Semaglutide vs Tirzepatide: What the Head-to-Head Trials Show

Semaglutide activates one gut-hormone receptor, GLP-1. Tirzepatide activates two, GLP-1 and GIP. That design difference sits behind the headline result: in SURMOUNT-5, the only head-to-head obesity trial so far, adults without diabetes lost an average of 20.2% of body weight on tirzepatide versus 13.7% on semaglutide over 72 weeks.¹ Both are prescription medicines with broadly similar side effects.

Both are once-weekly injections sold under several brand names: semaglutide as Ozempic, Wegovy and the oral Rybelsus, tirzepatide as Mounjaro and Zepbound. Each carries the same boxed warning about thyroid C-cell tumours seen in rodents, and each now has approved uses that go beyond weight.^8,9

This page compares them on the published evidence: how they work, what the pivotal trials found, where the safety data overlap and differ, and why compounded and “research” versions sold online are a different product altogether. It is not a guide to choosing, switching or dosing. Those decisions belong with a prescriber who knows your history.

At a glance

Property	Semaglutide	Tirzepatide
Receptors activated	GLP-1	GIP and GLP-1
US brands	Ozempic, Rybelsus, Wegovy	Mounjaro, Zepbound
Forms	Weekly injection; daily tablets	Weekly injection (pens or vials)
Half-life (label)	About 1 week	About 5 days
SURMOUNT-5 weight change, 72 weeks	-13.7%	-20.2%
Cardiovascular outcome data	SELECT: fewer events vs placebo	SURPASS-CVOT: non-inferior to dulaglutide
Extra weight-brand indications	Cardiovascular risk, MASH	Obstructive sleep apnoea
Boxed warning	Thyroid C-cell tumours (rodents)	Thyroid C-cell tumours (rodents)
US shortage ended	21 February 2025	19 December 2024
Legal status	Prescription only	Prescription only

How semaglutide and tirzepatide work: one receptor or two

Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1. A C18 fatty diacid chain lets it bind albumin in the blood, which protects it from breakdown and gives it an elimination half-life of about one week.⁹

Tirzepatide is built on the GIP sequence instead, and activates both the GIP and GLP-1 receptors. It carries a longer C20 fatty diacid and has a half-life of about five days.⁸ Its label is careful about why GIP matters: nonclinical studies “suggest” GIP may add to the regulation of food intake. The precise reason the dual agonist produces more weight loss in trials is still debated.

Both act on appetite centres in the brain and slow stomach emptying, which is why nausea and fullness dominate the side-effect lists. Neither is a hormone replacement or a “peptide supplement”. Both are engineered drugs, reviewed and approved as such. For how the GLP-1, GIP and glucagon labels are sometimes muddled in marketing, see our explainer on GLP-1 vs GLP-2 vs GLP-3.

Brands and approved uses in the US (September 2026)

• Ozempic and Rybelsus (semaglutide): type 2 diabetes.
• Wegovy (semaglutide injection and tablet): long-term weight management (the injection from age 12), reducing the risk of major cardiovascular events in adults with established cardiovascular disease and obesity or overweight, and MASH with moderate to advanced liver fibrosis under accelerated approval.⁹
• Mounjaro (tirzepatide): type 2 diabetes.
• Zepbound (tirzepatide): long-term weight management in adults, and moderate to severe obstructive sleep apnoea in adults with obesity.⁸

What the trials found: SURMOUNT-5 and the placebo-controlled studies

SURMOUNT-5 is the most direct evidence. It was a phase 3b, open-label trial in 751 adults with obesity but without type 2 diabetes, who received the maximum tolerated weekly dose of tirzepatide (10 or 15 mg) or semaglutide (1.7 or 2.4 mg) for 72 weeks. Mean weight change was -20.2% with tirzepatide and -13.7% with semaglutide, and waist circumference fell by 18.4 cm versus 13.0 cm. More tirzepatide users reached every threshold tested, from 10% to 25% weight loss.¹

The placebo-controlled trials point the same way, though comparing across them is shaky because populations and analysis methods differ.

Trial	Who took part	Length	Mean weight change
STEP 1 (semaglutide 2.4 mg)2	1,961 adults, no diabetes	68 weeks	-14.9% vs -2.4% placebo
SURMOUNT-1 (tirzepatide 5, 10, 15 mg)3	2,539 adults, no diabetes	72 weeks	-15.0%, -19.5%, -20.9% vs -3.1% placebo
STEP UP (semaglutide 7.2 mg)7	1,407 adults, no diabetes	72 weeks	-18.7% vs -15.6% (2.4 mg) and -3.9% placebo
SURMOUNT-5 (head-to-head)1	751 adults, no diabetes	72 weeks	-20.2% tirzepatide vs -13.7% semaglutide

In type 2 diabetes, SURPASS-2 randomised 1,879 adults to tirzepatide 5, 10 or 15 mg or semaglutide 1 mg for 40 weeks. HbA1c fell by 2.01 to 2.30 percentage points with tirzepatide against 1.86 with semaglutide, and weight differences favoured tirzepatide by 1.9 to 5.5 kg.⁴ Semaglutide 1 mg is well below the doses now approved for weight management, so the trial says more about diabetes care than about obesity.

One development muddies the picture. A higher 7.2 mg semaglutide dose, tested in STEP UP, has since joined the Wegovy label.^7,9 It has not been tested head-to-head against tirzepatide, so the size of the gap at today’s top doses is unknown.

Heart, liver and sleep apnoea: outcomes beyond the scales

Weight is not the only endpoint that matters, and here the two evidence bases differ in shape rather than simply in size.

Semaglutide has a completed placebo-controlled cardiovascular outcomes trial in obesity. SELECT enrolled 17,604 adults aged 45 or over with established cardiovascular disease and overweight or obesity but no diabetes. Cardiovascular death, heart attack or stroke occurred in 6.5% on semaglutide 2.4 mg versus 8.0% on placebo (hazard ratio 0.80) over a mean follow-up of 39.8 months.⁵ That result underpins the cardiovascular indication on the Wegovy label.⁹

Tirzepatide’s largest outcomes trial so far used an active comparator instead of placebo. SURPASS-CVOT randomised 13,299 adults with type 2 diabetes and atherosclerotic cardiovascular disease to tirzepatide or dulaglutide, an older GLP-1 drug already shown to reduce events. The primary outcome occurred in 12.2% versus 13.1% (hazard ratio 0.92), which met the test for non-inferiority but not superiority.⁶ The Zepbound label does not carry a cardiovascular risk-reduction indication.⁸

Each drug also holds an indication the other lacks on its weight-management label: obstructive sleep apnoea for Zepbound, and MASH with liver fibrosis for Wegovy.^8,9 Greater weight loss is plausible as a route to wider benefits, but it is not the same thing as a trial showing them.

How strong is the evidence, and who funded it?

By drug-trial standards, the evidence here is strong: large, randomised trials published in leading journals, with thousands of participants followed for well over a year. The caveats are about who ran them and how.

• Industry funding. The STEP and SELECT trials were funded by Novo Nordisk, which makes semaglutide. SURMOUNT-1, SURMOUNT-5, SURPASS-2 and SURPASS-CVOT were funded by Eli Lilly, which makes tirzepatide.^1,2,3,5 The head-to-head comparison was run by one competitor.
• Open-label design. In SURMOUNT-5 and SURPASS-2, participants knew which drug they received, which can influence reporting of side effects and adherence.^1,4
• Different estimands. Trials report results “regardless of stopping treatment” or “if everyone had kept taking it”. The second gives bigger numbers. Always check which one a headline uses.
• Long-term treatment. Both weight-management labels describe use “long term” alongside diet and physical activity.^8,9 Trials last one to four years, while real-world use may be far longer.

What remains open: whether tirzepatide reduces cardiovascular events in obesity without diabetes, how the 7.2 mg semaglutide dose compares with tirzepatide, and how much individual response varies beyond the averages.

Side effects, label warnings and interactions compared

The side-effect profiles overlap heavily. Nausea, diarrhoea, vomiting and constipation are the most common problems with both, and in SURMOUNT-5 most were mild to moderate and clustered during dose escalation.¹ Discontinuation because of gastrointestinal events was lower with tirzepatide (2.7%) than semaglutide (5.6%) in that trial, though its open-label design limits how far this can be pushed.¹

Warnings both labels share

• A boxed warning for thyroid C-cell tumours seen in rodents, with human relevance undetermined. Both are contraindicated in people with a personal or family history of medullary thyroid carcinoma or MEN 2.^8,9
• Acute pancreatitis, gallbladder disease, acute kidney injury linked to dehydration, severe gastrointestinal reactions, raised heart rate, and hypoglycaemia when combined with insulin or sulfonylureas.^8,9
• Pulmonary aspiration risk during anaesthesia or deep sedation, because stomach emptying is slowed. Surgical teams need to know.^8,9

In early 2026 the FDA removed suicidal behaviour and ideation from the warnings sections of both labels after a class-wide review found no increased risk.^8,9

Where the labels differ

The Zepbound label addresses oral hormonal contraceptives specifically. Because slowed gastric emptying may reduce their absorption, it advises a non-oral method or an added barrier method for four weeks after starting and after each dose increase.⁸ The Wegovy label now lists dysaesthesia (altered skin sensation) among common reactions, reported mainly with the 7.2 mg dose.^7,9

Neither drug is a controlled substance under US federal law. Any interaction questions, including with other diabetes medicines, belong with a prescriber or pharmacist.

Compounded and “research” versions: what the FDA has said

During the shortages that ran from 2022 into early 2025, US compounding pharmacies were allowed to make copies of both drugs. That window has closed. The FDA declared the tirzepatide shortage resolved on 19 December 2024 and the semaglutide shortage resolved on 21 February 2025, with the grace periods for compounders ending in the first half of 2025.¹¹ Our overview of weight-loss peptides in 2026 tracks what has happened since, including the FDA’s 2026 crackdown on mass-marketed compounded products.

The FDA’s own list of concerns, updated in September 2026, is direct:¹⁰

• As of 31 May 2026 it had received 990 adverse event reports involving compounded semaglutide and more than 730 involving compounded tirzepatide.
• Some reports involved hospitalisation linked to dosing errors, by patients measuring from multi-dose vials and by clinicians miscalculating.
• Semaglutide sodium and semaglutide acetate are different salt forms from the approved drug, and the agency has no information that they behave the same way.
• Products labelled “for research purposes” or “not for human consumption” are being sold directly to consumers, sometimes with dosing instructions.

Warning letters show how this works in practice. In March 2026 the FDA told one online seller that its retatrutide and tirzepatide products were drugs for human use despite “not intended for human consumption” disclaimers, citing the site’s own appetite and glucose claims.¹² A “research use only” label is not a quality standard; see what “research use only” really means. Grey-market vials have no verified identity, purity, sterility or dose, and we do not give sourcing or dosing guidance for them.

What to check on a prescribed product

• The brand or approved generic name, strength and manufacturer match an FDA-approved product.
• It was dispensed by a licensed pharmacy against a prescription.
• Marketing does not claim a compounded product is “the same as” or “generic” Wegovy or Zepbound.
• Side effects are reported to the prescriber and to FDA MedWatch.

Legal status in September 2026: US, UK and Canada

United States: semaglutide and tirzepatide are FDA-approved, prescription-only medicines and are not federally scheduled. State pharmacy boards regulate compounding pharmacies and telehealth prescribing, so the practical rules around who can supply them vary by state. Retatrutide, often sold alongside them online, is not approved anywhere and cannot legally be used in compounding.¹⁰

United Kingdom: Wegovy and Mounjaro are licensed prescription-only medicines. NHS access follows NICE guidance, and private supply still requires a prescription.

Canada: both are prescription drugs. Health Canada began approving generic semaglutide products in 2026, including the first generic for weight management in June.

In all three countries, buying either drug without a prescription from an unregulated seller means buying an unverified product. Our research peptides hub covers the wider regulatory picture.

Frequently asked questions

Is tirzepatide more effective than semaglutide for weight loss?

In the one head-to-head obesity trial, SURMOUNT-5, tirzepatide produced more weight loss: -20.2% versus -13.7% over 72 weeks in adults without diabetes.¹ The trial was open-label and funded by tirzepatide’s maker, and it used semaglutide doses up to 2.4 mg. A 7.2 mg semaglutide dose has since been approved but has not been compared directly with tirzepatide.

Which has more side effects, semaglutide or tirzepatide?

Their side-effect profiles are similar, dominated by nausea, diarrhoea, vomiting and constipation, mostly during dose increases. In SURMOUNT-5, fewer people stopped tirzepatide than semaglutide because of gastrointestinal effects.¹ Both labels carry the same boxed thyroid warning and similar precautions on pancreatitis, gallbladder disease and aspiration during anaesthesia.^8,9

Can you switch from semaglutide to tirzepatide?

Whether and how to change medicines is a clinical decision that depends on your health, current dose, response and side effects, so it is one to make with your prescriber. This page does not give switching or dosing advice. What the trials can tell you is how each drug performed on average, not how an individual will respond.

Are compounded semaglutide and tirzepatide the same as Wegovy and Zepbound?

No. Compounded products are not FDA-approved and are not reviewed for safety, effectiveness or quality. The FDA has received hundreds of adverse event reports for each, including dosing errors, and warns that some use different salt forms.¹⁰ Both shortages that allowed wide compounding ended in 2024 and 2025.¹¹

Is Mounjaro the same as Zepbound?

They contain the same active ingredient, tirzepatide, but carry different approved uses. Mounjaro is approved for type 2 diabetes. Zepbound is approved for long-term weight management and for moderate to severe obstructive sleep apnoea in adults with obesity.⁸ The same split applies to semaglutide: Ozempic for diabetes, Wegovy for weight and cardiovascular risk reduction.⁹

Sources

1. Aronne LJ, Horn DB, le Roux CW, et al; SURMOUNT-5 Trial Investigators. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. N Engl J Med. 2025;393(1):26-36. DOI: 10.1056/NEJMoa2416394. PMID: 40353578. pubmed.ncbi.nlm.nih.gov
2. Wilding JPH, Batterham RL, Calanna S, et al; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. DOI: 10.1056/NEJMoa2032183. PMID: 33567185. pubmed.ncbi.nlm.nih.gov
3. Jastreboff AM, Aronne LJ, Ahmad NN, et al; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216. DOI: 10.1056/NEJMoa2206038. PMID: 35658024. pubmed.ncbi.nlm.nih.gov
4. Frías JP, Davies MJ, Rosenstock J, et al; SURPASS-2 Investigators. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385(6):503-515. DOI: 10.1056/NEJMoa2107519. PMID: 34170647. pubmed.ncbi.nlm.nih.gov
5. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al; SELECT Trial Investigators. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2232. DOI: 10.1056/NEJMoa2307563. PMID: 37952131. pubmed.ncbi.nlm.nih.gov
6. Nicholls SJ, Pavo I, Bhatt DL, et al; SURPASS-CVOT Investigators. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes. N Engl J Med. 2025;393(24):2409-2420. DOI: 10.1056/NEJMoa2505928. PMID: 41406444. pubmed.ncbi.nlm.nih.gov
7. Wharton S, Freitas P, Hjelmesæth J, et al. Once-weekly semaglutide 7·2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial. Lancet Diabetes Endocrinol. 2025;13(11):949-963. DOI: 10.1016/S2213-8587(25)00226-8. PMID: 40961952. pubmed.ncbi.nlm.nih.gov
8. Eli Lilly and Company. ZEPBOUND (tirzepatide) injection: US prescribing information, including boxed warning. DailyMed, US National Library of Medicine; label version published 2 September 2026. dailymed.nlm.nih.gov
9. Novo Nordisk. WEGOVY (semaglutide) injection and tablets: US prescribing information, including boxed warning. DailyMed, US National Library of Medicine; label version published 30 June 2026. dailymed.nlm.nih.gov
10. US Food and Drug Administration. FDA’s Concerns with Unapproved GLP-1 Drugs Used for Weight Loss. Content current as of 1 September 2026. fda.gov
11. US Food and Drug Administration. FDA clarifies policies for compounders as national GLP-1 supply begins to stabilize. 2025. fda.gov
12. US Food and Drug Administration. Warning letter to Gram Peptides (MARCS-CMS 721806). 31 March 2026. fda.gov

Editorial note: This article is for general information only and is not medical or legal advice. Semaglutide and tirzepatide are prescription medicines; use them only as prescribed and supervised by a licensed clinician. Retatrutide is investigational and not approved anywhere. Laws vary by location and change often, so verify the rules that apply where you are. Always talk to a licensed healthcare provider before use, especially if you are under 21, pregnant or nursing, taking medication, or managing a health condition.