Aida Diaz sat down at a long table laden with fried chicken, french fries, salad and more.
Pick what you want for dinner, researchers at Columbia University instructed the 27-year-old New Yorker. Diaz filled her plate with salad, a bit of canned tuna, and chicken, grilled, not fried.
Then she grabbed a fry—because who can resist?—and a couple of spoonfuls of mac and cheese. “They said this is the hardest part,” said Diaz, who is trying to keep more than 35 pounds off.
It sure is. Researchers including the team at Columbia and drugmakers are trying to solve the biggest problem in the weight-loss industry today: how to keep weight off once you lose it.
Hundreds of thousands of people have shed tons of weight on blockbuster drugs including Ozempic and Wegovy. But many put the pounds back on when they stop taking the medications. Millions of others like Diaz who lost weight by changing their diets and exercise habits struggle not to regain.
Drugs or procedures to keep weight off could fuel an even bigger bonanza than Ozempic and its immensely profitable cousins. Losing weight is temporary, but maintaining it is lifelong. Maintaining weight is also a different challenge from losing it.
Makers of the weight-loss juggernauts have a big problem to overcome: Many people stop taking so-called GLP-1 drugs. Their insurers won’t pay for the drugs, they can’t tolerate side effects, or they don’t want to take medication long term. Only 14% of people surveyed in 2023 by KFF, the health-policy research organization, were interested in taking a weight-loss drug once they were told they might gain weight back if they stopped.
“The unmet need has shifted from how do you lose weight to how do you keep it off,” said Dr. Harith Rajagopalan, chief executive officer of Fractyl Health, a Burlington, Mass., biotech company working on two therapies to help people keep weight off.
New treatments
Drugmakers are designing treatments to help people maintain weight, as well as weight-loss pills or long-acting injections that might be easier for patients to use than current injectables. The biotech company Amgen is testing a long-acting injectable that helped people keep weight off for up to five months after they stopped taking it in an early study.
Novo Nordisk and Eli Lilly say their drugs Wegovy and Zepbound, respectively, are meant for weight loss and maintenance. Eli Lilly expects results in 2026 from a study of Zepbound specifically for weight maintenance.
Obesity is a chronic disease—such as hypertension—that requires ongoing treatment, according to Novo Nordisk, Eli Lilly and obesity doctors. Patients trying to maintain weight loss often switch to a lower dose.
In March 2023, Karsten Reiners underwent an endoscopic procedure developed by Fractyl Health to treat obesity and Type 2 diabetes. The procedure, approved in Europe and under study in the U.S. for diabetes treatment, removes a lining in the small intestine impaired by chronic exposure to high-fat or high-sugar diets.
Sloughing it off allows a new lining to form, restoring normal nerve and hormone signals between the gut and the brain and reducing hunger, Rajagopalan said.
Reiners, a 62-year-old salesman in Krefeld, Germany, lost more than 30 pounds over the following three months. His blood-sugar levels are under control now. He hasn’t had pizza in a year and avoids chocolate. “I do not eat as much as before,” he said.
Still, he has battled food temptations during holidays, and has put back on about 12 pounds.
Fractyl Health plans to launch a study of the procedure for weight maintenance in the U.S. this year. The company is also developing a one-time gene therapy for weight maintenance.
Researchers at Columbia, Drexel University, the University of Pennsylvania and other institutions are conducting a study of the brains, fat and muscle cells and eating patterns of people—such as Diaz—trying to maintain new body sizes. They hope their work, funded by the National Institutes of Health, will lead to personalized treatments.
While the researchers know generally what causes people to regain—the body thinks it is starving after losing weight—they want to understand why some people can keep it off while most can’t.
There is more at stake than looking better. If people put weight back on, they won’t reap the long-term health benefits that losing pounds provides. “Weight regain is the major problem at this point because it really impacts the long-term success medically or otherwise of weight loss,” said Dr. Rudolph Leibel, a researcher on the genetics and physiology of obesity at Columbia, and a study investigator.
Losing weight and keeping it off are metabolically different states, potentially requiring different treatments, Leibel said. He believes the study findings could help people who have lost weight either with drugs or diet and exercise.
The body is designed to fight weight loss, an ancient survival mechanism, Leibel said. When people lose weight, their drive to eat and restore body fat grows. At the same time, they burn fewer calories, because their metabolisms slow in response to weight loss.
“It’s like a perfect storm for weight regain,” Leibel said.
Patients who stopped taking Wegovy or Zepbound gained back more than half the weight they lost within a year. A group of contestants on the TV show “The Biggest Loser” put back, on average, two-thirds of their weight within six years, though some didn’t regain any weight.
More than 10,000 people participate in a long-running study known as the National Weight Control Registry. They follow diets lower in calories and exercise regularly. More than 87% kept off at least 10% of their body weight for 10 years in an analysis of one group of participants.
Maintaining weight loss is challenging in an environment of high-calorie foods and sedentary lifestyles, said Graham Thomas, a registry co-investigator and a professor of psychiatry and human behavior at Brown University. “It’s about learning to live in our environment in a way that people are comfortable with and can tolerate,” he said.
One participant, Heidi Underwood, has maintained a 125-pound weight loss for about six years. The 53-year-old accountant in Saratoga Springs, N.Y., had lost and regained several times. This time she didn’t set a goal and made lifestyle changes gradually.
She started walking regularly, then took up running, rowing and strength training. She cut back on convenience foods, cookies and doughnuts but didn’t ban them, and started eating more lean protein and vegetables. She came to evaluate foods not on whether they were bad or good but rather on what she was getting for the calories.
“I discovered if I made a small change and mastered it, I could keep going,” Underwood said.
Weight trackers
In the new NIH-funded study, researchers are gathering reams of data as Diaz and other participants lose weight, then try to maintain it over 12 months.
Diaz has tried many fad diets since she was a teen, but could never stick to them. She didn’t want to lose weight with an Ozempic-like drug. She enrolled in August 2023 in the study, which first helps participants lose weight with changes in nutrition and exercise. She felt the lifestyle changes were more doable than the extreme ones she had tried before.
By March, Diaz had lost about 15% of her body weight. That was more than enough to move on to the weight-maintenance phase of the study.
Over two days, Diaz underwent a battery of tests at Columbia University Irving Medical Center. Researchers extracted fat and muscle cells, measured her body fat, and took a functional MRI—consisting of images of her brain as she looked at photos of food and decided what to eat. They want to see if activity in specific regions of the brain changes over time in ways that influence food intake.
The researchers laid out comestibles with a total of 10,000 calories on a big table and stepped into a hallway to watch Diaz on video from an iPhone rigged up on a wall behind her chair in the tiny room. Their goal was to see what and how much she ate and how it relates to her weight-maintenance efforts.
Hungry after a long day of tests, Diaz dug in. The smell of the fries and the array of so many foods tempted her. But she tried to stick to what she had learned losing weight: controlling portions and eating more greens and less sugar and fat.
She picked up a bottle of Snapple, looked at the label, then put it back. It wasn’t a diet version. She chose bottled water instead.
Diaz ate her fill in about 20 minutes, including a few fries, more spoonfuls of mac and cheese and a Munchkin along with fruit for dessert. “I’m a sucker for Munchkins,” she said.
She hasn’t sworn off any foods; she just limits how much of them she eats. “It’s learning your body and having a healthier relationship with food,” she said.
Diaz is determined not to regain weight, and wants to lose more. Her tastes and social life have changed, she said. She used to sit with friends over food; now they go on walks or biking.
“I’ve kind of been telling my friends and everybody in my life, it’s not that I’m on a diet or that I’m trying to lose weight for a specific event,” she said. “This is my life now.”