Clinical trials

Semaglutide vs Tirzepatide Head to Head: What SURMOUNT-5 Found

Q: What was SURMOUNT-5?

SURMOUNT-5 was a phase 3b, open-label, randomized trial run by Eli Lilly comparing tirzepatide against semaglutide for 72 weeks in 751 adults with obesity and without type 2 diabetes. It was published in the New England Journal of Medicine in May 2025.

Q: Which drug won SURMOUNT-5?

Tirzepatide. Average weight change was -20.2% with tirzepatide versus -13.7% with semaglutide at week 72, a difference of about 6.5 percentage points. Waist circumference fell 18.4 cm versus 13.0 cm.

Q: Does that mean tirzepatide is better for everyone?

No. SURMOUNT-5 measured weight and waist circumference, not heart attacks, strokes, kidney function or liver disease. Semaglutide has proven benefits in several of those areas that tirzepatide has not yet demonstrated. Which drug suits a particular person depends on their other health conditions, tolerance, insurance and cost — a discussion for a healthcare provider.

Q: Was SURMOUNT-5 blinded?

No. It was an open-label trial, meaning participants and investigators knew which drug was being given. That is a real limitation for a subjective outcome such as eating behavior, though body weight itself is objectively measured.

Q: What doses were compared?

Both arms used the maximum tolerated dose. For tirzepatide that was 10 mg or 15 mg weekly; for semaglutide it was 1.7 mg or 2.4 mg weekly. Because some semaglutide participants stayed at 1.7 mg rather than the full 2.4 mg dose, the comparison has been debated.

Q: Is there a head-to-head trial in people with diabetes?

Yes — SURPASS-2, published in 2021. Tirzepatide beat semaglutide on HbA1c and weight, but the semaglutide comparator was the 1 mg diabetes dose, not the 2.4 mg obesity dose, so it does not answer the same question.

Q: Do the two drugs differ on heart protection?

In randomized trials, semaglutide reduced major cardiac events by 20% versus placebo in SELECT. Tirzepatide was non-inferior to dulaglutide in SURPASS-CVOT but not superior. A large real-world claims analysis in people with type 2 diabetes found no meaningful difference between the two drugs on heart attack, stroke or death, but no randomized trial has compared them directly on heart outcomes.

Q: What is the biggest side effect difference between them?

In SURMOUNT-5 the most common adverse events in both arms were gastrointestinal, mostly mild to moderate and concentrated during dose escalation. The trial did not find a dramatic tolerability difference between the two drugs.

SURMOUNT-5 is the only large randomized trial that pitted tirzepatide directly against semaglutide at obesity doses — here are the numbers, the caveats, and what the trial could not measure.

Last verified September 14, 2026·17 sources cited·Ozempic Wegovy Mounjaro Zepbound

Semaglutides.org is for information only and is not medical advice. Always talk to a licensed healthcare provider about your own care. Some links to telehealth services are affiliate links, labeled where they appear.

For years, comparing semaglutide and tirzepatide meant comparing two separate trials run in two separate groups of people. That is an unreliable way to draw conclusions — different populations, different starting weights, different levels of support. SURMOUNT-5 fixed that by randomizing people to one drug or the other in the same trial.

The result made headlines in May 2025: tirzepatide produced substantially more weight loss. But the trial measured one thing, and “which drug is better” depends on a lot more than one thing. Here is the full picture.

What exactly did SURMOUNT-5 test?

SURMOUNT-5 (registered as NCT05822830) was a phase 3b, open-label, active-comparator trial funded by Eli Lilly, the maker of tirzepatide [1].

A total of 751 adults were randomized 1:1 to receive either the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg), given subcutaneously once weekly for 72 weeks [2].

Participants had obesity — or overweight with at least one weight-related condition such as high blood pressure, abnormal cholesterol or cardiovascular disease — and did not have type 2 diabetes. The mean age was 44.7 years, 64.7% were women, mean starting weight was about 113 kg, and mean BMI was 39.4 [3].

The primary endpoint was the percent change in weight from baseline to week 72. Key secondary endpoints were the proportions achieving at least 10%, 15%, 20% and 25% weight loss, and change in waist circumference.

What were the results?

The least-squares mean percent weight change at week 72 was:

Tirzepatide: -20.2% (95% CI -21.4 to -19.1)
Semaglutide: -13.7% (95% CI -14.9 to -12.6)

The difference was statistically significant at p<0.001 [2]. In absolute terms that worked out to roughly 22.8 kg versus 15.0 kg — about 50 pounds versus 33 pounds [4].

Waist circumference fell 18.4 cm with tirzepatide and 13.0 cm with semaglutide, also significant at p<0.001 [2].

The threshold data tells the story more usefully than the averages. Participants on tirzepatide were more likely to reach every weight-loss threshold tested. At the most demanding threshold, 31.6% of the tirzepatide group lost at least 25% of their body weight, versus 16.1% of the semaglutide group [4][5]. Roughly twice as many people hit the very large weight-loss category.

Side effects looked broadly similar. The most common adverse events in both arms were gastrointestinal, most were mild to moderate, and most occurred during dose escalation rather than maintenance [2]. SURMOUNT-5 did not identify a dramatic tolerability advantage for either drug.

What are the limitations of SURMOUNT-5?

Three deserve attention.

It was open-label. Nobody was blinded. Participants knew which drug they were on, and so did the investigators. For a hard outcome like body weight on a scale this matters less than it would for a symptom score, but expectation effects can influence eating behavior, adherence and how side effects are reported.

It was funded and designed by the manufacturer of the winning drug. That does not make the result wrong — the trial was published in a top journal with a standard protocol — but it is relevant context. Novo Nordisk has not run the mirror-image trial.

The semaglutide dosing has been debated. Both arms used a maximum tolerated dose design, so some semaglutide participants remained at 1.7 mg rather than escalating to the full 2.4 mg. Critics argue that dilutes the semaglutide arm. Defenders point out the same flexibility applied to tirzepatide, where some people stayed at 10 mg rather than 15 mg, and that maximum tolerated dosing is what actually happens in clinical practice.

One more piece of context worth knowing: SURMOUNT-5 tested the 2.4 mg semaglutide dose, which was the highest available when the trial ran. In March 2026 the FDA approved a higher 7.2 mg semaglutide dose, marketed as Wegovy HD, on the strength of the STEP UP trial. STEP UP reported 18.7% weight loss at 7.2 mg under the strictest analysis and 20.7% under the analysis Novo Nordisk quotes [6]. Nobody has run a randomized comparison of semaglutide 7.2 mg against tirzepatide 15 mg, so the current head-to-head evidence is one generation behind what is now on pharmacy shelves.

Is there a head-to-head trial in type 2 diabetes?

Yes, and it is a different trial with a different answer, so do not confuse the two.

SURPASS-2, published in 2021, randomized 1,879 adults with type 2 diabetes on metformin to tirzepatide 5 mg, 10 mg or 15 mg, or semaglutide 1 mg, for 40 weeks. HbA1c fell 2.01%, 2.24% and 2.30% with tirzepatide versus 1.86% with semaglutide, and tirzepatide produced 1.9 to 5.5 kg more weight loss depending on dose [7].

The critical detail: the comparator was semaglutide 1 mg, the diabetes dose. Ozempic’s maximum dose is now 2 mg, and Wegovy’s weight-management dose is 2.4 mg or 7.2 mg. SURPASS-2 tells you about tirzepatide versus Ozempic at a 2021-era dose. It does not tell you about tirzepatide versus Wegovy.

Which drug is better for your heart?

Here the picture flips.

Semaglutide has SELECT: 17,604 adults with cardiovascular disease and excess weight but no diabetes, showing a 20% reduction in cardiovascular death, heart attack and stroke over about 40 months (hazard ratio 0.80) [8]. That is a placebo-controlled outcome trial in exactly the population most people taking these drugs for weight fall into.

Tirzepatide has SURPASS-CVOT, published in the New England Journal of Medicine on December 18, 2025. It randomized 13,299 adults with type 2 diabetes and established atherosclerotic disease to tirzepatide or dulaglutide — an active comparator already proven to reduce cardiac events. The primary endpoint occurred in 12.2% on tirzepatide versus 13.1% on dulaglutide, a hazard ratio of 0.92 (95.3% confidence interval 0.83 to 1.01). That met the non-inferiority threshold (p=0.003) but not superiority (p=0.09) over a median follow-up of about four years [9]. In other words, tirzepatide protects the heart about as well as a drug that already works, but it did not beat it.

Tirzepatide’s equivalent of SELECT is SURMOUNT-MMO, which enrolled 15,374 adults with obesity and without diabetes. As of September 2026 the trial is active but not recruiting, and its registry record lists an estimated primary completion date of October 2027 — so results are not expected before then. Until it reports, semaglutide remains the only drug in this class with randomized proof of cardiac event reduction in people who have obesity but not diabetes.

There is one more data point worth knowing. A Nature Medicine analysis published online in November 2025 used propensity-matched US insurance data across five cohort studies to compare the two drugs directly in routine care among patients with type 2 diabetes and elevated cardiovascular risk. For the composite of heart attack, stroke or death from any cause, the head-to-head hazard ratio was 1.06 (95% CI 0.95 to 1.18) — essentially no difference [10]. The authors first validated their method by reproducing the SUSTAIN-6 and SURPASS-CVOT results from claims data, with high agreement on every endpoint except all-cause mortality in the SUSTAIN-6 emulation. That benchmarking step makes the finding more credible than a typical observational study, but it is still observational: it cannot rule out confounding the way a randomized trial can.

So: tirzepatide produces more weight loss, but that extra weight loss has not translated into a measurable extra cardiac benefit in the evidence available today.

What about everything else — kidneys, liver, sleep apnea?

Each drug has territory the other has not entered.

Semaglutide only:

Kidney disease. FLOW showed a 24% reduction in major kidney events and a 20% reduction in death from any cause in people with type 2 diabetes and chronic kidney disease [11]. Ozempic carries an FDA kidney indication.
Knee osteoarthritis pain. STEP 9 showed significantly greater pain reduction than placebo.
Cardiovascular event reduction in obesity without diabetes, via SELECT.
Proven benefit as a daily pill. Both the Rybelsus tablet and the Wegovy tablet are semaglutide; there is no tirzepatide pill.

Tirzepatide only:

Obstructive sleep apnea. SURMOUNT-OSA cut the apnea-hypopnea index by 25 to 29 events per hour versus about 5 on placebo, leading to an FDA sleep apnea indication in December 2024 [12].
Heart failure with preserved ejection fraction, with hard event reduction. The SUMMIT trial showed a hazard ratio of 0.62 for cardiovascular death or worsening heart failure. Semaglutide’s HFpEF trials showed symptom improvement but were not powered for events.

A Nature Medicine network meta-analysis of 56 obesity drug trials covering 60,307 patients, published in October 2025, summed this up: both drugs showed restoration of normal blood sugar, diabetes remission and reduced heart failure hospitalization; semaglutide alone showed cardiovascular event reduction and knee pain relief; tirzepatide alone showed sleep apnea remission and improvement in metabolic dysfunction-associated steatohepatitis (MASH) [13].

One caveat on that last item, because it is a live source of confusion. The meta-analysis searched the literature only through January 31, 2025, which is before semaglutide’s own MASH trial, ESSENCE, was published. ESSENCE led to an FDA accelerated approval of Wegovy for MASH in August 2025 [15]. So as of today both drugs have MASH evidence, and semaglutide is the one with an FDA-approved MASH indication. Read the meta-analysis as a snapshot of early 2025, not of the present.

What does the real world look like?

Trial results describe what happens with free medication, regular visits and structured support. Ordinary care looks different for both drugs.

A Cleveland Clinic cohort of 7,881 people who started injectable semaglutide or tirzepatide for obesity found mean one-year weight loss of 8.7% overall, far below either trial figure. The gap was driven by dosing and persistence, not biology: 80.8% never reached a high maintenance dose. Among people who stayed on treatment at a high maintenance dose, weight loss was 13.7% with semaglutide and 18.0% with tirzepatide [14] — close to the trial numbers and preserving the same ordering.

The practical lesson is that whether you stay on the drug and reach a full dose probably matters more than which of the two you start with.

So which one should you take?

That is not a question a web page can answer, and anyone who tells you otherwise is selling something.

What the evidence supports is a set of honest statements. If the single goal is maximum weight loss and you have no other conditions in play, the randomized head-to-head data favors tirzepatide. If you have established cardiovascular disease, semaglutide has direct randomized outcome evidence in that population that tirzepatide does not yet have. If you have chronic kidney disease with type 2 diabetes, semaglutide has an approved indication. If you have moderate-to-severe obstructive sleep apnea, tirzepatide has one. If you cannot or will not inject, only semaglutide is available as a pill.

And for a very large number of people, the decision is settled by something neither trial measured: what your insurance covers, what the cash price is, and which product your pharmacy can actually supply. Those are worth checking before the clinical comparison even starts.

Bring the specifics of your own health history to a healthcare provider. The trial data narrows the question; it does not answer it.

Sources

Questions people ask

What was SURMOUNT-5?

SURMOUNT-5 was a phase 3b, open-label, randomized trial run by Eli Lilly comparing tirzepatide against semaglutide for 72 weeks in 751 adults with obesity and without type 2 diabetes. It was published in the New England Journal of Medicine in May 2025.

Which drug won SURMOUNT-5?

Tirzepatide. Average weight change was -20.2% with tirzepatide versus -13.7% with semaglutide at week 72, a difference of about 6.5 percentage points. Waist circumference fell 18.4 cm versus 13.0 cm.

Does that mean tirzepatide is better for everyone?

No. SURMOUNT-5 measured weight and waist circumference, not heart attacks, strokes, kidney function or liver disease. Semaglutide has proven benefits in several of those areas that tirzepatide has not yet demonstrated. Which drug suits a particular person depends on their other health conditions, tolerance, insurance and cost — a discussion for a healthcare provider.

Was SURMOUNT-5 blinded?

No. It was an open-label trial, meaning participants and investigators knew which drug was being given. That is a real limitation for a subjective outcome such as eating behavior, though body weight itself is objectively measured.

What doses were compared?

Both arms used the maximum tolerated dose. For tirzepatide that was 10 mg or 15 mg weekly; for semaglutide it was 1.7 mg or 2.4 mg weekly. Because some semaglutide participants stayed at 1.7 mg rather than the full 2.4 mg dose, the comparison has been debated.

Is there a head-to-head trial in people with diabetes?

Yes — SURPASS-2, published in 2021. Tirzepatide beat semaglutide on HbA1c and weight, but the semaglutide comparator was the 1 mg diabetes dose, not the 2.4 mg obesity dose, so it does not answer the same question.

Do the two drugs differ on heart protection?

In randomized trials, semaglutide reduced major cardiac events by 20% versus placebo in SELECT. Tirzepatide was non-inferior to dulaglutide in SURPASS-CVOT but not superior. A large real-world claims analysis in people with type 2 diabetes found no meaningful difference between the two drugs on heart attack, stroke or death, but no randomized trial has compared them directly on heart outcomes.

What is the biggest side effect difference between them?

In SURMOUNT-5 the most common adverse events in both arms were gastrointestinal, mostly mild to moderate and concentrated during dose escalation. The trial did not find a dramatic tolerability difference between the two drugs.

This article summarizes FDA labeling, published research and company information current as of September 14, 2026. It is not medical advice and does not replace a conversation with your own healthcare provider. How we research and verify.