Clinical evidence · SURMOUNT-5
SURMOUNT-5 Explained: Tirzepatide vs Semaglutide Head-to-Head Results
The first direct trial of tirzepatide against semaglutide for weight loss: 751 adults, 72 weeks, 20.2% versus 13.7% average body-weight reduction, and what the result does and does not mean for compounded treatment.
In one paragraph: SURMOUNT-5 (NCT05822830) randomized 751 adults with obesity, or overweight with a weight-related condition, and without diabetes, to tirzepatide or semaglutide for 72 weeks. Average body-weight reduction was 20.2% with tirzepatide and 13.7% with semaglutide. 87.7% of tirzepatide participants lost at least 10% of body weight versus 66.7% on semaglutide; 71.7% versus 45.0% lost at least 15%. Both drugs were used at their highest tolerated labeled maintenance doses. The trial studied the brand products; compounded versions were not studied and are not FDA-approved.
Why This Trial Matters
Before SURMOUNT-5, comparisons between the two leading GLP-1 medications relied on lining up separate trials: the STEP-1 trial of semaglutide (14.9% average loss at 68 weeks) against SURMOUNT-1 of tirzepatide (20.9% at 72 weeks on the top dose). Cross-trial comparisons are unreliable because the populations, durations, and definitions differ. SURMOUNT-5 removed that problem by randomizing the same kind of participants to the two drugs in one study, so the gap it measured is the first direct answer to the question patients ask most: which one works better?
How the Trial Was Designed
| Design element | SURMOUNT-5 |
|---|---|
| Participants | 751 adults with obesity, or overweight plus at least one weight-related comorbidity, without diabetes |
| Comparison | Tirzepatide (10 or 15 mg weekly) versus semaglutide (1.7 or 2.4 mg weekly), each at the highest tolerated labeled maintenance dose |
| Duration | 72 weeks |
| Blinding | Open-label (participants and clinicians knew the assigned drug); randomized allocation |
| Primary endpoint | Percent change in body weight from baseline to week 72 |
| Registration and publication | ClinicalTrials.gov NCT05822830; New England Journal of Medicine, 2025 |
The Results
| Outcome at week 72 | Tirzepatide | Semaglutide |
|---|---|---|
| Average body-weight change | −20.2% | −13.7% |
| Participants losing ≥10% of body weight | 87.7% | 66.7% |
| Participants losing ≥15% of body weight | 71.7% | 45.0% |
The average gap of about 6.5 percentage points is large in clinical terms. Secondary measures reported by the investigators, including waist circumference, also favored tirzepatide. Both drugs produced substantial weight loss; the finding is that tirzepatide produced more, not that semaglutide failed.
Two features of the design matter for interpretation. The trial was open-label, so participants knew which drug they were taking, which can influence behavior. And it compared each drug at its full labeled dose, so it says little about lower maintenance doses that many patients use in practice. Neither caveat changes the direction of the result.
Why Two Receptors Beat One
Semaglutide mimics GLP-1, a gut hormone that slows stomach emptying and signals fullness to the brain. Tirzepatide activates the GLP-1 receptor and a second one, GIP. The combined signal appears to reduce appetite more than GLP-1 activation alone, which is the working explanation for the consistent difference across the SURMOUNT and STEP programs. Our tirzepatide vs semaglutide comparison covers the mechanism, dosing schedules, and side-effect profiles in more depth.
What This Means for Compounded Treatment
SURMOUNT-5 studied Zepbound and Wegovy, the FDA-approved brand products. Compounded tirzepatide contains the active ingredient in Zepbound and compounded semaglutide the active ingredient in Wegovy; both are prepared per individual prescription by state-licensed 503A pharmacies and are not themselves FDA-approved as drugs, and neither was part of this trial. The trial is the strongest evidence available about what the two molecules do at labeled doses, and it should be read with that distinction kept clear. Individual results vary with dose, adherence, diet, activity, and biology.
Trimi offers both compounded tirzepatide and compounded semaglutide, prescribed by licensed clinicians through Arora Health's 50-state network and dispensed by named 503A pharmacies (VialsRx, Texas State Board of Pharmacy license #35264, and GreenwichRx). Which medication is appropriate, if either, is determined by a licensed provider through the online visit.
Frequently Asked Questions
What did SURMOUNT-5 find?
SURMOUNT-5 was a 72-week, randomized, open-label trial that compared tirzepatide with semaglutide head-to-head in 751 adults with obesity, or overweight plus at least one weight-related condition, who did not have diabetes. At week 72, participants on tirzepatide lost an average of 20.2 percent of their body weight versus 13.7 percent on semaglutide. The share of participants reaching at least a 10 percent reduction was 87.7 percent with tirzepatide and 66.7 percent with semaglutide, and the share reaching at least 15 percent was 71.7 percent versus 45.0 percent. The results are recorded on ClinicalTrials.gov (NCT05822830) and were published in the New England Journal of Medicine in 2025.
Is tirzepatide better than semaglutide for weight loss?
In this trial, at the doses studied, tirzepatide produced greater average weight loss than semaglutide, and a larger share of participants reached the 10 and 15 percent thresholds. That is a population-level finding about the two brand products used in the trial, not a guarantee for any individual. Some people respond strongly to semaglutide, tolerate it better, or have reasons to prefer it. Which medication is appropriate for you is a decision for a licensed clinician based on your history and goals.
Why does tirzepatide produce more weight loss?
Semaglutide activates one hormone receptor, GLP-1. Tirzepatide activates two, GLP-1 and GIP. The dual action is the leading explanation for the larger effect on appetite and body weight seen across the SURMOUNT program, though the exact mechanism of the GIP contribution is still being studied.
Do the SURMOUNT-5 results apply to compounded tirzepatide or semaglutide?
The trial studied the FDA-approved brand products, Zepbound and Wegovy, at their labeled doses. Compounded tirzepatide contains the active ingredient in Zepbound and compounded semaglutide the active ingredient in Wegovy; both are prepared per individual prescription by state-licensed 503A pharmacies and are not themselves FDA-approved as drugs, and neither was studied in this trial. The trial is the best available evidence about the molecules, and it should be read with that distinction in mind. Individual results vary.
What were the side effects in SURMOUNT-5?
As in earlier trials of both drugs, the most common side effects were gastrointestinal, such as nausea, diarrhea, constipation, and vomiting, mostly mild to moderate and most frequent during dose escalation. Both drugs carry the same class warnings, including the boxed warning about thyroid C-cell tumors seen in rodents. Both drug classes also carry warnings for pancreatitis, gallbladder disease, and kidney injury, and GLP-1 medicines are not appropriate for people with a personal or family history of medullary thyroid carcinoma or MEN 2. A clinician screens for these and manages the dose schedule to keep side effects tolerable.
How were the doses chosen in the trial?
Participants were titrated to the highest tolerated maintenance dose of their assigned drug: 10 mg or 15 mg weekly for tirzepatide, and 1.7 mg or 2.4 mg weekly for semaglutide. Those are the maximum labeled doses for weight management, which is why the trial is read as a comparison of each drug at full strength.
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Medical Disclaimer: This content is for informational purposes only and does not constitute medical advice. Trial results describe averages in study populations; individual results vary. GLP-1 medicines carry risks including nausea and other gastrointestinal effects, pancreatitis, gallbladder disease, kidney injury, and a boxed warning for thyroid C-cell tumors observed in rodents. Compounded medications are not FDA-approved. Always consult a qualified healthcare provider before starting any medication or treatment program.
Sources & References
- ClinicalTrials.gov. A Phase 3b, Randomized Controlled Study to Evaluate the Efficacy and Safety of Tirzepatide Compared to Semaglutide in Adults Who Have Obesity or Overweight With Weight Related Comorbidities (SURMOUNT-5), NCT05822830, results posted. clinicaltrials.gov
- Aronne LJ, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. New England Journal of Medicine, 2025. DOI 10.1056/NEJMoa2416394.
- Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). New England Journal of Medicine 2021;384:989-1002.
- Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). New England Journal of Medicine 2022;387:205-216.
- FDA Prescribing Information for Zepbound (tirzepatide) and Wegovy (semaglutide).