy at Baruch College in New York.

related to obesityalmost 42 percentof American adults, and yet, said Dr. Engel, "We were powerless." Research into possible medical treatments for the condition has met with failure. Drug companies lost interest and many executives - like most doctors and members of the public - thought that obesity was a moral flaw and not a chronic disease.

While other drugs discovered in recent decades for diseases like cancer, heart disease and Alzheimer's have been found through a logical process that led to clear goals for drug developers, the path to obesity drugs was not like that. In fact, much about the drugs remains a mystery. Researchers accidentally discovered that exposing the brain to a natural hormone that never occurs in nature leads to weight loss. They really don't know why and if the drugs can have long-term side effects.

"Everyone would say that there has to be some logical explanation or sequence that allows predictions about what's going to work," says Dr. David D'Alessio, chief of endocrinology at Duke, who consults Eli Lilly, among others. "Not yet."

Although the drugs appear to be safe, obesity medicine specialists urge caution because anti-obesity drugs — like drugs for high cholesterol or high blood pressure — must be taken indefinitely or patients lose the weight they've lost. Get back.

Dr. Susan Yanovski, co-director of the Office of Obesity Research at the National Institute of Diabetes and Digestive and Kidney Diseases, warned that patients should be monitored for rare but serious side effects, especially since scientists still don't know why the drugs work .

However, she added that obesity itself is linked to a long list of serious medical problems, including diabetes, liver disease, heart disease, cancer, sleep apnea and joint pain.

(Video) How do the new weight loss drugs work?

"You have to consider the serious illnesses and increased mortality that obese people suffer," she said.

For some, the drugs can cause temporary nausea and diarrhea. But their main effect is what matters. Patients say that they constantly lose the desire to eat. They settle for much smaller portions. They lose weight because they naturally eat less - not because they burn more calories.

InResults of a clinical studyDrugs reported last week suggest that Wegovy may do more than help people lose weight — it may also protect against heart complications like heart attacks and strokes.

But why this happens is still poorly understood.

"Companies don't like the concept of trial and error," says Dr. Daniel Drucker, who studies diabetes and obesity at the Lunenfeld-Tanenbaum Research Institute in Toronto and advises Novo Nordisk and other companies. "They like to say, 'We were extremely clever in designing the molecule,'" said Dr. Printer.

But he said, "You were lucky."

A lonely origin story

In the 1970s, treating obesity was the last thing Dr. Joel habener thought. He was an academic endocrinologist starting his own laboratory at Massachusetts General Hospital looking for a challenging but doable research project.

He chose diabetes. The disease is caused by high blood sugar levels and is usually treated with injections of insulin, a hormone secreted by the pancreas that helps cells store sugar. But an insulin shot lowers blood sugar levels, even when the level is already low. Patients should plan their injections carefully, as very low blood sugar levels can cause confusion, tremors, and even unconsciousness.

Two other hormones also play a role in regulating blood sugar - somatostatin and glucagon - and little was known about their origins at the time. Dr. habener decided to study the genes that tell cells to produce glucagon.

It was a real surprise for him. He's in his early eightiesdiscovered a hormoneGLP-1, an excellent blood sugar regulator. It only acts on the insulin-producing cells in the pancreas and only when blood sugar gets too high.

In theory, it was perfect as a targeted treatment to replace sledgehammer insulin injections.

Another researcher, Dr. Jens Juul Holst, from the University of Copenhagen, stumbled independentlythe same discovery.

But there was a problem: when injected, GLP-1 disappeared before it reached the pancreas. It had to last longer.

DR. Drucker, who introduced the GLP-1 discovery efforts in Dr. directed. habener has been working on the challenge for years. It's, he said, "a pretty lonely field."

When he applied to speak at the Endocrine Society, he was scheduled at the very end of the last day of annual meetings.

"Everyone had gone to the airport - people were cleaning up the exhibits," he said.

From the late 1980s to the early 1990s, he spoke to almost empty halls.

The sample of Dr. scary

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Its success was based on an accidental discovery that was not appreciated at the time.

In 1990, John Eng, a researcher at Veterans Affairs Medical Center in the Bronx, said,looking for interesting new hormonesin nature that can be useful for medicine in humans.

He was attracted to the poisonous Gila monster when he somehow discovered itkept his blood sugar stablewhen there wasn't much to eat, according to a report by the National Institutes of Health, which funded his work. So decided Dr. Looking for chemicals in lizards' saliva is scary. He found a variant of GLP-1 that lasted longer.

DR. Eng told The New York Times in 2002 that the U.A. hadrejectedto patent the hormone. So dr Eng patented it himself and licensed it to Amylin Pharmaceuticals, who began testing it as a diabetes drug. The drug Exenatide, or Byetta, was launched in the United States in 2005.

(Video) WeGovy, Ozempic or Mounjaro? How a new wave of weight loss drugs could transform the diet industry

But Byetta had to be injected twice a day, which was a real incentive to use it. Drug company chemists have been looking for even more sustainable versions of GLP-1.

At Novo Nordisk, the chemists started with a well-known trick. They loosely attached GLP-1 to a blood protein that kept it stable enough to circulate for at least 24 hours. However, when GLP-1 slips off the protein, it is quickly broken down by enzymes in the blood. So chemists had to change the building blocks of the hormone — a chain of amino acids — to find a more sustainable variant.

After trying hardNovo Nordisk produced liraglutide, a GLP-1 drug that worked long enough for daily injections. They called it Victoza and the F.D.A. approved it for the treatment of diabetes in 2010.

It had an unexpected side effect: slight weight loss.

A dark story

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Obesity had become a dead end in the pharmaceutical industry. No drug tried worked very well, and every drug that caused even a small amount of weight loss had serious side effects.

There was hope for a fleeting moment in the late 1990s when Dr. Jeffrey Friedman of Rockefeller University in New York found a hormone that tells the brain how much fat is in the body. Laboratory mice genetically engineered to lack hormones ate greedily and became very fat. Researchers could optimize an animal's weight by changing the amount of the hormone it receives.

DR. Friedman called the hormone leptin. Amgen bought the rights to leptin and began testing it in humans in 1996. They didn't fall down.

Dr. Matthias Tschöp from Helmholtz Munich in Germany talks about the frustration. He left academia three decades ago to work for Eli Lilly in Indianapolis, passionate about leptin and determined to use science to find a weight loss drug.

"I was so inspired," said Dr. chop

When leptin failed, he tried another gut hormone, ghrelin, which had the opposite effect of leptin. The more ghrelin an animal had, the more it would eat. Maybe a drug that blocks ghrelin would make people lose weight.

"Once again, it wasn't that easy," said Dr. Tschöp, who left Lilly in 2002.

The body has so much excess circuitry of interacting nerve impulses and hormones used to control weight that adjusting just didn't make a difference.

And there was another obstacle, noted Dr. Tschöp's former colleague at Lilly, Dr. Richard Di Marchi, who was also an executive at Novo Nordisk.

"There was little interest from industry," said Dr. Di Marchi, now at Indiana University. “Obesity was not considered a disease. It was seen as a behavioral problem.”

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Starving Rats

Novo Nordisk, which now accounts for 45.7 percentglobal insulin market, saw itself as a diabetes company. Period of time.

But one corporate scientist, Lotte Bjerre Knudsen, couldn't stop pondering the tantalizing results of studies on liraglutide, the GLP-1 drug that worked long enough to be injected just once a day.

In the early 1990s, Novo researchers investigatedRats implanted with tumorsStudies on pancreatic cells, which produce large amounts of glucagon and GLP-1, found that the animals had almost stopped eating.

"These rats starved to death," said Dr. knudsena video seriespublished by the Novo Nordisk Foundation. "So we knew that some of these peptides contained something that was really important in appetite regulation."

Other studies by academic researchers found that rats lost their appetite when GLP-1 was injected into their brains. Subjects who received an intravenous infusion of GLP-1 ate 12 percent less at the lunch buffet than those who received a placebo.

So why not explore liraglutide as both a diabetes drug and an anti-obesity drug, says Dr. knudsen

(Video) Promising new weight loss medication in short supply and often not covered by insurance | 60 Minutes

It met with resistance, in part because some business leaders believed obesity was the result of a lack of willpower. One of the pioneers of GLP-1 research for weight loss, Mads Krogsgaard Thomsen, the current CEO of the Novo Nordisk Foundation and the company's former chief scientific officer, said in the video released by the foundation that he "half of my C.E.O. for" be a year where obesity isn't just a lifestyle."

Dr. Knudsen also pointed out that the company's division struggled with the idea of ​​promoting liraglutide for two different purposes.

"Either it's diabetes or it's weight loss," she recallsBasis-Videoserie.

Finally, after liraglutide was approved in 2010for diabetes, the suggestion of Dr. Knudsen will investigate the drug for weight loss in the future. After clinical studies, the F.D.A. approved it as Saxenda for obesity in 2014. The dose was about twice as highder Diabetes-Dosis.The patients lost about 5 percent of their weight, a modest amount.

But dr Martin Holst Lange, executive vice president of development at Novo Nordisk, said in a telephone interview that it was at least as good as other weight loss drugs and without side effects such as heart attacks, strokes and death.

"We were super excited," he said.

Beyond Diabetes

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Despite the advances in weight loss, Novo Nordisk remained focused on diabetes and trying to find ways to sustain GLP-1 longer so patients didn't have to inject themselves every day.

The result was another GLP-1 drug, semaglutide, that worked for so long that patients only had to afford an injection once a week. It was approved in 2017 and is now marketed as Ozempic.

It alsocauses weight loss- 15 percent, which is three times the loss of Saxenda, the once-daily drug, although there was no clear reason for that. Suddenly, the company had what appeared to be a revolutionary treatment for obesity.

But Novo Nordisk couldn't market Ozempic for weight loss without the FDA. Permission for this specific use.

In 2018, a year after Ozempic was approved for diabetes, the company went livea clinical study. In 2021, Novo Nordisk received F.D.A. to market the same anti-obesity drug with a weekly injection at a higher maximum dose. It called the drug Wegovy.

But even before Wegovy was approved, people started using Ozempic for obesity. Novo Nordisk, in its Ozempic commercials,mentioned that many who used it lost weight.

It turned out that hints were more than sufficient. Soon, said Dr. Jeffrey Mechanick, an endocrinologist at the Icahn School of Medicine at Mount Sinai, the patients clung to Ozempic. Doctors prescribed it off-label to those who didn't have diabetes.

"There was a bit of gaming," said Dr. Mechanick, while some doctors coded patients as prediabetic to make it easier for them to get insurance coverage.

By 2021, fueled by social media, a general weight loss craze andaggressive marketing by Novo Nordisk, the news that Ozempic is helping people lose weight has reached a tipping point, said Dr. Caroline Apovian, co-director of the Center for Weight Management and Wellness at Brigham and Women's Hospital and consultant to Novo Nordisk and other companies. Ozempic was the talk of the town despite Wegovy being the approved anti-obesity drug that year.

But Wegovy caught up.

In July, US physicians were writing about 94,000 prescriptions per week for Wegovy, compared to about 62,000 per week for Ozempic. However, the demand for Wegovy is so great that the company cannot earn enough, said spokeswoman Ambre James-Brown. While the company ramps up production, it will initially only sell the drug in Norway, Denmark, Germany and the United States. And in these countries there are regular bottlenecks in the pharmacies.

and dr Like many other specialists in obesity medicine, Apovian is now fully booked for patients a year in advance.

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More drugs, more secrets

The reason why Ozempic and Wegovy are so much more potent than Saxenda remains a mystery. Why would a once-a-week injection result in much greater weight loss than a once-a-day injection?

The drugs, said Randy Seeley, an obesity researcher at the University of Michigan, don't make up for the GLP-1 deficiency in the body — obese people produce a lot of GLP-1. Instead, the drugs expose the brain to hormone levels that never occur naturally. Patients taking Wegovy get five times the amount of GLP-1 they would produce in response to a Thanksgiving dinner, said Dr. seeley

And, he added, "the drugs are going to unusual places in the brain." They're not just invading areas thought to control overeating.

"If you were developing a drug, you would say that's a bad idea," says Dr. Seeley, who has advised for Novo Nordisk and Eli Lilly, among others. Drug developers strive for precision - a drug should only get into the cells where it is needed.

Because of its chemical structure, GLP-1 shouldn't even get to certain parts of the brain where it slips in.

(Video) New weight loss drug could break sales records

"Nobody understands that," said Dr. seeley

However, Wegovy is only the beginning.

Lilly's diabetes drug tirzepatide, or mounjaro, is expected to pass the F.D.A. will defeat. Approval for obesity this year. It links GLP-1 to another gut hormone, GIP.

GIP alone results in moderate weight loss at best. However, by combining two hormones, people can lose about 20 percent of their weight on average.

"No one quite understands why," said Dr. Printer.

Lilly has another drug, Retatrutid, which, while still in early testing, appears to produce a mean24 percent weight loss.

Amgen's experimental drug, AMG 133, could be even better, but it's even more of a mystery. It binds GLP-1 to a molecule that blocks GIP.

There is no logical explanation as to why seemingly contradictory approaches would work.

Researchers continue to wonder about these biochemical mysteries. But doctors and patients have their own insight: the drugs work. people lose weight. The constant chatter in their brains about eating and eating is gone.

And while the stigma of obesity and the cultural stereotype that obese people don't try hard enough to lose weight remain, some experts are optimistic. Now, they say, patients no longer have to blame themselves or feel like a failure when they can't lose weight.

"The era of 'just get out, diet and exercise' is over now," said Dr. Rudolph Leibel, professor of diabetes research at Columbia University's Irving Medical Center. "Now doctors have tools to fight obesity."

A correction has been made

17. August 2023

:

A previous version of this article misrepresented the name of a drug approved for diabetes in 2010. It was Victoza, not Saxenda. It also misattributed a quote from a video about trying to convince a CEO that obesity isn't just a lifestyle disorder. It was said by Mads Krogsgaard Thomsen, not Lars Rebien Sorensen.

How we handle corrections

Gina Kolatawrites about science and medicine. A two-time Pulitzer Prize finalist, she is the author of six books, including Mercies in Disguise: A Story of Hope, a Family's Genetic Destiny and The Science That Saved Them. More about Gina Kolata

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(Video) What happens to your body when you stop taking weight-loss drugs l GMA

FAQs

How effective are the new weight loss drugs? ›

A Statistic That Sums It Up: 15 percent. That's the median weight loss experienced by people who take Wegovy, a drug from Novo Nordisk. The new drugs are the first truly effective obesity medicines. They act by stemming people's appetites and cravings for food.

What is the new weight loss pill called? ›

The bottom line

Tirzepatide may be next in line to obtain FDA approval, but retatrutide, oral semaglutide, and orforglipron are also making waves. Medications like Wegovy (semaglutide), Saxenda (liraglutide), and Contrave (naltrexone / bupropion) are already approved and available as weight loss treatments.

Are there any weight loss pills that actually work? ›

Prescription weight loss medications, including GLP-1 agonists, orlistat, and setmelanotide, may be effective for some people. But other lifestyle changes are still necessary for long-term success.

What are the problems with new weight loss drugs? ›

Symptoms of delayed gastric emptying, nausea and vomiting are listed as side effects,” the statement said. Gastroparesis can have many causes, including diabetes, which is a reason many people are on these drugs in the first place. Women are known to be at higher risk for the condition, too.

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