Tirzepatide vs Semaglutide: What the Trials Show

Two big names, one direct comparison in obesity. Here is what it found, who funded it and what it cannot tell you.

Tirzepatide produced more weight loss than semaglutide in the one head-to-head trial in adults with obesity and without diabetes: an average of 20.2% of body weight at 72 weeks against 13.7%.¹ Tirzepatide also lowered blood sugar and weight more than semaglutide 1 mg in adults with type 2 diabetes.² Both are weekly injections with the same class risks, and the trials do not show one to be free of gastrointestinal effects.¹²

This guide covers what each drug is approved for, what the trials found, how the side effects compare, and what to ask a clinician. It cannot say which suits you, because that depends on your health history and coverage.

How do tirzepatide and semaglutide differ?

The tablet and injection forms of Wegovy are described on the same label; the trials below used the weekly injection.⁴ For the oral options see our guide to oral GLP-1 medications.

What did the head-to-head trials find?

SURMOUNT-5 (obesity, no diabetes). In this open-label phase 3b trial, 751 adults were randomly assigned to the maximum tolerated dose of tirzepatide (10 or 15 mg) or semaglutide (1.7 or 2.4 mg) weekly for 72 weeks. Mean weight change was -20.2% on tirzepatide and -13.7% on semaglutide, and waist circumference fell 18.4 cm against 13.0 cm. More men and women on tirzepatide reached each weight-loss threshold from 10% to 25%. The most common adverse events in both groups were gastrointestinal, mostly mild to moderate and during dose escalation. The trial was funded by Eli Lilly, which makes tirzepatide, and open-label, so participants knew their drug.¹

SURPASS-2 (type 2 diabetes). In this 40-week open-label trial, 1,879 adults received tirzepatide 5, 10 or 15 mg or semaglutide 1 mg weekly. Hemoglobin A1c fell 2.01, 2.24 and 2.30 percentage points on tirzepatide against 1.86 on semaglutide, and body weight fell 1.9, 3.6 and 5.5 kg more. Nausea occurred in 17 to 22% of tirzepatide patients and 18% of semaglutide patients; serious adverse events were 5 to 7% against 3%. This trial was also funded by Eli Lilly, and semaglutide 1 mg is below the 2.4 mg obesity dose.²

For context, the semaglutide obesity trial against placebo (STEP 1, 1,961 adults, 68 weeks, Novo Nordisk-funded) found a mean change of -14.9% against -2.4% on placebo.⁵ The tirzepatide equivalent (SURMOUNT-1, 2,539 adults, 72 weeks, Lilly-funded) found -15.0% to -20.9% by dose against -3.1%.⁶ Comparing trials this way is weaker than SURMOUNT-5, because populations and durations differ.

How do the side effects compare?

Both drugs cause mainly gastrointestinal effects. The Zepbound label lists nausea, diarrhea, vomiting, constipation, abdominal pain, dyspepsia, injection site reactions, fatigue, hypersensitivity reactions, eructation, hair loss and reflux among reactions in 5% or more of patients.³ The Wegovy label lists nausea, diarrhea, vomiting, constipation, abdominal pain, headache, fatigue, dyspepsia, dizziness and others; discontinuation for nausea was 1.8% against 0.2% on placebo.⁴ Percentages from separate labels cannot be compared directly. Both carry a boxed warning for rodent thyroid C-cell tumors; neither is for anyone with a personal or family history of medullary thyroid carcinoma or MEN 2.³⁴ For a longer list see our guide to GLP-1 side effects.

Which suits which situation?

• Weight loss is the main goal, without diabetes. SURMOUNT-5 favored tirzepatide on average weight change.¹
• Heart disease with obesity. Wegovy's label includes a cardiovascular risk reduction indication that Zepbound's label does not list.⁴³
• Sleep apnea with obesity. Zepbound's label includes moderate to severe obstructive sleep apnea.³
• Preferring a pill. Wegovy has a daily tablet with fasting rules; tirzepatide is an injection only.⁴

Averages hide individual variation: some people lose less on tirzepatide than the average on semaglutide, and tolerability, coverage and supply often decide the choice.

Our pick (sponsored): compounded tirzepatide from Vea Health

Compounded tirzepatide from Vea Health is our pick in this comparison because we have a financial relationship with Vea Health. That is the basis for the placement, not a test or a ranking of products. We make no claim that it is safer, stronger or better than Zepbound, Wegovy or any other provider.

Vea Health says it offers compounded tirzepatide injections, prescribed only after a licensed clinician reviews an online health questionnaire, and that a patient is not charged unless a clinician approves the prescription.⁷ The SURMOUNT-5 result describes the approved product, not a compounded one, and compounded drugs are not reviewed by the FDA for safety, effectiveness or quality.⁸⁹ It suits a reader who has discussed this with a clinician, understands the product is compounded, and prefers an online consultation. A clinician may decide an approved product is the better fit. We cover the differences in compounded tirzepatide versus Zepbound.

Questions to ask a clinician

• Do I have a history of thyroid cancer, pancreatitis or gallbladder problems?
• Which drug does my coverage allow, and is it in stock at my pharmacy?
• What is the dose-escalation plan, and what do I do if nausea is bad?
• If a product is compounded, which pharmacy prepares it and how do I measure each dose?

Quick questions

Is tirzepatide better than semaglutide for weight loss?

In the only head-to-head trial in adults with obesity and no diabetes, tirzepatide produced a larger average weight loss (20.2% vs 13.7% at 72 weeks). Individual results vary and the trial was funded by Eli Lilly.

Do tirzepatide and semaglutide have the same side effects?

Both mainly cause gastrointestinal effects such as nausea, diarrhea and vomiting, and both carry a boxed warning for thyroid C-cell tumors in rodents.

Is Wegovy the same as semaglutide?

Wegovy is the FDA-approved brand of semaglutide for weight reduction and other uses listed on its label.

Is there a pill version of either?

Wegovy has a once-daily tablet taken on an empty stomach. Tirzepatide is an injection.

Is compounded tirzepatide FDA-approved?

No. Compounded drugs are not reviewed by the FDA for safety, effectiveness or quality.

More briefs

• Compounded Tirzepatide vs Zepbound: What Actually Differs
• Is There an Oral GLP-1?
• Does a GLP-1 Cause Muscle Loss?
• Compounded GLP-1s Explained: What They Are and What to Ask