Tirzepatide: High Efficacy, But Lost Weight May Return

A novel weight loss drug, Mounjaro, is highly effective at removing excess pounds, but they may return within a year after stopping taking the medication.

Tirzepatide, sold under the brand name Mounjaro, is part of a new class of drugs called GLP-1 receptor agonists. Initially developed to control blood glucose in type 2 diabetes patients, the medications have been increasingly used off-label for weight loss.

Last month, the U.S. Food and Drug Administration (FDA) approved tirzepatide under the trade name of Zepbound for weight management in people with obesity or overweight patients with at least one related condition, such as high cholesterol or hypertension.


Although the drug has been previously shown to reduce body weight by up to 21%, most of the shed pounds returned within a year of discontinuation, according to a phase 3 clinical trial published in JAMA Network and sponsored by Eli Lilly and Company, the manufacturer of tirzepatide.

The lead-in period of the SURMOUNT-4 trial included 783 participants receiving once-weekly injections of the maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. As expected, participants lost 20.9% of their body weight and saw improvements in blood pressure, blood sugar metrics, and lipid levels.

Then, 670 eligible participants were randomly assigned to continue with the tirzepatide for an additional year (52 weeks) or switch to a placebo.

During the study period, all participants received lifestyle counseling and were encouraged to adhere to a healthy 500 kcal/day deficit diet and engage in at least 150 minutes of physical activity per week.

Those continuing on tirzepatide lost an additional 5.5% of their body weight. The participants on placebo regained 14% of their weight, and the improvements in cardiometabolic risk factors were reversed.

Overall, 89.5% of the participants receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with only 16.6% in the placebo group.

"Those who went on the placebo regained about half the weight they had lost," said lead study author Dr. Louis Aronne, the Sanford I. Weill Professor of Metabolic Research and director of the Comprehensive Weight Control Center in a press release. "Whereas those who continued on the drug lost another 5%, so their overall weight loss was about 25%."

Moreover, the use of tirzepatide was associated with significant improvements in the body mass index, blood sugar and fasting glucose levels, insulin, lipid levels, and blood pressure.


Adverse events were common

During the lead-in treatment period, most (81%) of the participants reported at least one treatment-related adverse event, with the most frequent ones being gastrointestinal: 35.5% experienced nausea, 21.1% diarrhea, 20.7% constipation, and 16.3% vomiting.

A recent study associated the use of GLP-1 receptor agonists with an increased risk of pancreatitis, bowel obstruction, and stomach paralysis. European regulators are probing the reports on the medications allegedly causing suicidal thoughts.

Between January and November 2023, poison control centers in the United States reported a 1,500% increase in phone calls due to symptoms of accidental overdoses with semaglutide, another GLP-1 receptor agonist, mostly known as Ozempic and Wegovy.

The study is also subject to several limitations. First, the researchers did not evaluate the effects of intensive behavioral therapy in maintaining or reducing weight. Moreover, findings should be generalized with caution, as only certain people may be able to tolerate the treatment with 10-mg or 15-mg tirzepatide doses.

The study authors note that obesity is a chronic condition, and it must be treated chronically. While novel weight loss drugs are generally safe and effective, lifestyle interventions are also needed.


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