Drugs such as Ozempic, Wegovy, Mounjaro and Zepbound have revolutionized the treatment of obesity, helping people lose significant amounts of weight without surgery. With 70% of Americans overweight or obese, people are clamoring to take them. Soaring demand has outstripped their manufacturers' capacity to make them, reshaped the economy of an entire country, and even has food sellers nervous that grocery markets may shrink as the masses eat less.
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As effective as these medications are, however, they can be hard to take. They are pricey, with a cost of about $1,000 a month before insurance coverage. They can also have significant side effects, like nausea and vomiting, stomach pain and, more rarely, stomach paralysis, pancreatitis, and bowel obstructions. In clinical trials, about 1 in 5 patients who started on the active drugs, didn't make it to the end of the study.
So a looming question about their use has been whether people could eventually stop taking them, or whether the drugs might need to be a lifelong commitment for people wanting to maintain their weight loss.
A new study published Monday in the medical journal JAMA fills in some of the details by showing what weight regain looks like after people stopped taking Zepbound.
Trial tested weight regain
The trial, sponsored by Zepbound maker Eli Lilly, followed 670 overweight and obese adults after they successfully stayed on the drugs for nine months. At that point, half the group was assigned to continue taking Zepbound, while the other half was switched to a placebo shot. Neither the researchers nor the study participants knew whether they were getting the active drug or a dummy shot.
Everyone in the study was counseled to try to cut about 500 calories from their diet and exercise at least 150 minutes a week.
Over the next year, people taking Zepbound continued to lose weight, dropping an average of another 6% of their weight, although their weight eventually stabilized. People who were switched to the placebo regained weight. About 9 in 10 of the people taking tirzepatide were able to maintain at least 80% of the weight they lost, while 17% of the placebo group maintained at least 80% of their weight loss.
"If you look at the magnitude of the weight gain, they gain back about half the weight they had originally lost over a one-year period of time," said lead study author Dr. Louis Aronne, an obesity medicine specialist and professor of metabolic research at Weill Cornell Medicine in New York City.
Like the drugs Ozempic and Wegovy, tirzepatide mimics the gut hormone GLP-1, which lowers blood sugar levels, slows the passage of food through stomach, and dials down a person's appetite in the brain.
Tirzepatide also simulates a second complimentary hormone called GIP, which boosts its effects. In clinical trials, people who could tolerate the maximum dose of the drug - 15 milligrams per week - lost an average of about 20% of their starting body weight after about a year and a half on the drug.
It was first approved as the drug Mounjaro to help people with type 2 diabetes control their blood sugar. In November, the FDA gave its manufacturer, Eli Lilly, the green light to market the medication for the treatment of obesity. When it's taken for weight loss, it's sold as Zepbound.
Adults were eligible for the study if their BMI was 30 or greater, or if they had a BMI of at least 27 with at least one weight-related health complication, like high blood pressure. People with diabetes were excluded.
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Gradual creep back to baseline
From the start of the study to the end, the group that stayed on Zepbound weighed an average of 60 pounds less and had shed 9 inches from their waist circumference compared with when they entered the trial. People who had been switched to the placebo were down about 22 pounds from their starting weight, and still had trimmed more than 3 inches around their waist.
Aronne says that based on his experience, it's likely that people on the placebo would continue to regain the weight they lost.
"How long would it take? I honestly don't know," he said.
While that may sound depressing for people who had hoped to one day wean off the shots, there were some bright spots in the data.
Some people who stop taking the medication don't seem to gain it back, at least not right away.
"It's not like every single person regains weight. One out of six, this would say, is able to maintain the weight loss without medication," Aronne said.
Aronne says they don't have any information about what helped the maintainers keep their weight off even after the medication was stopped, so that's something future research will need to tackle.
Beyond that, when researchers looked at their health improvements in other areas, their blood pressure, blood sugar, cholesterol and metabolic improvements all seemed to drift back to where they were at the start of the study. But they didn't go above their baselines.
"So there was no, you know, what some people would call damage. They were not worse off than they were before," Aronne said, "And in some cases, they were significantly better than where they started. So there was some type of maintained benefit in certain cases."
Do weight loss drugs become less effective over time?
There were some puzzling findings on the other side, too.
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About 1 in 10 of the people who continued on the drug were not able to maintain at least 80% of their weight loss by a year, so they, too, began to regain weight - even on the medication.
Aronne says there's some evidence that the body may compensate for the effects of the medications over time. The hormone leptin, which suppresses hunger, goes down. Ghrelin, a hormone that tells the body it's time to eat, goes up.
"So there are a lot of things going on that ultimately stop you because they think you're starving to death," he said.
At that point, it may be necessary to add in another drug.
"Your body develops this kind of compensation, and when you hit it in two different places, you get a better result," Aronne said.
Dr. Melanie Jay, who directs the NYU Langone Comprehensive Program on Obesity, says in many ways the results of the trial are not surprising.
"Obesity is a chronic disease and the medications are not a cure," said Jay, who was not involved in the study. "As an analogy, in most cases, when I put someone on a blood pressure medication for hypertension and it lowers their blood pressure, I expect that when I take them off them the medication that their blood pressure will go back up."
Jay says most of her patients don't love the idea of staying on the medications indefinitely.
She says she's not aware of any studies looking into other strategies to maintain weight lost on these drugs, but they're needed.
"I know patients and clinicians are experimenting with less frequent dosing strategies to see if they can still maintain their weight but not necessarily in formal studies," she said.
On the plus side, Jay says many patients on these medications improve their health so much that they're able to get off other medications for diabetes and hypertension.
"Thus, even if they have to stay on the anti-obesity medications long term, the net number of medications may be fewer than if they never started," Jay said.