In May 2025, the New England Journal of Medicine published the first head-to-head clinical trial comparing two of the most effective anti-obesity medications on the market: tirzepatide (Zepbound) and semaglutide (Wegovy). This was the phase 3b open label extension of the SURMOUNT-5 clinical trial involving 751 non-diabetic obese patients. The main finding was that tirzepatide led to significantly more weight loss than semaglutide over 72 weeks of treatment. Noteably, for patients understandably eager to lose weight quickly, the maximum efficacy was seen at the highest doses of both medications and after close to 1.4 years of treatment.
In this blog post, we review the study design, outcomes, side effects, and what these findings mean for patients and providers considering medication for weight loss.
Why This Study Matters
GLP-1 receptor agonists like semaglutide offer patients with obesity never-seen-before efficacy, and often life changing results. Tirzepatide differs from semaglutide, as it is a dual GIP/GLP-1 agonist that uses two mechanisms to help people lose weight. Before this clinical trial, there were no head-to-head comparisons for these two medications. As described in our recent blog post [Comparing Wegovy and Zepbound in Non-Diabetic Patients – Which is Best for You? – BeLite Medical Center], there was some evidence that tirzepatide was on average more efficacious than semaglutide.
This randomized controlled trial helped answer a critical question: Which drug is more effective for weight loss—tirzepatide or semaglutide?
Study Design: Tirzepatide vs. Semaglutide (NEJM, 2025)
| Category |
Details |
| Published |
May 11, 2025 – New England Journal of Medicine |
| Participants |
751 adults with obesity (BMI ≥30) or BMI ≥27 with comorbidities |
| Diabetes status |
Excluded patients with type 2 diabetes |
| Treatment Duration |
72 weeks |
| Groups |
Tirzepatide (10 or 15 mg weekly) vs. Semaglutide (1.7 or 2.4 mg weekly) |
| Endpoints |
% body weight loss, ≥25% weight loss, waist circumference, side effects |
Key Results: Tirzepatide Outperforms Semaglutide
- Total Body Weight Loss
| Drug |
Average % Weight Loss |
| Tirzepatide |
20.2% |
| Semaglutide |
13.7% |
Tirzepatide users lost nearly 50% more weight on average than those taking semaglutide.
- “Amazing” Weight Loss (>25% Body Weight)
- 32% of tirzepatide-treated patients lost ≥25% of body weight
- 16% of semaglutide-treated patients met the same threshold
- Waist Circumference Reduction
| Drug |
Reduction |
| Tirzepatide |
18.4 cm [7.2 inches] |
| Semaglutide |
13.0 cm [5.1inchaes] |
- Side Effects and Tolerability
Quoting from the article:
“Serious adverse events were reported by 31 participants [4.1%] overall with a similar occurrence in the tirzepatide group [4.8%] and the semaglutide group [3.5%]. One adjudication-confirmed case of pancreatitis was reported in the semaglutide group. .. No adjudication-confirmed major cardiovascular events, deaths, cases of medullary thyroid cancer, or cases of pancreatic cancer were reported.”
Common Side Effects
| Side Effect |
Tirzepatide [%] |
Semaglutide [%] |
| Nausea |
44 |
44 |
| Diarrhea |
23.5 |
23.4 |
| Vomiting |
15 |
21.3 |
| Fatigue |
10.4 |
12.2 |
- Discontinuation due to side effects were similar for both medications
- Two semaglutide patients, and no Tirzepatide patients discontinued due to Cholelithiasis [gall bladder problems].
Clinical Implications: What This Means for Patients
This trial confirms that tirzepatide is the most effective obesity medication currently available, producing superior weight loss and waist reduction compared to semaglutide in non-diabetic patients. Its important to note that these are averages, and do not predict the results that might be seen with any individual patient.
However, both drugs remain effective, and choice should be based in part on:
- Cost and insurance coverage
- Side effect tolerance
- Medical history
- Provider guidance and patient preference.
Summary
The 2025 NEJM trial provides strong evidence that tirzepatide leads to greater weight loss than semaglutide, on average, in patients without diabetes. For individuals struggling with obesity, tirzepatide may offer a more powerful treatment option, though many do very well on semaglutide.As always, treatment decisions should be made in consultation with a qualified healthcare provider.
The providers at BE-Lite Medical Center are experts with years/decades of experience using medications, such as wegovy or semaglutide, to help patients lose weight. Book an appointment for a free consultation.
Citation
Jastreboff AM, et al. (2025). Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. New England Journal of Medicine, May 11, 2025.
https://www.nejm.org/doi/full/10.1056/NEJMoa2416394
Signed:
Richard B. Rothman MD, PhD
Medical Director
BE-Lite Medical Center
Medical Disclaimer:This blog post is provided for informational purposes only and does not constitute medical advice, diagnosis, or treatment. It is not intended to substitute for consultation with a licensed healthcare provider. Readers should not use this information to diagnose or treat a medical or health condition without consulting an appropriately qualified healthcare professional. Any reliance on the information in this blog is at the reader’s own risk. Individual weight loss results vary based on personal health status and adherence to medical advice. No doctor-patient relationship is created by accessing or reading this content.
About Richard B Rothman MD, PhD, Medical Director, BeLite Medical Center
Dr. Rothman is the Medical Director of BeLite Medical Center, which has been helping patients lose weight in the Northern Virginia area since 1996. Board certified in Psychiatry, Dr. Rothman earned his M.D. and Ph.D. in Pharmacology from the University of Virginia in 1982.
