In the 72-week SURMOUNT-5 trial, adults with obesity or overweight and a weight-related condition, without diabetes, lost more weight on average with tirzepatide than with the semaglutide regimen studied: 20.2% versus 13.7% of starting body weight. Both were injected treatments alongside diet and activity support. This is a direct group comparison, not a prediction for one person or a comparison of every product now sold under those drug names. It did not test current Wegovy HD or oral semaglutide. SURMOUNT-5 primary report; official trial record.
Who and what did the head-to-head trial compare?
Semaglutide and tirzepatide attract attention because they can help people in the studied populations lose weight. Semaglutide acts at the GLP-1 receptor; tirzepatide acts at both GIP and GLP-1 receptors. Those are hormone-signaling pathways involved in appetite and metabolism. Having two targets does not by itself prove a better health outcome: the human comparison and the outcome measured matter. Both medicines have specific product labels, uses and risks. Wegovy prescribing information; Zepbound prescribing information.
SURMOUNT-5 randomly assigned 751 adults to tirzepatide or semaglutide for 72 weeks. Participants had obesity, or overweight with a qualifying weight-related condition, and did not have diabetes. The trial compared maximum-tolerated weekly injection regimens, with reduced-calorie eating and increased physical activity in both groups. It was open-label: participants and investigators knew which treatment was assigned. Eli Lilly, the tirzepatide manufacturer, sponsored the trial. Study design, eligibility and sponsor.
The study belongs to the weight-management injection setting associated with Zepbound and Wegovy. It does not turn Ozempic, Mounjaro, oral semaglutide, current Wegovy HD or compounded preparations into the same tested comparison. In particular, the newer high-dose Wegovy and oral presentations listed in the current Wegovy label were not the semaglutide regimen tested here. The results cannot establish how those options compare. Tested regimens; current Wegovy formulations.
What did the trial find at 72 weeks?
Both groups lost weight; the tirzepatide group lost more on average
- Tirzepatide: an estimated mean reduction of 20.2% of starting body weight.
- Semaglutide: an estimated mean reduction of 13.7% of starting body weight.
The difference was 6.5 percentage points in the primary comparison, which was statistically significant. These percentages describe change in body weight; they are not the percentages of participants who responded. They also do not mean every participant lost that amount. Individual results varied. Primary weight outcome and uncertainty.
The main analysis estimates outcomes under specified rules for treatment changes and missing information. It is not simply the average among people who finished taking the medicines. A separate hypothetical analysis asks a different question about continued treatment; its larger percentages should not replace these primary results without explaining that difference. The optional methods note below describes the distinction.
The difference also favored tirzepatide for waist reduction
- Tirzepatide: an estimated mean reduction of 18.4 cm.
- Semaglutide: an estimated mean reduction of 13.0 cm.
The waist comparison was statistically significant. It supports a difference in this measurement at 72 weeks in the trial population. A smaller waist measurement is not, by itself, a direct measurement of fewer heart attacks, longer life or a better result for every person. Those questions need evidence that actually measures them. Published waist outcome.
A larger average weight change does not settle which medicine is safer
Gastrointestinal problems were the most common adverse events in both groups. The primary report describes most as mild or moderate, mainly during treatment escalation. That description does not mean the medicines were free of serious risks or that everyone could tolerate them. The registry also reports serious adverse events in both groups; these descriptive counts cannot establish that the treatments have equivalent safety or that one is safer for an individual. Primary safety summary; registered adverse-event results.
Study withdrawal and stopping a study medicine are different events. The accessible registry's participant-flow reasons should not be relabeled as precise drug-discontinuation rates. We have not verified the full publication's drug-discontinuation table, so this guide does not supply a percentage for that question.
Why not compare the percentages in separate drug studies?
The semaglutide profile and tirzepatide profile retain useful results from other trials. Different studies can involve different participants, treatment regimens, follow-up, comparators and analysis rules. Putting two placebo-controlled results next to each other does not recreate random assignment between the medicines.
SURMOUNT-5 answers the direct weight-management comparison more closely because it assigned participants within the same trial. It still has boundaries: open-label treatment, selected eligibility, specified injection regimens and a 72-week endpoint. Diabetes comparisons answer another question and should retain their own populations and regimens. None of these studies supplies a personal switching plan.
Are the medicines used for the same things?
Both Wegovy injection and Zepbound are labeled for long-term weight management in specified populations, together with diet and activity. Other uses differ by the exact product and formulation. The current U.S. Wegovy injection label also includes cardiovascular-event risk reduction in adults with established cardiovascular disease and obesity or overweight. It includes a separate accelerated-approval use for adults with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) and moderate-to-advanced fibrosis, stages F2–F3; that approval rests on liver findings, and continued approval may depend on confirmation of clinical benefit. The current Zepbound label includes moderate-to-severe obstructive sleep apnea in adults with obesity. These are distinct labeled populations and outcomes, not extra conclusions from the weight-loss comparison. Wegovy, June 2026, section 1; Zepbound, August 2026, section 1.
An indication present in one product's label does not prove that the other drug has no benefit for that condition. It also does not make every formulation, age group or differently branded product interchangeable. Check the current label for the actual product and the condition being considered.
What side effects and serious cautions matter?
Nausea, diarrhea, vomiting and constipation are important tolerability issues with these treatments. Serious label cautions include pancreatitis, gallbladder disease, severe gastrointestinal reactions, dehydration-related kidney injury and serious allergic reactions. Both labels say the products are not recommended in severe gastroparesis. Low blood sugar is an additional concern particularly with insulin or medicines that stimulate insulin release. The labels also address diabetic-retinopathy complications in people with type 2 diabetes and aspiration risk during general anesthesia or deep sedation. These issues require assessment in the relevant clinical setting; the no-diabetes weight trial does not resolve all of them. Wegovy warnings and precautions; Zepbound warnings and precautions.
Both carry a boxed warning about thyroid C-cell tumors seen in rodents; the relevance to humans is unknown. Both are contraindicated with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN2), and with the product's specified serious hypersensitivity. This is not a statement that the medicines have been proved to cause thyroid cancer in humans or that every thyroid condition is the same contraindication. Wegovy boxed warning and section 4; Zepbound boxed warning and section 4.
Pregnancy and other medicines also change the discussion. Weight-loss treatment is not an appropriate goal during pregnancy; the labels describe potential fetal harm and product-specific considerations. Zepbound can reduce the effectiveness of oral hormonal contraceptives, and delayed stomach emptying can affect oral medicines. These are reasons for individualized clinician or pharmacist review, not instructions to start, stop or adjust a treatment from this article. Wegovy interactions and pregnancy information; Zepbound sections 7 and 8.
Does this result answer which is better for me?
It answers a group-level weight and waist question for the studied setting. It does not select a medicine for you. If your situation involves diabetes, an oral product, Wegovy HD, pregnancy, another important condition or a different treatment goal, the main comparison does not directly answer that version of the question. A result favoring one drug on average weight loss is not an overall health ranking.
Useful questions to bring to a clinician are: Does my condition and exact product match the evidence? Which benefit matters for my treatment goal? Which contraindications, adverse effects and interactions apply to me? What other evidence addresses the outcome I care about? If the product or goal is unclear, clarify that first instead of substituting a familiar brand name into the trial result.
For the underlying compound profiles and their additional studies, return to semaglutide, tirzepatide or the hub's weight-management topic. This guide provides no dosing, administration, switching or purchasing protocol.
Methods note: what the primary percentages estimate
The publication reports least-squares mean percentage changes, which are statistical estimates rather than a promise of individual results. The trial's statistical analysis plan identifies a primary modified treatment-regimen estimand: it addresses outcomes under specified handling of treatment discontinuation, other weight-loss treatment and certain treatment changes. This is more specific than calling the result simply a completer average or an unqualified intention-to-treat analysis.
The plan also defines a hypothetical efficacy estimand asking about continued treatment without other weight-loss therapies. Separately reported highest-dose/on-treatment values answer that different analysis question. Registry threshold results can have different denominators and observed-value rules; they should not be combined casually with the primary mean-weight estimates. Statistical analysis plan, October 23, 2024, sections 1.1 and 4.3; trial protocol, August 24, 2023.
Sources6 linked sources
- Aronne and colleagues. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. New England Journal of Medicine, 2025. DOI: 10.1056/NEJMoa2416394. Primary indexed abstract.
- ClinicalTrials.gov NCT05822830. SURMOUNT-5 study design, eligibility, sponsor-reported results, participant flow and adverse events. Results posted November 26, 2025.
- SURMOUNT-5 protocol, August 24, 2023.
- SURMOUNT-5 statistical analysis plan, October 23, 2024.
- Wegovy U.S. prescribing information, revised June 2026. Sections 1, 3–5, 7, 8 and 12; product-specific indications, presentations and risks.
- Zepbound U.S. prescribing information, revised August 2026. Sections 1, 3–5, 7, 8 and 12; product-specific indications, presentations and risks.
Selected-source and editorial check: November 2, 2026. We reviewed the indexed primary abstract, official trial results, protocol and analysis plan, and the full current product labels. The full NEJM paper and supplement were inaccessible during this check; no full-paper or complete literature review, clinician approval or individualized recommendation is claimed. Source access date and document editions are different.