Credit...Ryan David Brown for The New York Times
go throughGina Colata
Gina Kolata has been reporting on obesity research for 25 years, until recently it was discovered that drugs and changes in diet or exercise had little lasting effect on weight.
Every once in a while a drug emerges that has the potential to change the world. The latest drugs to offer this possibility are new treatments for obesity -- Ozempic, Wegovy, Mounjaro and others -- that may hit the market soon, medical experts say.
It's still early days, but no similar drug existed before.
"A game changer," said Jonathan Engel, a historian of medicine and health care policy at Baruch College in New York.
Obesity effectsNearly 42%"There's been nothing we can do about it," Dr. Engel said. Research on potential treatments for the disease has failed. Pharmaceutical companies lost interest, and many executives, like most doctors and the public, viewed obesity as a moral lapse rather than a chronic disease.
While other drugs discovered in recent decades to treat conditions such as cancer, heart disease and Alzheimer's disease were discovered through a logical process that provided drug designers with clear targets, the same was not the case for obesity drugs . In fact, much about these drugs remains shrouded in mystery. Researchers have discovered by accident that exposing the brain to natural hormone levels never seen in nature leads to weight loss. They don't really know why, or if there may be any long-term side effects from these drugs.
"Everyone wants to say there has to be some sort of logical explanation or sequence to be able to predict what's going to happen," said Dr. work." "Not yet."
Although the drugs appear to be safe, obesity medicine experts have called for caution because, like drugs for high cholesterol levels or high blood pressure, obesity drugs must be taken indefinitely or patients will regain the weight they lose.
Dr. Susan Yanofsky, co-director of the Office of Obesity Research at the National Institute of Diabetes and Digestive and Kidney Diseases, cautioned that patients must be monitored for rare but serious side effects, especially because scientists still don't know why the drugs work.
But, she added, obesity itself has been linked to a host of serious health problems, including diabetes, liver disease, heart disease, cancer, sleep apnea and joint pain.
"You have to keep in mind the serious disease and increased mortality that obese people suffer from," she said.
These medicines may cause brief nausea and diarrhea in some people. But their primary role is what matters. Patients report that they lose their constant cravings for food. They found themselves satisfied with much smaller portions. They lose weight because they naturally eat less, not because they burn more calories.
andclinical trial resultsReports last week suggested that Wegovy could not only help people lose weight, but also prevent heart complications such as heart attacks and strokes.
But why this happens is still poorly understood.
"Companies don't like the term 'trial and error,'" said Dr. Daniel Drucker, who studies diabetes and obesity at the Lunenfeld-Tanenbaum Institute in Toronto and advises Novo Nordisk and others. "They like to say, 'We're very clever in the way we design molecules,' says Dr Drucker.
But, he said, "they did get lucky."
lonely origin story
In the 1970s, Dr. Joel Habener wasn't even thinking about obesity treatment. He is an academic endocrinologist who established his own laboratory at Massachusetts General Hospital and looked for challenging but doable research projects.
He chose diabetes. The disease is caused by high blood sugar and is usually treated with injections of insulin, a hormone secreted by the pancreas that helps cells store sugar. But insulin injections can cause blood sugar to plummet, even when blood sugar levels are already low. Patients must plan their injections carefully, as extremely low blood sugar levels can cause confusion, tremors, and even loss of consciousness.
Two other hormones -- somatostatin and glucagon -- also play a role in regulating blood sugar, but how they were produced was poorly understood at the time. Dr. Habner decided to study the gene that instructs cells to produce glucagon.
This took him by surprise. In the early 1980s, heA hormone was discovered,GLP-1, finely regulates blood sugar. It only acts on the insulin-producing cells in the pancreas, and only when blood sugar rises too high.
In theory, it is the perfect targeted therapy alternative to sledgehammer insulin injections.
Another researcher, Dr. Jens Juul Holst of the University of Copenhagen, independently and accidentally discoveredsame discovery。
But there's a problem: When GLP-1 is injected, it disappears before it reaches the pancreas. It needs to last longer.
Dr. Drucker, who led the GLP-1 discovery efforts of Dr. Habener's team, has been working on this challenge for several years. It's "a pretty lonely field," he said.
When he applied to speak at the Endocrine Society, he found himself scheduled for the last day of the annual meeting.
"Everyone's gone to the airport — people are removing exhibits," he said.
From the late 1980s to the early 1990s, he spoke to virtually empty auditoriums.
dr enger's monster
Success came from serendipitous discoveries that were not appreciated at the time.
In 1990, John Eng, a researcher at the Bronx Veterans Affairs Medical CenterFind interesting new hormonesMay be useful in human medicine in nature.
He was drawn to the venomous Gila monster when he learned that monsters somehow existed.keep blood sugar levels stableThat's when it doesn't have much to eat, according to a report from the National Institutes of Health that funded his research. So Dr Engel decided to look for the chemical in the lizard's saliva. He found a longer-lasting variant of GLP-1.
In 2002, Dr. Eng told The New York Times that the V.A. hadrejectApply for a patent for hormones. So Dr. Eng patented it himself and licensed it to Amylin Pharmaceuticals, which began testing it as a diabetes drug. The drug, exenatide, or Byetta, became available in the United States in 2005.
But Byetta has to be injected twice a day, which is a real hindrance to its use. Chemists at pharmaceutical companies seek longer-lasting versions of GLP-1.
At Novo Nordisk, chemists first used a well-known trick. They attached GLP-1 loosely to a blood protein, making it stable enough to remain in circulation for at least 24 hours. But when GLP-1 falls off the protein, enzymes in the blood quickly degrade it. So chemists have to change the hormone's building blocks -- chains of amino acids -- to find longer-lasting variants.
After tedious trial and error,Novo Nordisk produces liraglutide, a GLP-1 drug that lasts long enough for daily injections. They named it Victoza, and the F.D.A. approved it as a treatment for diabetes in 2010.
It had an unexpected side effect: slight weight loss.
a bleak history
Obesity has become a dead end for the pharmaceutical industry. None of the drugs tried worked very well, and every drug that produced even modest weight loss had serious side effects.
For a brief moment in the late 1990s, Dr. Jeffrey Friedman of The Rockefeller University in New York discovered a hormone that tells the brain how much body fat there is, giving people hope. Laboratory mice genetically engineered to be free of any hormones eat voraciously and grow fat. Researchers can fine-tune an animal's weight by changing the amount of hormones in the animal's body.
Dr. Friedman named this hormone leptin. Amgen bought the rights to leptin and began testing it in humans in 1996. They didn't lose weight.
Dr. Matthias Tschöp of Helmholtz Munich, Germany, talks about his frustrations. He left academia three decades ago to work for Eli Lilly in Indianapolis, excited about leptin and determined to use science to find weight-loss drugs.
"I was inspired," says Dr. Tschöp.
When leptin failed, he tried another gut hormone, ghrelin, which has the opposite effect of leptin. The more ghrelin an animal has, the more it eats. Maybe drugs that block ghrelin can make people lose weight.
"Again, it's not that simple," said Dr. Tschöp, who left Eli Lilly in 2002.
The body has so many redundant circuits of nerve impulses and hormonal interactions to control weight that tweaking one of them will have no effect at all.
Dr. Tschöp's former colleague at Eli Lilly, Dr. Richard Di Marchi, a Novo Nordisk executive, points out that there is another hurdle.
"There's not a lot of interest from the industry," said Dr. Di March, now at Indiana University. "Obesity is not considered a disease. It's considered a behavioral problem."
Novo Nordisk currently owns 45.7%Global Insulin Market, considers itself a diabetes company. period.
But one of the company's scientists, Lotte Bjerre Knudsen, couldn't stop thinking about the tantalizing results of a study of liraglutide, a GLP-1 drug that lasted long enough to require just a once-daily injection.
In the early 1990s, Novo researchers studiedmice implanted with tumorsPancreatic cells that produce large amounts of glucagon and GLP-1 noted that the animals almost stopped eating.
"The rats, they starved themselves to death," Dr. Knudsen said in the book.video seriesPublished by the Novo Nordisk Foundation. "So we know that something in some of these peptides is really important for appetite regulation."
Other studies by academic researchers have found that when GLP-1 is injected into the brains of mice, the mice lose their appetite. Human subjects who received an IV infusion of GLP-1 ate 12% less at the lunch buffet than those who received a placebo.
So why not study liraglutide as a diabetes drug and an obesity drug? asked Dr. Knutson.
She faced resistance in part because some corporate executives believed obesity was caused by a lack of willpower. Mads Krogsgaard Thomsen, current CEO of the Novo Nordisk Foundation and the company's former chief scientific officer, is one of the advocates of studying GLP-1 for weight loss, saying in a video released by the foundation that he "had to spend half the time "A year in convincing my CEO that obesity is more than just a lifestyle condition. "
Dr. Knudsen also noted that the company's business units have struggled to promote the idea of liraglutide for two different purposes.
"It was either diabetes or weight loss," she recalls in the book.Basics Video Series。
Finally, after liraglutide was approved in 2010for diabetesAfterwards, Dr. Knudsen's proposal to study weight-loss drugs advanced. The FDA approved it in 2014 as Saxenda for the treatment of obesity after clinical trials. The dose is about doublediabetes dosage。Patient loses about 5% of body weight, appropriate amount.
But it's at least as good as other weight-loss drugs, and without the side effects of heart attack, stroke and death, Dr. Martin Holst Lange, executive vice president of development at Novo Nordisk, said in a telephone interview.
"We're very excited," he said.
Despite the progress in weight loss, Novo Nordisk continues to focus on diabetes, trying to find ways to make a longer-lasting version of GLP-1 so patients don't have to self-inject it every day.
The result is a different GLP-1 drug, semaglutide, that lasts long enough that patients only need to inject it once a week. It was approved in 2017 and is currently marketed under the name Ozempic.
it is alsolead to weight loss— 15%, which is three times the loss of the once-daily drug Saxenda, although for no apparent reason. Suddenly, the company had found a seemingly revolutionary cure for obesity.
But Novo Nordisk can't market the Ozempic weight-loss drug without FDA approval. approved for that particular use.
In 2018, a year after Ozempic was approved to treat diabetes, the company startedClinical Trials. In 2021, Novo Nordisk will receive FDA approval. The same obesity drug is marketed as a once-weekly injection in higher doses. The drug was named Wegovy.
But even before Wegovy was approved, people were already taking Ozempic to treat obesity. Novo Nordisk in its Ozempic advertisement,mentioned that many people take it to lose weight。
As it turns out, hinting was enough. Soon, patients started using Ozempic, said Dr. Jeffrey Mechanick, an endocrinologist at the Icahn School of Medicine at Mount Sinai. Doctors prescribe the drug for those who do not have diabetes.
"There's some gaming going on," Dr. Mechanik said. Some doctors are coding patients as prediabetic to help them get insurance.
General craze for weight loss and fat loss fueled by social media by 2021Novo Nordisk aggressive marketingDr. Caroline Apovian, co-director of the Center for Weight Management and Wellness at Brigham and Women's Hospital and an advisor to companies including Novo Nordisk, said the news that Ozempic is making people lose weight has reached a tipping point. Even though Wegovy was the drug approved for obesity that year, Ozempic was still on everyone's lips.
But Wegowe caught up.
U.S. doctors filled about 94,000 prescriptions a week for Wegovy in July, while Ozempic filled about 62,000 a week. However, Wegovy's spokesman Ambre James-Brown said the company was unable to produce enough of the product because the demand was so high. As a result, for now the company is only marketing the drug in Norway, Denmark, Germany and the US, while ramping up production. In pharmacies in these countries, shortages occur frequently.
Like many other obesity medicine specialists, Dr. Apovian now accepts patient appointments a year in advance.
More Drugs, More Mysteries
The reason why Ozempic and Wegovy are so much more effective than Saxenda remains a mystery. Why do weekly injections produce more weight loss than daily injections?
Randy Seeley, an obesity researcher at the University of Michigan, says the drugs don't correct a deficiency in the body's GLP-1 -- which obese people make a lot of. Instead, these drugs expose the brain to levels of hormones never seen in nature. Patients taking Wegovy got five times the amount of GLP-1 they produced at Thanksgiving dinner, Dr. Seeley said.
In the brain, "drugs go to unusual places," he added. They don't just go to places that are thought to control overeating.
"If you're designing a drug, you're saying it's a bad idea," said Dr. Sealy, who has advised companies including Novo Nordisk and Eli Lilly. Drug designers strive for precision -- a drug should only reach the cells that need it.
GLP-1, due to its chemical structure, should not even enter some areas of the brain where it enters.
"Nobody understood that," Dr. Seely said.
However, Wegovy is just the beginning.
Eli Lilly's diabetes drug tezeparatide, or Mounjaro, is expected to win FDA approval. Obesity approved this year. It links GLP-1 to another gut hormone, GIP.
GIP by itself produces only modest weight loss effects at best. But the combination of the two hormones can make people lose about 20 percent of their body weight on average.
"No one fully understands why," Dr. Drucker said.
Eli Lilly has another drug, retaglutide, which, while still in the early stages of testing, appears to have caused a median24% weight loss。
Amgen's experimental drug AMG 133 could be better, but more confusing. It hooks GLP-1 to a molecule that blocks GIP.
There is no logical explanation for why the seemingly opposite approach would work.
Researchers continue to marvel at these biochemical mysteries. But doctors and patients have their own conclusions: the drug works. People lose weight. The constant chatter in their brains about food and eating has disappeared.
And, despite the persistence of the fat stigma and cultural stereotypes that obese people don't make an effort to lose weight, 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.
"Gone are the days of 'get out, diet and exercise,'" said Dr. Rudolf Lebel, a professor of diabetes research at Columbia University Irving Medical Center. "Now clinicians have the tools to address obesity."
August 17, 2023
An earlier version of this article misrepresented the name of a drug approved in 2010 to treat diabetes. It's Victoza, not Saxenda. It also misquoted a line from a video about convincing a chief executive that obesity is more than a matter of lifestyle. That's what Max Krogersgaard Thomson said, not Lars Rebion Sorensen.
how we handle corrections
Gina ColataWrite about science and medicine. She is a two-time Pulitzer Prize finalist and the author of six books, including Mercy in Disguise: Stories of Hope, the Genetic Destiny of Families, and the Science to Save Them. About Gina Colata
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