Tirzepatide enhances weight loss with sustained treatment but discontinuation leads to weight regain

The current class of anti-obesity drugs is proving remarkably effective at removing excess pounds. However, a phase 3 randomized clinical trial led by researchers at Weill Cornell Medicine and NewYork-Presbyterian found that people who stopped taking the medication regained much of that weight within a year. At the same time, the study shows that remaining on the drug not only promotes additional weight loss but preserves improvements in metabolic and cardiovascular health.

The results from the SURMOUNT-4 study, which appeared Dec. 11 in JAMA and was sponsored by Eli Lilly and Company, demonstrated that the drug can substantially help people struggling with health issues related to their weight, but it is not a quick-fix to weight loss.

“Obesity is a leading driver of many diseases that we spend our time treating in medicine; illnesses like hypertension, heart disease, diabetes and fatty liver disease are either caused by or worsened by obesity,” said lead study author Dr. Louis Aronne, the Sanford I. Weill Professor of Metabolic Research and director of the Comprehensive Weight Control Center, which is part of the Division of Endocrinology, Diabetes, and Metabolism at Weill Cornell Medicine. “The fact that we now have drugs that are proving to be effective is exciting and rewarding.”

Diabetes Drug Promotes Weight Loss

Tirzepatide is part of a new class of drugs called called GLP-1 receptor agonists that were developed to treat type 2 diabetes. Besides controlling blood sugar, the drugs also resulted in weight loss, so pharma companies created specific formulations to help patients shed pounds.

In 2022, a phase 3 randomized, controlled clinical trial demonstrated that tirzepatide led to a 20 percent reduction in body weight over 72 weeks. The findings prompted the U.S. Food and Drug Administration to approve the drug last month, with the trade name Zepbound, for weight loss in individuals with a body mass index (BMI) of 30 or higher—or for those with a BMI of 27 or greater who also had health conditions such as high cholesterol or hypertension.

Although the initial effects were dramatic, the researchers were uncertain whether the weight loss would persist beyond the period of active treatment. To find out, they launched the SURMOUNT-4 trial, which was conducted at 70 sites in Argentina, Brazil, Taiwan and the United States between March 2021 and May 2023. The participants took a maximum tolerated dose of tirzepatide for 36 weeks, which yielded the expected weight reduction of 20.9 percent with improvements in blood pressure, blood sugar metrics and lipid levels.

Then 670 eligible participants were randomly assigned to either continue with the tirzepatide for an additional year (52 weeks) or to switch to a placebo. Those who continued on tirzepatide lost an additional 5.5 percent versus the placebo group which regained 14 percent of their weight.

Though the placebo group was still almost 10 percent lighter than their initial weight, the improvements in cardiometabolic risk factors had been reversed. Relative to placebo, tirzepatide was associated with significant improvements in BMI, lipid levels, diabetes indicators and blood pressure.

“Those who went on the placebo regained about half the weight they had lost,” said Dr. Aronne, who is also an internist specializing in diabetes and obesity at NewYork-Presbyterian/Weill Cornell Medical Center. “Whereas those who continued on the drug lost another 5 percent, so their overall weight loss was about 25 percent.”

The findings indicate that people may need to remain on tirzepatide to keep off the pounds. “If you stop the medication, you regain the weight. There’s no question that will happen,” said Dr. Aronne. But that shouldn’t be surprising. “Obesity is a chronic condition, like diabetes or high blood pressure. So, it must be treated chronically.”

The researchers noted that they didn’t evaluate the effects of intensive behavioral therapy on the maintenance of body weight reduction, which could make a difference in preventing weight regain after coming off the drug.

Tirzepatide Mimics Natural Hormones that Foster Feeling Full

Tirzepatide works by mimicking the GLP-1 and GIP hormones that are naturally secreted by the intestine after a meal, which prompts insulin secretion. It also reduces appetite by slowing down the time it takes the stomach to empty and interacting with areas in the brain harboring GLP-1 receptors to signal satiety.

“Instead of counting calories, the medicine helps a person eat less because it signals to the brain that you’re full,” said Dr. Aronne. “The dual mechanism of action helps overcome the plateau phenomenon that is seen at some point and produces additive weight loss.”

Since the drug mimics hormones that are produced in the gastrointestinal system, side effects tended to be nausea, vomiting, diarrhea or constipation and resolved with time. The study had few people dropout because of side effects.

“People feel much better when they lose this kind of weight, so they are extremely enthusiastic about these treatments. But they also should realize this may require them to stay on the drug long term,” said Dr. Aronne. Further studies will need to assess the long-term risks and benefits associated with these drugs, especially considering the potential for their lifelong use.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. Dr. Louis J. Aronne serves as a paid advisory board member for Eli Lilly and Company. For further information, see the profile for Dr. Louis Aronne.