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In a nutshell
- Tirzepatide (Mounjaro) produced 20.2% weight loss compared to semaglutide’s (Wegovy) 13.7% after 72 weeks of treatment
- Tirzepatide users experienced greater waistline reduction (7.2 inches vs. 5.1 inches) and more significant improvements in health markers
- Both medications caused similar side effects, but fewer people discontinued tirzepatide due to stomach issues (2.7% vs. 5.6%)
NEW YORK — For the first time, scientists have pitted the two most popular weight loss drugs against each other in a direct competition – and one clearly dominates. A new study led by Weill Cornell Medicine researchers reveals that tirzepatide (Mounjaro, Zepbound) helps people lose significantly more weight than semaglutide (Wegovy).
The difference is striking: people taking tirzepatide lost 20.2% of their body weight over 72 weeks, while those on semaglutide dropped 13.7%. For a 250-pound person, that translates to about 50 pounds with tirzepatide versus 34 pounds with semaglutide – a 16-pound gap that could dramatically impact quality of life.
Results of the study are published in the New England Journal of Medicine.
Tirzapetide vs. Semaglutide
Both medications work by mimicking hormones that our bodies naturally produce, but they target different receptors. Semaglutide activates only one hormone pathway – glucagon-like peptide-1 (GLP-1) – which helps control appetite and slows digestion. Tirzepatide hits that same GLP-1 target but also activates a second hormone called GIP. This dual-action approach appears to be more effective for weight loss.
The SURMOUNT-5 trial, led by Dr. Louis Aronne from Weill Cornell Medicine, recruited 751 adults with obesity but without diabetes. Half received weekly tirzepatide injections, while the other half got weekly semaglutide shots. Both medications required gradual dose increases to reach their maximum strength.
Beyond the Scale: Health Benefits and Waistline Reduction
The benefits extended beyond just weight. Tirzepatide users saw their waistlines shrink by 7.2 inches on average, compared to 5.1 inches with semaglutide. This difference matters because abdominal fat surrounds vital organs and increases the risk of heart disease, diabetes, and other conditions.
As weight dropped, health markers improved with both medications. Blood pressure, blood sugar, and cholesterol levels all showed improvements, with tirzepatide generally showing a stronger effect. Participants who lost more weight – especially those dropping 20% or more – experienced the most significant health improvements.
Side Effects and Real-World Implications
Stomach issues topped the side effect list for both medications – nausea affected about 44% of participants in both groups, while constipation troubled roughly 28%. Interestingly, twice as many people quit taking semaglutide due to digestive problems (5.6% versus 2.7% for tirzepatide).
Demand for weight loss medications continues to climb, with both manufacturers struggling to meet demand amid ongoing shortages. Insurance coverage remains inconsistent, forcing many patients to pay over $1,000 monthly out-of-pocket for either medication.
With the CDC estimating that more than 35% of American adults living with obesity – which increases risks for heart disease, stroke, diabetes, and certain cancers – these medications represent a major advance in treatment options. However, they work best alongside lifestyle changes like healthier eating and regular physical activity.
As remarkable as these results are, they come with limitations. The trial was open-label, meaning participants knew which medication they were receiving. And though the medications were tested for 72 weeks, obesity is a chronic condition requiring long-term management. Questions remain about what happens when people stop taking these medications, with some studies suggesting significant weight regain.
For now, tirzepatide has claimed the weight loss crown. The outstanding question is whether its superior results will justify what will likely be a higher price tag – and whether insurance companies will agree to cover it.
Paper Summary
Methodology
The SURMOUNT-5 trial was a phase 3b, multicenter, open-label, randomized controlled trial conducted at 32 sites in the United States and Puerto Rico. A total of 751 adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one obesity-related complication were randomly assigned in a 1:1 ratio to receive either tirzepatide or semaglutide. Participants received weekly subcutaneous injections for 72 weeks, with tirzepatide doses starting at 2.5mg and increasing to a maximum tolerated dose of 10mg or 15mg, and semaglutide starting at 0.25mg and increasing to a maximum tolerated dose of 1.7mg or 2.4mg. The primary endpoint was percent change in weight from baseline to week 72, with key secondary endpoints including weight reductions of at least 10%, 15%, 20%, and 25%, and change in waist circumference.
Results
Tirzepatide demonstrated superior efficacy compared to semaglutide across all primary and secondary endpoints. The least-squares mean percent change in weight at week 72 was -20.2% with tirzepatide versus -13.7% with semaglutide (p<0.001). The least-squares mean change in waist circumference was -18.4cm with tirzepatide and -13.0cm with semaglutide (p<0.001). More participants in the tirzepatide group achieved weight reductions of at least 10% (81.6% vs 60.5%), 15% (64.6% vs 40.1%), 20% (48.4% vs 27.3%), and 25% (31.6% vs 16.1%). For the exploratory endpoint of weight reduction of at least 30%, tirzepatide was superior at 19.7% versus 6.9% for semaglutide. Both medications also improved cardiometabolic risk factors including blood pressure, glycated hemoglobin, fasting serum glucose, and lipid levels, with more significant improvements observed with tirzepatide.
Limitations
The trial had several limitations. It was open-label, meaning participants and investigators knew which medication they were receiving, which could have influenced results. Though the trial lasted 72 weeks, obesity is a chronic condition requiring long-term management, so longer-term efficacy and safety data would be valuable. The study also included a higher percentage of men (35%) than previous similar trials, which may have affected the overall weight reduction results since men in both groups lost approximately 6% less weight than women.
Funding and Disclosures
The study was funded by Eli Lilly, the manufacturer of tirzepatide. Multiple authors reported financial relationships with Eli Lilly, including employment. The sponsor was involved in the trial design, data collection, site monitoring, data analysis, and manuscript preparation.
Publication Information
The paper titled “Tirzepatide as Compared with Semaglutide for the Treatment of Obesity” was published in the New England Journal of Medicine on May 11, 2025. The trial was registered on ClinicalTrials.gov (number NCT05822830) under the name SURMOUNT-5. The lead author was Louis J. Aronne from the Comprehensive Weight Control Center, Division of Endocrinology, Diabetes, and Metabolism at Weill Cornell Medicine.
