Is Tirzepatide Better Than Semaglutide? What the Research Shows

Semaglutide and tirzepatide both influence hormones involved in appetite, digestion, and blood sugar regulation.

Semaglutide works primarily by activating the GLP-1 receptor. GLP-1 signaling can help reduce appetite, increase feelings of fullness, and slow the rate at which food leaves the stomach.

Tirzepatide takes a slightly different approach. It activates both the GLP-1 and GIP receptors.

That dual mechanism is one of the major differences between the medications and may help explain why tirzepatide has produced greater average weight loss in clinical trials.

For years, researchers had strong results for both medications, but most major studies evaluated them separately.

That changed with the SURMOUNT-5 trial, which directly compared tirzepatide and semaglutide in 751 adults with obesity who did not have type 2 diabetes.

Participants received the maximum tolerated dose of either medication for 72 weeks. The results were significant:

Participants taking tirzepatide also experienced a greater average reduction in waist circumference: 18.4 cm compared with 13.0 cm with semaglutide.

People receiving tirzepatide were also more likely to reach weight-loss milestones of at least 10%, 15%, 20%, and 25% of their starting body weight.

In this head-to-head trial, tirzepatide was therefore superior to semaglutide for average weight reduction and waist-circumference reduction.

The head-to-head results generally align with what researchers had already observed in the individual clinical trial programs for these medications.

In the STEP 1 trial, adults receiving semaglutide 2.4 mg lost an average of approximately 14.9% of their starting body weight over 68 weeks, compared with 2.4% among those receiving placebo.

In the SURMOUNT-1 trial, average weight loss after 72 weeks with tirzepatide was approximately:

• 15.0% with 5 mg
• 19.5% with 10 mg
• 20.9% with 15 mg

The placebo group lost approximately 3.1%.

These were separate trials with different participants and protocols, so their percentages shouldn't be treated as a direct comparison. However, the later SURMOUNT-5 head-to-head trial provided stronger evidence that tirzepatide can produce greater average weight loss.

Not necessarily.

Clinical trials tell us how groups of patients respond on average. They cannot predict exactly how one individual will respond.

Some patients may achieve excellent results with semaglutide and have no reason to switch medications. Others may respond more strongly to tirzepatide.

A healthcare provider may also consider factors such as:

• Previous experience with GLP-1 medications
• Treatment goals
• Side effects and tolerability
• Medical history
• Current medications
• Cost and accessibility
• Individual response to treatment

The medication associated with the greatest average weight loss isn't automatically the best medication for every person.

Both medications commonly cause gastrointestinal side effects, particularly while the dose is being increased.

These can include:

• Nausea
• Diarrhea
• Constipation
• Vomiting
• Abdominal discomfort
• Decreased appetite

In SURMOUNT-5, gastrointestinal problems were the most commonly reported adverse events with both medications. Most were considered mild to moderate and occurred primarily during dose escalation.

This is one reason GLP-1 medications are typically started at lower doses and gradually increased rather than beginning immediately at higher maintenance doses.

SURMOUNT-5 primarily compared weight change over 72 weeks in adults with obesity without type 2 diabetes. It did not establish which treatment better prevents cardiovascular events or treats sleep apnea. Greater average weight loss is not proof of superiority for every health outcome or a compounded formulation.

SURMOUNT-5: original comparison trial

If we're asking one narrow question — which medication produces more weight loss on average? — the strongest direct comparison currently points toward tirzepatide.

In the SURMOUNT-5 head-to-head trial, participants taking tirzepatide lost an average of 20.2% of their body weight, compared with 13.7% with semaglutide after 72 weeks.

But weight-loss treatment isn't simply about choosing whichever medication produced the highest percentage in a clinical trial.

Semaglutide remains an effective option for weight management, and individual results can vary considerably with either medication. The appropriate choice should ultimately be based on a patient's health history, treatment goals, response, tolerability, and a healthcare provider's clinical judgment.

At Luma, eligible patients can discuss their weight-loss goals and available treatment options with a licensed healthcare provider to determine which approach may be appropriate for them.