Tirzepatide: Pausing treatment can reverse weight loss, study suggests

People taking the new injectable medication tirzepatide – marketed under the name Zepbound – to lose weight will need to continue using it if they want to maintain results, a new study confirms.

Medications such as Ozempic, Wegovy, Mounjaro and Zepbound have revolutionized the treatment of obesity, helping people lose significant amounts of weight without resorting to surgery. With 70% of Americans overweight or obese, people are eager to take their medications. Rising demand has outstripped manufacturers’ ability to produce them, reshaped an entire country’s economy and even made food sellers nervous that food markets would shrink as the population eats less.

Despite the effectiveness of these medications, they can be difficult to take. They are expensive, costing around US$1,000 (more than R$4,800 at the current exchange rate) per month. They can also have significant side effects, such as nausea and vomiting, stomach pain and, more rarely, stomach paralysis, pancreatitis and intestinal obstructions. In clinical trials, about 1 in 5 patients who started using active medications did not reach the end of the study.

A looming question about the use of these medications was whether people could eventually stop taking them or whether the medications should be a lifelong commitment for anyone wanting to maintain weight loss. A new study published Monday in JAMA medical journal fills in some details, showing how weight regain occurs after people stop using Zepbound.

The study, sponsored by Zepbound maker Eli Lilly, followed 670 overweight and obese adults after they successfully stayed on the medications for nine months. At that point, half of the group was assigned to continue using Zepbound, while the other half was switched to a placebo injection. Neither researchers nor study participants knew whether they were receiving the active drug or a dummy injection.

Everyone in the study was advised to try to reduce about 500 calories from their diet and get at least 150 minutes of exercise a week.

Over the next year, people who continued using Zepbound continued to lose weight, reducing an average of another 6% of their weight, although eventually their weight stabilized. People who were switched to placebo gained weight back. About 9 out of 10 people taking tirzepatide were able to keep off at least 80% of the weight they lost, while 17% of the placebo group kept off 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,” said study lead author Dr. Louis Aronne, an expert in obesity medicine. 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 the stomach, and reduces appetite in the brain. Tirzepatide also simulates a second complementary hormone called GIP, which intensifies its effects. In clinical trials, people who tolerated the maximum dose of the drug – 15 milligrams per week – lost an average of about 20% of their initial body weight after about a year and a half of use.

Initially approved as the drug Mounjaro to help people with type 2 diabetes control their blood sugar, in November the FDA gave the green light for its manufacturer, Eli Lilly, to market the drug to treat obesity. When used for weight loss, it is sold as Zepbound.

Adults were eligible for the study if their body mass index (BMI) was 30 or higher, or if they had a BMI of at least 27 with at least one weight-related health complication, such as high blood pressure. People with diabetes were excluded.

From the beginning of the study to the end, the group that continued using Zepbound weighed an average of 27 kg less and had lost 23 centimeters in waist circumference compared to the beginning of the study. People who were switched to placebo were about 10 kg lighter than their starting weight and still had reduced more than 7.5 centimeters in waist circumference.

Aronne says that based on her experience, it’s likely that people in the placebo group will continue to gain back the weight they lost.

“How long would it take? Honestly, I don’t know,” he said.

While this may seem discouraging to people who hoped to one day wean themselves off injections, there are some positives in the data.

Some people who stop taking their medication don’t seem to gain the weight back, at least not right away.

“It’s not like every person gains weight back. One in six, that would say, manages to maintain weight loss without medication,” said Aronne.

Aronne says they don’t have information about what helped these people keep their weight off even after stopping their medication, so that’s something future research will need to address.

Additionally, when researchers looked at health improvements in other areas, blood pressure, blood sugar, cholesterol, and metabolic improvements all seemed to return to what they were at the start of the study. But they did not exceed the initial values.

“So there was no, you know, what some people would call harm. They were no worse than they were before,” Aronne said. “And in some cases, they were significantly better than when they started. So there was some kind of benefit maintained in certain cases.”

Do weight loss medications become less effective over time?

There have been some intriguing discoveries on the other side as well.

Approximately 1 in 10 people who continued the medication were unable to maintain at least 80% of their weight loss within a year, so they also began to gain weight back despite using the medication.

Aronne says there is some evidence that the body can compensate for the effects of medications over time. The hormone leptin, which suppresses hunger, decreases. Ghrelin, a hormone that tells the body it’s time to eat, increases.

“So there are a lot of things going on that ultimately stop you because they think you’re starving,” he said.

At this point, another medication may need to be added.

“Your body develops this type of compensation, and when you hit that in two different places, you get a better result,” Aronne said.

Dr. Melanie Jay, who directs the Comprehensive Obesity Program at NYU Langone, says that in many ways, the study’s results are not surprising.

“Obesity is a chronic disease and 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 high blood pressure medication and it lowers their blood pressure, I expect that when we take them off the medication, their blood pressure will go up.”

Jay says most of his patients don’t like the idea of ​​staying on medications indefinitely.

She says she’s not aware of studies investigating other strategies for maintaining weight lost with these medications, but they are needed.

“I know patients and clinicians are experimenting with less frequent dosing strategies to see if they can still maintain weight, but not necessarily in formal studies,” she said.

On the positive side, Jay says that many patients who use these medications improve their health so much that they are able to come off other diabetes and high blood pressure medications.

“So even if they have to stay on anti-obesity medications long-term, the net number of medications may be lower than if they had never started,” Jay said.