A head-to-head trial published in 2025 compared the effectiveness and side effects of semaglutide and tirzepatide. Its results are useful, but your medical history, past experiences, and access to treatment also matter.
How semaglutide and tirzepatide work
Wegovy (semaglutide) and Zepbound (tirzepatide) are prescription medicines used for adult weight management in the United States, alongside diet and physical activity. These medications belong to a class of weight loss drugs referred to as incretin mimetics or incretin-based therapies. While they’re in the same drug class, they work slightly differently: Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist, while tirzepatide is a dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist. By activating these hormone receptors, they help the body regulate appetite, feel fuller, and empty the stomach more slowly.
What did the study find?
The SURMOUNT-5 study compared tirzepatide to semaglutide in a group of 751 adults with obesity who did not have type 2 diabetes over the course of 72 weeks. This open-label study means the participants and healthcare providers knew which medication was being used. Lilly funded the study, which was published in the New England Journal of Medicine in 2025.
In the trial, people were randomly assigned to receive either the maximum tolerated weekly dose of tirzepatide, 10 mg or 15 mg, or the maximum tolerated weekly dose of semaglutide, 1.7 mg or 2.4 mg, injections. At the end of 72 weeks, the average amount of weight lost was greater with tirzepatide than semaglutide: 20.2% and 13.7%, respectively, which is a difference of 6.5 percentage points. Digestive side effects were most commonly reported by people taking either medication in the trial and tended to occur when increasing to higher doses. Most side effects were mild to moderate.
How to interpret the SURMOUNT-5 study
Here are some important factors to consider as you think about these results and whether one medication is better than the other.
Percentages aren’t individualized: Keep in mind, these are the percentage outcomes for the group of people in the study, not necessarily what you can expect to experience if prescribed either medication.
It’s important to compare medications using results from head-to-head trials like SURMOUNT-5 rather than by looking at each medication’s individual clinical trials. This is because factors like the medications’ doses, the types of people in the trials, how long people were followed, and even how the data is calculated can be different across different studies, making them not comparable.
Look at the type of medication used: SURMOUNT-5 included two doses of semaglutide at 1.7 mg or 2.4 mg once weekly, while there are other formulations of semaglutide, including an oral semaglutide pill as well as a higher-dose, once-weekly version (7.2 mg) known as Wegovy HD. Neither of these options was included in the study.
Check with your insurer on what’s covered: If your healthcare provider prescribes one of these medications for weight management, make sure your health insurance covers the specific brand name of the drug. For example, even if your insurance approves Ozempic® (semaglutide) for a different medical condition, it doesn’t necessarily mean Wegovy will be approved for weight management.
FDA-approved products are the starting point for this comparison. Compounded versions are not FDA-approved and do not automatically share the clinical trial evidence for Zepbound or Wegovy. FDA advises that compounded drugs should be used only when a patient’s medical needs cannot be met by an approved drug. Ask your prescriber exactly what product they are considering.
Are they FDA-approved for your specific goals?
Both drugs are FDA-approved for weight management. Wegovy is also FDA-approved to reduce the risk of major cardiovascular events, such as heart attack, stroke, and cardiovascular death, in adults who have obesity or are overweight, and already have cardiovascular disease. Zepbound is FDA-approved to treat moderate to severe obstructive sleep apnea in adults with obesity. But these additional FDA-approved indications don’t apply to everyone using GLP-1-related drugs, only certain populations. Talk with your provider about your specific treatment goals and discuss if Wegovy’s or Zepbound’s unique FDA-approved uses apply to you. For instance, if you have obesity-related sleep apnea, know that a GLP-1 medication does not take the place of your breathing treatment, such as CPAP or BiPAP. You may find that tracking your symptoms, checking in with your provider, and using Zepbound can improve your sleep apnea over time. Your provider will decide if you can stop using your breathing treatment at some point.
Can you afford them?
Be sure to ask about more than just the price of the medication itself. Costs can vary by location and include any or all of the following: medication, doctor’s visit, monthly membership, and other costs like needles and alcohol swabs. Introductory pricing can be helpful, but consider asking what happens after the introductory price. Be sure to check eligibility and refill limits; prices can change when an offer ends. AllyRx's price comparison tool can help you compare provider costs.
Measuring progress beyond weight
For some, progress on the scale isn’t the most important treatment outcome. Your provider may track your response to Wegovy or Zepbound using glucose readings and/or changes to specific symptoms. Ask what sort of outcome they recommend monitoring to make sure your medication is working.
Your experience with either medication
It’s not possible to know ahead of time which medication will agree with you better. Both commonly cause digestive issues, including nausea, vomiting, diarrhea, constipation, and other gastrointestinal side effects. Percentages seen in each medication’s individual FDA approval studies won’t tell you how you’ll respond. If you’ve used one or both medications in the past, ask yourself how they worked for you and what happened when you stopped. Then bring that information to your healthcare provider. They’ll consider your past experiences when prescribing Wegovy or Zepbound.
Other health conditions
The decision about Wegovy or Zepbound also depends on your overall health. Neither medicine should be used if you have a personal or family history of medullary thyroid carcinoma, or if you have multiple endocrine neoplasia syndrome type 2. Other medical conditions that could be relevant for your provider to know about before prescribing include allergies, a history of pancreatitis, diabetic eye disease, kidney problems, gallbladder problems, and/or any severe digestive issues.
How would you switch medications?
The milligram doses of semaglutide and tirzepatide aren’t interchangeable. If you’re thinking of starting, stopping, or transitioning between GLP-1-related weight loss injections, talk with your provider to find out which medication and starting dose is best for you and what to expect when making a switch. Neither Wegovy’s nor Zepbound’s FDA-approved label advises combining or alternating tirzepatide and semaglutide medications. Ask your provider for detailed instructions on what to expect, including medication timing, what to monitor, and symptoms to watch out for.
Pregnancy, contraception, and serious symptoms
If you’re pregnant or planning pregnancy, contact your prescriber about the treatment plan. Weight-management medicines should not be used during pregnancy. Zepbound has a separate precaution for people using oral hormonal birth control: use a non-oral contraceptive method or add a barrier method for 4 weeks after starting and for 4 weeks after every dose increase. Ask your prescriber or pharmacist how to put that advice into practice with your current contraception. Discuss with your provider how you’d monitor for severe reactions like a severe allergic reaction, dehydration, persistent vomiting, and/or severe stomach pain, and what you should do if they happen.
Questions to discuss with your healthcare provider
Am I eligible to use semaglutide or tirzepatide for weight management?
What side effects can I expect? How will I know if they’re serious enough to contact my healthcare team? What steps can I take to minimize side effects?
What’s the cost of the medication with my health insurance? Does my insurance require a prior authorization? If so, is there a form I can fill out at home?
How long will I need to stay on the medication? What happens to my weight if I stop?
What else can I do to support my efforts? Who else is on my healthcare team that I should loop into this process?
How often will we meet to monitor my progress? What kind of realistic, sustainable plan can we make to support my health?