Tirzepatide vs. Semaglutide for Obesity: Which One Works Better?

---

Review of a head to head clinical trial published in The New England Journal of Medicine 5.11.25

By Katie Sorensen, NP-C

If you’re considering medical weight loss, you’ve likely heard of two powerful medications making headlines: tirzepatide (brand names include Mounjaro and Zepbound) and semaglutide (marketed as Ozempic and Wegovy). These injectable medications belong to a class called GLP-1 receptor agonists and have helped many people lose significant weight—but how do they compare?

A new head-to-head clinical trial published May of 2025 in the New England Journal of Medicine gives us some answers. At Weight Loss NP, we’re focused on offering personalized, evidence-based treatment. Here’s a look at what the latest research says and how it might apply to your journey.

---

What the Study Looked At

Researchers followed 750 adults with obesity (and no diabetes) for 72 weeks. The mean BMI for study participants was 39.4 Participants were randomly assigned to take either:

• Tirzepatide, up to 15 mg weekly
• Semaglutide, up to 2.4 mg weekly

The study was designed to directly compare weight loss and health outcomes between the two groups.

---

Tirzepatide Led to More Weight Loss

By the end of the study:

• People taking tirzepatide lost an average of 20.2% of their body weight
• Those on semaglutide lost 13.7%

In pounds, that works out to (Remember, the mean BMI in the study participants was 39.4)

• Tirzepatide: around 50 pounds
• Semaglutide: around 33 pounds

People on tirzepatide were also more likely to lose significant amounts of their body weight.

For someone dealing with joint pain, high blood pressure, or other weight-related conditions, these kinds of results can be life-changing.

---

Waist Circumference and Health Markers

Another important measure in the study was waist circumference, which reflects the amount of visceral fat (the fat around organs that’s closely tied to disease risk).

• On tirzepatide, waist size dropped by an average of 18.4 centimeters
• On semaglutide, the average drop was 13 centimeters

That difference—over 5 centimeters—is meaningful, especially since even a modest reduction in waist circumference can lower your risk for heart disease, stroke, and certain cancers.

Both medications also improved other health markers:

• Blood pressure went down
• Cholesterol and triglycerides improved
• Blood sugar levels decreased (even in people without diabetes)

As expected, the more weight people lost, the better their overall health outcomes.

---

Why Tirzepatide May Work Better

One of the reasons tirzepatide appears to be more effective is that it targets two hormones—GIP and GLP-1—whereas semaglutide only targets GLP-1. This dual action may lead to greater appetite control, better blood sugar regulation, and more weight loss.

---

Side Effects and Safety

Both medications had similar side effect profiles, with gastrointestinal symptoms like nausea, constipation, or diarrhea being the most common. These typically occurred during dose increases and were manageable for most patients.

• About 6% of people on tirzepatide stopped the medication due to side effects
• About 8% of those on semaglutide did the same

Injection site reactions were more common with tirzepatide, but they were mild and didn’t lead to anyone stopping treatment.

---

Which One Is Right for You?

There’s no one-size-fits-all answer. Choosing between tirzepatide and semaglutide depends on your specific health goals, how much weight you’d like to lose, what side effects you might tolerate, and what your insurance might cover / affordability.

At Weight Loss NP, we take time to get to know you—your medical history, your lifestyle, and what matters most to you. Factors such as cost and insurance coverage are also a part of the equation. Together, we can decide which medication is the best fit for your goals.

---

Final Thoughts

This new study confirms what we’ve seen in practice: tirzepatide is an incredibly effective tool for weight loss—perhaps the most effective we’ve seen yet. That said, semaglutide remains a powerful option with proven health benefits, including protection against heart disease.

Whether you’re starting your weight loss journey or looking for better results, we’re here to guide and support you every step of the way—with compassion, science, and a plan that fits your life.

---

Curious which medication might be right for you?
Schedule a free consultation with our team at Weight Loss NP – Click “BOOK NOW” on the top right of our home page. We’ll walk you through your options and help you take the next step toward a healthier, more confident you!

---