Semaglutide vs tirzepatide: what the head-to-head trials show

Key points

• Two randomized, open-label trials compared the drugs directly, and both were sponsored by Eli Lilly, which makes tirzepatide. In SURPASS-2 (1,879 adults with type 2 diabetes, 40 weeks) tirzepatide lowered HbA1c more than semaglutide 1 mg. In SURMOUNT-5 (751 adults with obesity, no diabetes, 72 weeks) weight fell 20.2 percent on tirzepatide and 13.7 percent on semaglutide [1][2][3][4].
• Both drugs carry the same FDA boxed warning for thyroid C-cell tumors seen in rodents, and the same family of warnings: pancreatitis, gallbladder disease, severe gastrointestinal reactions and others [6][7][8][9].
• In SURMOUNT-5, gastrointestinal events were common and similar in both arms; vomiting was reported by fewer people on tirzepatide [3].
• No head-to-head trial of cardiovascular events or other long-term outcomes with randomized treatment exists in the registry records we checked. Weight regain after stopping was not covered by the sources we opened [5].

What each drug is

Semaglutide is a GLP-1 receptor agonist. Novo Nordisk markets it as Ozempic (injection, type 2 diabetes), Wegovy (injection and tablets, weight management and related uses), and as Rybelsus and Ozempic tablets (type 2 diabetes) [8][9][10].

Tirzepatide is described in its FDA label as a once-weekly GIP receptor and GLP-1 receptor agonist: one molecule that activates both receptors. Lilly markets it as Mounjaro (type 2 diabetes) and Zepbound (weight management and sleep apnea) [6][7]. The two-receptor design is the main pharmacological difference between the products; the sources we opened do not isolate how much of any trial difference comes from it.

For the company side, see Lilly vs Novo Nordisk: GLP-1 market share.

Regulatory status

Label statements are from DailyMed, read on 2026-11-09. We read the first 100,000 characters of each label page, so text beyond that was not seen.

Brand	Drug	FDA indications (adults unless stated)	Label revised
Ozempic injection	Semaglutide	Glycemic control in type 2 diabetes; fewer major cardiovascular events in type 2 diabetes with established cardiovascular disease; reduced risk of sustained eGFR decline, end-stage kidney disease and cardiovascular death in type 2 diabetes with chronic kidney disease [8]	5/2026
Rybelsus / Ozempic tablets	Semaglutide (oral)	Glycemic control in type 2 diabetes; fewer major cardiovascular events in type 2 diabetes at high risk [10]	1/2026
Wegovy injection and tablets	Semaglutide	Fewer major cardiovascular events with established cardiovascular disease and obesity or overweight; weight reduction and maintenance (injection also from age 12); the injection for MASH with moderate to advanced fibrosis, under accelerated approval [9]	6/2026
Mounjaro	Tirzepatide	Glycemic control in type 2 diabetes (age 10 and older); fewer major cardiovascular events in type 2 diabetes at high risk [6]	8/2026
Zepbound	Tirzepatide	Weight reduction and maintenance in obesity, or overweight with a weight-related condition; moderate to severe obstructive sleep apnea in adults with obesity [7]	8/2026

In the European Union, the EMA pages we read list Ozempic (authorised 8 February 2018) for type 2 diabetes [13]. Wegovy (6 January 2022) is authorised for weight management in adults and in adolescents aged 12 and older with obesity above 60 kg [12]. Mounjaro (15 September 2022) is authorised for type 2 diabetes in adults, adolescents and children aged 10 and older, and for weight management in adults [11]. The Rybelsus EMA page, the UK and Germany were not checked. All FDA products are prescription medicines per their labels; we did not look up scheduling separately.

What did the head-to-head trials find?

Both trials are open label (participants and investigators knew the treatment), were run by Lilly and enrolled adults only.

	SURPASS-2 [1][4]	SURMOUNT-5 [2][3]
Population	Type 2 diabetes on metformin, HbA1c 7.0 to 10.5%	Obesity or overweight with a weight-related condition, no type 2 diabetes
Size, length	1,879 randomized; primary endpoint at week 40	751 randomized; 72 weeks
Arms	Tirzepatide 5, 10, 15 mg vs semaglutide 1 mg	Maximum tolerated tirzepatide (10 or 15 mg) vs semaglutide (1.7 or 2.4 mg)
Primary outcome	Change in HbA1c	Percent change in body weight
Result	HbA1c change: -2.01, -2.24, -2.30 points (tirzepatide) vs -1.86 (semaglutide)	Weight change: -20.2% vs -13.7% (difference -6.5 points, 95% CI -8.1 to -4.9)
Other	Weight difference vs semaglutide: -1.9, -3.6, -5.5 kg	Waist: -18.4 cm vs -13.0 cm
Sponsor	Eli Lilly	Eli Lilly

SURPASS-2 (NCT03987919, New England Journal of Medicine, 2021) reported tirzepatide as noninferior and superior to semaglutide at all three doses [1]. The registry record lists HbA1c changes from a different analysis (-2.37 and -2.46 for the 10 and 15 mg arms, -2.09 for 5 mg, against -1.86); we did not verify which analysis rule each set follows, so the abstract values are used above [4]. The Mounjaro label gives about -2.2 and -2.3 against -1.9 for the higher arms [6].

SURMOUNT-5 (NCT05822830, New England Journal of Medicine, published online 11 May 2025) found tirzepatide superior for body weight and waist circumference. More tirzepatide participants reached each weight-loss threshold from 10 to 25 percent, though the abstract gives no proportions and we did not open the full paper [2]. The registry reports 375 randomized to tirzepatide and 376 to semaglutide, a mean age of about 45 and roughly two thirds women. Primary outcome data came from 318 participants in each arm [3]. Open-label design, a maximum-tolerated-dose comparison and a manufacturer sponsor are all limits on how far the result generalizes.

Which works better, semaglutide or tirzepatide?

The question depends on the outcome and population. In these two trials, tirzepatide produced larger changes in HbA1c (in adults with type 2 diabetes) and in body weight (in adults without diabetes) than the semaglutide dose tested. Whether either result applies to a given person is a matter for that person’s prescriber, and this article does not rank the drugs for individuals. Trials measured group averages over 40 and 72 weeks; they did not measure heart attacks, strokes or deaths between the two drugs.

Side effects compared

In the head-to-head trials. SURPASS-2 reported nausea in 17 to 22 percent on tirzepatide and 18 percent on semaglutide, diarrhea in 13 to 16 versus 12 percent, and vomiting in 6 to 10 versus 8 percent [1]. In the registry record, serious adverse events affected 33, 25 and 27 of about 470 people in the three tirzepatide arms and 13 of 469 on semaglutide; deaths numbered 4 in each tirzepatide arm and 1 on semaglutide [4]. We did not find an investigator assessment of those deaths in the sources opened.

In SURMOUNT-5 the registry counted nausea in 163 of 374 (tirzepatide) and 167 of 376 (semaglutide), diarrhea in 88 and 88, constipation in 101 and 107, and vomiting in 56 and 80. Serious adverse events were 18 versus 13, with no deaths in either arm. Six participants in each arm left the study because of an adverse event [3]. The abstract says gastrointestinal events were mostly mild to moderate and occurred mainly while doses were being increased [2].

On the labels. Each label states its own placebo-controlled figures, from different trials, so the numbers below cannot be ranked against one another:

• Mounjaro: any gastrointestinal reaction 37.1 to 43.6 percent against 20.4 percent on placebo; discontinuation for these reasons 3.0 to 6.6 percent [6].
• Zepbound: gastrointestinal reactions 56 percent in each dose group versus 30 percent on placebo; discontinuation for any adverse reaction 4.8 to 6.7 percent versus 3.4 [7].
• Ozempic: 32.7 and 36.4 percent against 15.3 on placebo; discontinuation for gastrointestinal reasons 3.1 and 3.8 percent [8].
• Wegovy injection: 73 percent against 47; discontinuation for any adverse reaction 6.8 percent against 3.2 [9].

Shared warnings. All four labels carry a boxed warning for thyroid C-cell tumors in rodents and say the human relevance is unknown or not determined. All are contraindicated with a personal or family history of medullary thyroid carcinoma or MEN 2. Warnings and precautions in each include acute pancreatitis, acute gallbladder disease, severe gastrointestinal reactions, acute kidney injury from volume depletion, hypersensitivity, diabetic retinopathy complications, and pulmonary aspiration during anesthesia or deep sedation [6][7][8][9]. Mounjaro’s label says delayed gastric emptying may reduce the effect of oral hormonal contraceptives and advises a non-oral or barrier method for four weeks after starting and after each increase [6]. The Wegovy label lists a heart-rate increase warning that the Zepbound and Mounjaro headings do not [9][7].

Risks and unknowns

• No long-term head-to-head outcomes. The two randomized trials ran 40 and 72 weeks and measured HbA1c, weight and tolerability. We found no completed randomized trial comparing the drugs on cardiovascular or kidney events [1][2][5].
• Registry entries are observational. ClinicalTrials.gov lists large “comparative effectiveness” records of tirzepatide and semaglutide in people at cardiovascular risk (NCT07096063, 887,132 participants; NCT07619508, 100,000). Both are observational studies sponsored by Brigham and Women’s Hospital that aim to emulate randomized trials using real-world data, and neither page posts results [5]. They are not randomized comparisons.
• A three-arm trial of bariatric surgery against both drugs (NCT06803888, 140 participants) was listed as active, not recruiting; we did not open that record [5].
• Weight regain after stopping. We did not open a source on this for either drug, so we make no statement.
• Populations not covered. SURMOUNT-5 excluded type 2 diabetes by design, and SURPASS-2 enrolled only people with it. Neither trial is described in the sources we opened as testing children or adolescents. Pregnancy: the Mounjaro label says data are insufficient to judge risk and animal studies suggest possible fetal risk [6].
• Sponsor. Both direct comparisons were funded by the manufacturer of one of the two drugs [1][2][3][4].
• Not checked: the full SURMOUNT-5 paper, so detailed adverse-event tables and the proportion reaching each weight threshold are untested here.

For a drug still in trials that targets a third receptor, see retatrutide phase 3: what is public. For the oral alternative to injectable semaglutide, see orforglipron vs oral semaglutide.

Compounded and research-use-only versions

The approvals, trials and labels above concern the manufacturers’ FDA-approved or EMA-authorised products. Compounded versions and research-use-only listings are a separate legal category and were not the subject of these trials. The rules are laid out in compounded GLP-1: the FDA rules explained. Research-use-only listings of these molecules are on the tirzepatide and semaglutide compound pages.

Frequently asked questions

Which works better, semaglutide or tirzepatide? In the two direct trials, both sponsored by Lilly, tirzepatide gave larger average reductions in HbA1c (SURPASS-2, 1,879 adults with type 2 diabetes) and body weight (SURMOUNT-5, 751 adults without diabetes) than the semaglutide dose tested [1][2]. These are group averages from open-label trials, not a verdict for an individual.

What did the head-to-head trial find? SURMOUNT-5 reported a 20.2 percent weight reduction with tirzepatide against 13.7 percent with semaglutide at 72 weeks (difference -6.5 percentage points). Gastrointestinal events were common in both arms [2][3].

What is the difference between them? Semaglutide activates the GLP-1 receptor; tirzepatide activates both the GIP and GLP-1 receptors, per the FDA label [6][8]. They have different brand names and approved uses, listed in the table above.

Are they approved for weight loss and diabetes? Yes, in different products. Ozempic and Mounjaro are FDA-approved for type 2 diabetes, Wegovy and Zepbound for weight management [6][7][8][9]. The EMA authorises Ozempic for diabetes, Wegovy for weight management, and Mounjaro for both [11][12][13].

Is tirzepatide or semaglutide cheaper? Prices change often, so we do not state them here. Current price facts are in GLP-1 pricing and direct-to-consumer in 2026.

Sources

1. Frías JP et al., “Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes (SURPASS-2),” N Engl J Med 385(6):503-515 (2021), PMID 34170647, abstract read via Europe PMC (2026-11-09); full text not opened. https://pubmed.ncbi.nlm.nih.gov/34170647/
2. “Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5),” N Engl J Med 393:26-36 (online 2025-05-11), PMID 40353578, abstract read via Europe PMC (2026-11-09); full text not opened. https://pubmed.ncbi.nlm.nih.gov/40353578/
3. ClinicalTrials.gov, NCT05822830 (SURMOUNT-5) record with posted results (last updated 2025-11-26; read 2026-11-09). https://clinicaltrials.gov/study/NCT05822830
4. ClinicalTrials.gov, NCT03987919 (SURPASS-2) record with posted results (read 2026-11-09; first 100,000 of 120,269 characters). https://clinicaltrials.gov/study/NCT03987919
5. ClinicalTrials.gov, registry query for tirzepatide and semaglutide studies, and records NCT07096063 and NCT07619508 (read 2026-11-09). https://clinicaltrials.gov/api/v2/studies?query.intr=tirzepatide&query.term=semaglutide
6. DailyMed (NLM), Mounjaro (tirzepatide) prescribing information, revised 8/2026 (read 2026-11-09; first 100,000 of 265,935 characters). https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0
7. DailyMed (NLM), Zepbound (tirzepatide) prescribing information, revised 8/2026 (read 2026-11-09; first 100,000 of 284,619 characters). https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=487cd7e7-434c-4925-99fa-aa80b1cc776b
8. DailyMed (NLM), Ozempic (semaglutide) injection prescribing information, revised 5/2026 (read 2026-11-09; first 100,000 of 213,364 characters). https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79
9. DailyMed (NLM), Wegovy (semaglutide) injection and tablets prescribing information, revised 6/2026 (read 2026-11-09; first 100,000 of 320,944 characters). https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ee06186f-2aa3-4990-a760-757579d8f77b
10. DailyMed (NLM), Rybelsus and Ozempic (oral semaglutide) tablets prescribing information, revised 1/2026 (read 2026-11-09; indications only). https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=27f15fac-7d98-4114-a2ec-92494a91da98
11. European Medicines Agency, Mounjaro EPAR page (read 2026-11-09). https://www.ema.europa.eu/en/medicines/human/EPAR/mounjaro
12. European Medicines Agency, Wegovy EPAR page (read 2026-11-09). https://www.ema.europa.eu/en/medicines/human/EPAR/wegovy
13. European Medicines Agency, Ozempic EPAR page (read 2026-11-09). https://www.ema.europa.eu/en/medicines/human/EPAR/ozempic

This article is information, not medical advice.