Tirzepatide beats semaglutide for weight loss in large real-world study

A study published July 8, 2024 in JAMA Internal Medicine found that adults prescribed tirzepatide lost more weight on average than adults prescribed semaglutide during routine medical care, in what researchers described as the first head-to-head comparison of the two drugs ^[1][2]. Tirzepatide is sold as Mounjaro and Zepbound; semaglutide is sold as Ozempic, Wegovy and Rybelsus.

Researchers at Truveta Research, a health data company, used de-identified electronic health records from a group of U.S. health systems ^[2]. The analysis began with more than 41,000 adults who were overweight or had obesity and received one of the two medicines for the first time; after matching patients on characteristics such as age and health history, the comparison included 18,386 people ^[1][2]. All patients had a body mass index of at least 27, and people with type 2 diabetes were not excluded ^[1][2].

At 3 months, people on semaglutide had lost an average of 3.6% of their body weight, compared with 5.9% for those on tirzepatide. At 6 months the figures were 5.8% versus 10.1%, and at 12 months 8.3% versus 15.3% ^[1][2]. In absolute terms, tirzepatide patients lost 2.5 percentage points more at 3 months, 4.3 points more at 6 months and 6.9 points more at 12 months ^[2].

People taking tirzepatide were also more likely to cross specific weight-loss thresholds. They were 76% more likely to lose at least 5% of their body weight (hazard ratio 1.76), more than twice as likely to lose at least 10% (HR 2.54) and more than three times as likely to lose at least 15% (HR 3.24) ^[2]. "The majority of patients on both medications experienced clinically meaningful weight loss, but those patients that took tirzepatide experienced significantly more," said study author Tricia Rodriguez of Truveta Research ^[1].

Rates of moderate-to-severe gastrointestinal side effects, the most commonly reported problems with this drug class, were similar between the two groups ^[2]. The study found no significant difference in the risk of serious side effects such as gastroparesis, also called stomach paralysis, Rodriguez said ^[1]. Stopping treatment was common in both groups: 55.9% of people on tirzepatide and 52.5% of those on semaglutide discontinued within 12 months ^[2].

Several limitations matter. The records analyzed were for Mounjaro and Ozempic, the versions of these molecules labeled for type 2 diabetes; prescriptions for Wegovy, the 2.4 mg semaglutide product approved for weight management, were not included, and tirzepatide had no weight-management approval at the time of the analysis ^[2]. The standard full dose for the diabetes indication is 0.5 mg for semaglutide and 5.0 mg for tirzepatide ^[2]. About 52% of patients had type 2 diabetes, and those patients lost less weight on average than those without it ^[2]. Because the study used electronic records, side effects may have been underreported ^[2].

A Novo Nordisk spokesperson said the study had some "key limitations," including the inclusion of patients with type 2 diabetes, who often have a harder time losing weight than people without the condition. The spokesperson also said the study did not provide sufficient information about the doses patients started with and progressed to ^[1].

Why it matters for patients

Both medicines produced clinically meaningful weight loss for most people in this analysis, so the finding is about averages, not about how any one person will respond ^[1]. The comparison also does not line up exactly with the products most people recognize. The records studied were for Mounjaro and Ozempic at doses approved for type 2 diabetes, not Zepbound or Wegovy at their weight-management doses, so the results are not a direct read on those branded products ^[2].

The study is observational, meaning it looked back at records rather than assigning treatments by chance. That design can show an association but cannot prove that one drug caused the difference ^[2]. The high discontinuation rates in both groups are another practical detail: more than half of patients in each group stopped within a year, and the study did not report why ^[2].

Tirzepatide works by mimicking two hormones, GLP-1 and GIP; semaglutide mimics GLP-1 alone ^[1].

What happens next

Eli Lilly started a phase 3 randomized trial of 700 patients comparing the two medicines, and it is expected to be completed in November, according to ClinicalTrials.gov ^[1]. Randomized trials assign treatments by chance, which addresses some of the limits of records-based research. The trial's results have not been reported, and whether they would change insurance coverage or prescribing has not been disclosed.