Zepbound outperforms Ozempic and Wegovy in head-to-head weight loss study

Tirzepatide, the active ingredient in Eli Lilly’s Mounjaro and Zepbound, leads to more weight loss than semaglutide, the active ingredient in Novo Nordisk’s Ozempic and Wegovy, new research suggests. 

The study, published Monday in JAMA Internal Medicine, is thought to be the first head-to-head comparison of the two blockbuster weight loss drugs. 

Since Zepbound was approved for weight loss in late 2023, it appeared to have an advantage over Wegovy. Patients taking the highest dose of Zepbound lost around 21% of their body weight over 72 weeks, compared to around 15% for patients on Wegovy after 68 weeks. 

But it was difficult to make a direct comparison without a study that looked at both drugs, which are part of a new class of medications called GLP-1s.

“We’ve tracked GLP-1 use over the last year and we’ve seen really dramatic increases, and yet, there’s not a ton of information available on head to head comparisons,” said lead study author Tricia Rodriguez, a principal applied scientist at Truveta Research, a health care data and analytics company.  

In the new study, Rodriguez and colleagues analyzed electronic health records from more than 41,000 adults who were overweight or had obesity and had been prescribed one of the two drugs for the first time. Participants weren’t excluded if they had Type 2 diabetes. More than 9,100 were prescribed tirzepatide, and more than 32,000 were prescribed semaglutide.  

The researchers looked at how much weight the patients lost after 3, 6 and 12 months.

People who took semaglutide lost, on average, 3.6% of their body weight after 3 months; 5.8% after 6 months; and 8.3% after 12 months.

Those who took tirzepatide lost a greater percentage of body weight each month, compared to semaglutide: an average of 5.9% of their body weight after 3 months; 10.1% after 6 months; and 15.3% after 12 months. 

“The majority of patients on both medications experienced clinically meaningful weight loss, but those patients that took tirzepatide experienced significantly more,” Rodriguez said. 

The researchers noticed no significant difference in the risk of serious side effects, such as gastroparesis, also known as stomach paralysis, between the two drugs, Rodriguez said. 

Semaglutide and tirzepatide work in similar ways. The GLP-1 drugs mimic a hormone that helps reduce food intake and appetite. However, tirzepatide also imitates a second hormone, called GIP, which along with reducing appetite, is thought to improve how the body breaks down sugar and fat.

Researchers will still need to do a randomized, controlled clinical trial to see which medication truly comes out on top. Last year, Lilly began a phase 3 trial of 700 patients comparing the two medications. The trial is expected to be completed in November, according to ClinicalTrials.gov.

A spokesperson for Novo Nordisk said that the new study had some “key limitations,” including the inclusion of patients with Type 2 diabetes, who often have a more difficult time losing weight than people without the condition. Additionally, the study did not provide sufficient information on the doses that patients started with and progressed to.

“While lowering body weight is an important goal of obesity management, it is important to also consider other needs when choosing a treatment,” the spokesperson said. 

Eli Lilly did not immediately respond to a request for comment.

Dr. Susan Spratt, an endocrinologist and senior medical director for the Population Health Management Office at Duke Health in North Carolina, said that while it’s clear from the study that tirzepatide is more effective, both medications are still good options for patients because they provide more weight loss than other drugs on the market right now. 

She also noted that more studies are needed comparing the effects on other health outcomes beyond weight loss.

Semaglutide, for example, has been shown in trials to cut the risk of cardiovascular problems — such as heart attack and stroke — in people who are overweight or have obesity, and to cut the risk of complications from kidney disease in people with Type 2 diabetes; tirzepatide has been shown to be a possible treatment for obstructive sleep apnea

“That being said, if someone’s main goal is weight loss, I’d probably go with tirzepatide,” Spratt said. 

Dr. Daniel Maselli, an obesity medicine physician at True You Weight Loss, a weight loss clinic in Atlanta, said the study supports previous research that has indicated tirzepatide provides more weight loss than semaglutide.

While important information for physicians, he noted that weight loss alone isn’t the only factor that he considers when prescribing weight loss drugs to patients.

He also takes into account the patient’s personal goals, medical needs, such as improving heart health, and how well they tolerate certain medications. Some patients, for example, may not do well on tirzepatide, but lose weight on semaglutide.

“This study helped address the weight loss component but, as the authors point out, was limited in discerning differences in tolerance, safety, or improvements in complications of obesity,” he wrote in an email.

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