Tirzepatide produced greater weight loss than semaglutide in SURMOUNT-5, the first randomized head-to-head obesity trial of the two injectable drugs. Published in The New England Journal of Medicine in 2025, the 72-week phase 3b study randomized 751 adults with obesity but without type 2 diabetes to the maximum tolerated dose of tirzepatide or semaglutide and found average weight reductions of 20.2% and 13.7%, respectively.
SURMOUNT-5 finally compared the two drugs in the same randomized trial
Before SURMOUNT-5, comparisons between tirzepatide and semaglutide usually placed results from separate trials side by side. That approach is useful for generating hypotheses but cannot control for differences in enrolled patients, study duration, adherence, dose escalation, and statistical methods.
SURMOUNT-5 addressed that problem directly. Participants were randomly assigned 1:1 to once-weekly tirzepatide at a maximum tolerated dose of 10 or 15 mg, or semaglutide at 1.7 or 2.4 mg, for 72 weeks. Everyone received diet and physical-activity counseling. The trial was open label because the drugs were administered with visibly different injection devices.
Principal investigator Louis Aronne summarized the value of the design simply: “This study allowed us to do a direct comparison.” The trial was conducted at 32 sites in the United States and Puerto Rico and was funded by Eli Lilly, the manufacturer of tirzepatide.
Tirzepatide produced a larger reduction in both body weight and waist circumference
The primary endpoint was percentage change in body weight from baseline to week 72. The least-squares mean reduction was 20.2% with tirzepatide and 13.7% with semaglutide, a between-group difference of 6.5 percentage points. The 95% confidence intervals were 19.1% to 21.4% for tirzepatide and 12.6% to 14.9% for semaglutide, with P<0.001.
Waist circumference also decreased more with tirzepatide. The least-squares mean reduction was 18.4 cm with tirzepatide versus 13.0 cm with semaglutide, again with P<0.001.
Participants assigned tirzepatide were also more likely to reach prespecified weight-loss thresholds of at least 10%, 15%, 20%, and 25%. The trial therefore showed a consistent efficacy advantage across several measures rather than a difference confined to the mean weight change.
The mechanism differs because tirzepatide engages two incretin receptors
Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. Tirzepatide activates both the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor. Our GIP and GLP-1 explainer examines why that dual pharmacology is more complicated than simply adding the effects of two hormones together.
Both drugs reduce appetite and food intake and improve glucose regulation, but tirzepatide has its own receptor potency, signaling profile, pharmacokinetics, and dose-response relationship. SURMOUNT-5 demonstrates a clinical difference between the two treatment strategies. It does not identify exactly how much of that difference comes from GIP-receptor signaling.
For a broader overview of how these medicines affect appetite, insulin secretion, glucagon, and gastric emptying, see our GLP-1 drugs explainer.
Gastrointestinal side effects remained the dominant tolerability issue for both drugs
The most common adverse events in both groups were gastrointestinal. Most were mild to moderate and occurred mainly during dose escalation, consistent with the established tolerability profile of incretin-based obesity medicines.
Nausea, vomiting, diarrhea, constipation, and abdominal symptoms can occur with either drug. Our GLP-1 side-effects guide covers the common symptoms and the less frequent warning signs that require medical attention.
SURMOUNT-5 was not designed to establish that one drug is universally easier to tolerate. Individual response depends on dose, titration, comorbidities, other medications, and the highest dose a person can continue taking.
The head-to-head result does not compare every dose now available in 2026
This is an important limitation for interpreting SURMOUNT-5 today. The semaglutide arm used a maximum tolerated dose of 1.7 or 2.4 mg weekly. In March 2026, FDA approved a higher 7.2 mg dose of Wegovy for weight reduction and long-term weight maintenance in certain adults with obesity or overweight.
SURMOUNT-5 therefore does not answer how tirzepatide 10 or 15 mg compares directly with Wegovy 7.2 mg. The randomized result remains valid for the doses that were actually studied, but it should not be silently extended to a dose that was not part of the trial.
The same principle applies to brand-level comparisons. Ozempic and Mounjaro are diabetes products with different approved dosing frameworks from Wegovy and Zepbound. A trial comparing obesity doses of Wegovy and Zepbound should not be treated as a direct comparison of every semaglutide and tirzepatide product.
The drugs also have different evidence and approvals beyond weight loss
Weight reduction is only one part of treatment selection. Wegovy has an FDA indication to reduce the risk of cardiovascular death, heart attack, and stroke in adults with established cardiovascular disease and obesity or overweight. It is also approved for noncirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis.
Zepbound is approved for moderate to severe obstructive sleep apnea in adults with obesity. We cover that indication in our tirzepatide sleep-apnea approval explainer.
Those indications were established in different clinical programs. SURMOUNT-5 compared weight loss and waist circumference, not cardiovascular-event prevention, liver outcomes, or sleep-apnea outcomes. A larger average weight reduction therefore does not automatically make tirzepatide superior for every clinical objective.
What the evidence cannot yet answer
SURMOUNT-5 enrolled adults with obesity but without type 2 diabetes, so the weight-loss difference should not be assumed to be identical in people with diabetes. It was also open label, which can influence adherence, reporting of subjective adverse events, and treatment expectations even when the primary outcome is objectively measured.
The study was funded by Eli Lilly. Several authors were Lilly employees, and Aronne disclosed paid relationships with both Eli Lilly and Novo Nordisk. Those relationships do not invalidate a randomized trial, but they are relevant context when interpreting manufacturer-sponsored comparative research.
Most importantly, average results do not predict an individual’s response. Some people lose substantially more or less weight than the trial mean, and treatment choice also depends on indication, contraindications, adverse effects, access, cost, and the dose a patient can tolerate.
The direct comparison answers one question clearly, but not every question about the two drugs
SURMOUNT-5 established that, at the doses tested in adults with obesity without diabetes, tirzepatide produced greater average weight loss and a larger reduction in waist circumference than semaglutide over 72 weeks. That is stronger evidence than comparing separate trials. It is not evidence that tirzepatide is automatically the right choice for every patient, every indication, or every dose now available.
References
- Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. N Engl J Med. 2025;393:26-36. DOI: 10.1056/NEJMoa2416394.
- U.S. Food and Drug Administration. FDA Approves Fourth Product Under National Priority Voucher Program, Higher Dose Semaglutide. March 19, 2026. FDA announcement.