Comparing Two GLP-1 Medications: A Closer Look at the SURMOUNT-5 Trial

Most GLP-1 trials compare a medication with a placebo. A much smaller number compare two medications against each other, which is what many people actually want to know. This guide walks through the SURMOUNT-5 trial, who it studied and what it cannot tell us. It is general education, not medical advice, and it does not suggest any product or provider.

How the comparison was set up

SURMOUNT-5 was a phase 3b trial in the United States and Puerto Rico, run at 32 sites between April 2023 and November 2024. It randomly assigned 751 adults with obesity, or with overweight and at least one weight-related health problem, to one of two weekly injectable medications: tirzepatide or semaglutide. Nobody in the trial had diabetes. The average age was 45, and 35 percent of participants were men. Each person took the highest dose they could tolerate, and everyone received lifestyle counseling. The trial was open-label, which means participants and clinicians knew which medication was being used, and it was sponsored by Eli Lilly, which makes tirzepatide.

The results

• Weight: at 72 weeks, average weight change was -20.2% with tirzepatide and -13.7% with semaglutide. In kilograms that was about 22.8 kg and 15.0 kg.
• Waist: waist circumference fell by 18.4 cm with tirzepatide and 13.0 cm with semaglutide.
• Thresholds: more people on tirzepatide reached weight losses of 10 percent and higher, up to 25 percent.
• Stopping because of stomach side effects: 2.7% with tirzepatide and 5.6% with semaglutide.

The percentages are model-based averages for the whole group, not what any one person should expect. Weight loss was smaller in men than in women in both groups.

Putting the numbers in context

Most headlines about this trial focus on one comparison, but the results are an average of hundreds of different experiences. Some people lost far more than the average and some lost far less. A difference between two medications on average does not tell you which is better for one person, who may have different risks, other medications, costs or side effects. The trial was also not designed to compare safety, so the side-effect figures should be read with care and are not a verdict. Our guide to side effects in the big GLP-1 trials goes through what participants reported.

Limits worth knowing

• It lasted 72 weeks. What happens over several years, or after stopping, is a separate question; see what happens when you stop a GLP-1 medication.
• It did not measure what the weight was made of. The trial reports total weight and waist, so it does not settle the questions in our guide to muscle loss on GLP-1 medications.
• It was open-label and sponsored. That is common for large drug trials and does not make a result wrong, but it is worth knowing when you read about it.
• It excluded people with diabetes. The results may not carry over to them.

Talking it over with a clinician

If you are thinking about whether any prescription medication makes sense for you, the useful next step is a conversation with a clinician who knows your history. A trial like this is one input. A prescriber weighs it against your health conditions, goals, costs, how you tolerate the medication and what you plan to do long term.

In short

SURMOUNT-5 is among the first direct comparisons of two leading GLP-1 medications, and on average the group on tirzepatide lost more weight and waist size over 72 weeks than the group on semaglutide. It does not show that one is right for everyone, and it is a reminder to read averages as averages.

Sources

• Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as compared with semaglutide for the treatment of obesity (SURMOUNT-5). New England Journal of Medicine, 2025;393(1):26-36.
• American College of Cardiology, “SURMOUNT-5: Greater Loss of Weight, Waist Circumference With Tirzepatide Than Semaglutide,” journal scan, July 2025.
• Eli Lilly and Company, news release on the SURMOUNT-5 results, May 2025 (design and sponsor details).
• Healio, “Tirzepatide bests semaglutide for weight loss in adults with obesity,” May 2025.