SURMOUNT-5: The Head-to-Head Trial of Tirzepatide vs Semaglutide

SURMOUNT-5 is the first large randomised trial to compare tirzepatide (Mounjaro) directly with semaglutide (Wegovy) for weight management. Published in the New England Journal of Medicine in 2025, it found that adults with obesity taking tirzepatide lost about 20% of their body weight on average over 72 weeks, compared with about 14% for those taking semaglutide. Waist circumference fell more with tirzepatide too, and side effects were broadly similar. This guide explains how the trial was designed, what it found, its limitations and what it means for people considering treatment in the UK.

Why a head-to-head trial matters

Before SURMOUNT-5, comparisons between tirzepatide and semaglutide relied on placing separate trials side by side. SURMOUNT-1 reported average weight loss of about 21% with the highest tirzepatide dose at 72 weeks, and STEP 1 reported about 15% with semaglutide 2.4mg at 68 weeks. But those trials enrolled different people, at different times, with different lengths and methods. Indirect comparisons can mislead.

A head-to-head trial randomly assigns people from the same population to each medicine and follows them in the same way. Randomisation means that, on average, the groups are similar at the start, so differences at the end are more likely to reflect the medicines themselves. That makes SURMOUNT-5 the most direct evidence available for comparing the two, although, as we explain below, it still has limitations.

For background on each medicine, see our guides to tirzepatide and semaglutide.

How the trial was designed

Maximum tolerated dose

Both groups had their doses increased gradually, following the usual schedules, and aimed to reach the highest dose they could tolerate. This "maximum tolerated dose" design reflects how the medicines are used in practice, where some people stay on a lower dose because of side effects.

Open-label

In an open-label trial, participants and investigators know which medicine is being taken. This was partly because the two medicines use different pens and dose schedules. Open-label designs can introduce bias, for example in how side effects are reported or how motivated participants are. For an objective outcome like body weight, the effect is likely to be smaller, but it cannot be ruled out entirely.

What the trial found

Weight loss

The difference in weight loss, about 6.5 percentage points, was statistically significant, meaning it is very unlikely to be due to chance. Tirzepatide was also ahead on all the key secondary outcomes: a larger proportion of people on tirzepatide reached each threshold of 10%, 15%, 20% and 25% weight loss. Roughly a third of people on tirzepatide lost at least a quarter of their body weight, about twice the proportion on semaglutide.

What these numbers mean in practice

For a person weighing 110kg at the start, average losses of this size would mean around 22kg with tirzepatide and around 15kg with semaglutide. But these are averages across hundreds of people. Within each group, results ranged widely: some people on semaglutide lost more weight than some on tirzepatide, and some in each group lost relatively little. See realistic weight loss expectations.

Waist circumference

Waist circumference is a useful marker because fat stored around the abdomen is more closely linked to metabolic and cardiovascular risk. The larger fall in waist circumference with tirzepatide is consistent with the greater overall weight loss. See measuring progress beyond the scales.

Side effects

Side effects in SURMOUNT-5 were similar in type to those in earlier trials of each medicine.

• Gastrointestinal side effects (nausea, diarrhoea, constipation, vomiting, indigestion) were the most common in both groups.
• Most were mild to moderate and occurred mainly during the dose-escalation period.
• Stopping because of gastrointestinal side effects was less common with tirzepatide (about 2.7%) than with semaglutide (about 5.6%).

The lower discontinuation rate with tirzepatide is interesting, but it should be interpreted cautiously. The trial was open-label, the numbers are small, and the dose-escalation schedules differ between the medicines. It does not prove that tirzepatide is better tolerated by any given person. Some people tolerate one medicine better than the other, and this is one reason people sometimes switch.

The serious risks associated with both medicines, including pancreatitis, gallbladder problems and dehydration-related kidney problems, were not the focus of a trial of this size and length. These are set out in the Summary of Product Characteristics (SmPC) for each medicine. See Mounjaro side effects and Wegovy side effects.

Who took part, and does it apply to UK patients?

The participants had an average age of about 45 and, as in most obesity trials, the majority were women. None had type 2 diabetes. All were recruited at sites in the United States and Puerto Rico.

Several points are worth bearing in mind when applying the results to people in the UK:

• Ethnicity. UK guidance uses lower BMI thresholds for people of South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family background, because health risks rise at lower BMIs in these groups. Trial populations do not always reflect the UK's diversity. See lower BMI thresholds for some ethnic groups.
• Diabetes. People with type 2 diabetes typically lose less weight on both medicines, so the absolute numbers would probably be lower, although tirzepatide has also outperformed semaglutide 1mg in a diabetes trial.
• Support. Trial participants receive regular visits and lifestyle advice. Support in everyday care, whether NHS or private, varies, and this may affect results.
• Access to doses. In the UK, both medicines are licensed at the doses used in the trial, and a higher semaglutide dose is now also authorised for some adults with obesity.

None of this undermines the main finding, but it is a reminder that trial averages are a starting point for a conversation, not a forecast.

Strengths and limitations

Strengths

• Randomised and direct. Participants were randomly assigned, so the comparison is much more reliable than comparing separate trials.
• Clinically relevant doses. Both medicines were used at their licensed maintenance doses, adjusted to tolerability.
• Reasonable length. At 72 weeks, it captured most of the weight-loss phase for both medicines.
• Peer reviewed. Published in a major journal with full methods available.

Limitations

• Open-label. Participants knew which medicine they were taking.
• Industry-funded. Eli Lilly, the maker of tirzepatide, funded the trial. Industry funding is common, and peer review and trial registration provide safeguards, but it is still a relevant consideration.
• Population. It took place in the US and Puerto Rico, and excluded people with type 2 diabetes. Results may differ in other populations, including UK patients and people with diabetes.
• Semaglutide dose. The trial used semaglutide at up to 2.4mg. The MHRA authorised a higher dose of up to 7.2mg weekly in January 2026 for adults with obesity, which was not tested.
• Outcomes. It measured weight and waist circumference, not long-term health outcomes such as heart attacks or strokes.
• Duration. It does not tell us about differences beyond 72 weeks, or what happens after stopping.

Why might tirzepatide lead to more weight loss?

Both medicines activate GLP-1 receptors, which reduce appetite, increase fullness and slow stomach emptying. Tirzepatide also activates GIP (glucose-dependent insulinotropic polypeptide) receptors. Researchers are still working out exactly how GIP contributes, and the picture is not straightforward: some research suggests GIP receptor activation in the brain may add to the appetite-reducing effect and may reduce nausea, while effects on fat tissue may also play a part.

Dose is another factor. Tirzepatide and semaglutide are different molecules with different strengths, so milligram doses cannot be compared directly. The trial compared each medicine at its own maximum tolerated dose, which is the most meaningful comparison for patients, but it cannot separate the effect of the GIP action from other differences between the molecules.

What SURMOUNT-5 shows is the overall result in practice: at their usual maintenance doses, tirzepatide produced more average weight loss. Why that is remains an area of active research. Our guide to how Mounjaro works covers the mechanism in more detail.

Understanding the statistics

Trial reports can be hard to interpret. A few terms help.

Least-squares mean. The headline figures in SURMOUNT-5 are "least-squares means", a statistical estimate of the average change in each group that adjusts for factors such as starting weight. In plain terms, they are the trial's central estimate of the average effect.

Statistical significance. The difference between the groups was statistically significant, which means it is very unlikely to have arisen by chance alone. It does not by itself tell you how important the difference is for an individual, though a difference of several percentage points of body weight is generally considered clinically meaningful.

Treatment regimen versus efficacy estimates. Many obesity trials report two estimates: one including everyone who was randomised, whatever happened to them (closer to "real world" use), and one estimating the effect if everyone stayed on treatment as intended. Headline figures from different sources may use different estimates, which is one reason numbers for the same trial sometimes differ slightly between reports.

Proportions reaching thresholds. Reporting how many people reached 10%, 15%, 20% or 25% weight loss gives a sense of the spread of results, not just the average. In SURMOUNT-5, tirzepatide was ahead at every threshold, but substantial numbers of people on semaglutide also reached high levels of weight loss.

Body composition: fat and muscle

Weight loss with any method includes some loss of lean mass (muscle, organs, bone and water) as well as fat. SURMOUNT-5 focused on weight and waist circumference rather than detailed body composition. Smaller studies within earlier trials of both medicines, using body scans, found that most of the weight lost was fat, with a smaller share from lean mass, broadly in line with other forms of weight loss.

Because people on these medicines eat much less, protecting muscle matters, particularly for older adults. Eating enough protein and doing regular resistance exercise are commonly advised. See preserving muscle on GLP-1 treatment.

How it fits with the wider evidence

The SURMOUNT-5 results are broadly consistent with the separate trials. Tirzepatide's result was close to SURMOUNT-1, while semaglutide's result was a little lower than in STEP 1, possibly reflecting differences in population, the maximum tolerated dose approach, or chance.

Cardiovascular outcomes

The SELECT trial (NEJM, 2023) showed that semaglutide 2.4mg reduced major adverse cardiovascular events by 20% compared with placebo in more than 17,600 adults with overweight or obesity and established cardiovascular disease, without diabetes. Wegovy is licensed in the UK to reduce cardiovascular risk on this basis. A comparable cardiovascular outcomes trial of tirzepatide in people with obesity without diabetes was ongoing at the time of writing. SURMOUNT-5 did not address this question. See Wegovy and heart health.

Diabetes trials

In people with type 2 diabetes, tirzepatide has also been compared with semaglutide. In the SURPASS-2 trial (NEJM, 2021), tirzepatide led to greater reductions in blood glucose and weight than semaglutide 1mg, a lower dose than Wegovy. SURMOUNT-5 extended this comparison to people without diabetes at weight-management doses.

After SURMOUNT-5: the ATTAIN-MAINTAIN trial

Some participants who completed SURMOUNT-5 went on to ATTAIN-MAINTAIN, a trial of whether orforglipron, a daily GLP-1 tablet now licensed in the UK as Foundayo, could maintain their weight loss. According to topline results announced by Eli Lilly in December 2025, people who switched from tirzepatide to orforglipron kept about three-quarters of their earlier weight loss on average over 52 weeks, compared with about half for those on placebo. Those switching from semaglutide kept about four-fifths, compared with under two-fifths on placebo. See our Foundayo guide.

What SURMOUNT-5 means for people in the UK

For people considering treatment

SURMOUNT-5 is useful evidence for discussions with a prescriber. If the main goal is weight reduction, the larger average effect of tirzepatide is relevant. If someone has established cardiovascular disease, semaglutide's SELECT evidence may weigh more. Medical history, side effects, other medicines, access and personal preference all matter too. Our detailed comparison of Mounjaro and Wegovy covers these factors.

For people already on treatment

SURMOUNT-5 does not mean that someone doing well on semaglutide needs to change. If treatment is working and well tolerated, there may be little reason to switch. People who are not reaching their goals, or who have difficulty with side effects, may discuss switching with their prescriber. See switching from Wegovy to Mounjaro.

For NHS access

NICE's recommendations for semaglutide (TA875, 2023) and tirzepatide (TA1026, 2024) were made before SURMOUNT-5 was published. NHS access depends on these recommendations and on local services. Wegovy is mainly available through specialist weight-management services; Mounjaro is being rolled out in phases in primary care, starting in June 2025 with people with the highest BMI and several weight-related conditions. See Mounjaro on the NHS.

For cost

We do not quote prices. Private costs depend on manufacturer list prices, dose and provider. The UK list price of Mounjaro rose in September 2025, which affected private prices. When comparing options, it is worth considering cost alongside effectiveness, because treatment is often long term. See our prices page.

Common misreadings of SURMOUNT-5

"Semaglutide doesn't work." It does. An average loss of about 14% is substantial, and semaglutide has proven cardiovascular benefits. SURMOUNT-5 shows a difference between two effective medicines.

"Everyone will lose 20% on tirzepatide." No. That was an average. Some people lost much less, and some much more.

"Tirzepatide has fewer side effects." The side-effect profiles were broadly similar. The difference in stopping because of gastrointestinal effects was small and needs cautious interpretation.

"This settles the question for good." New doses and medicines have arrived since, including the 7.2mg semaglutide dose and GLP-1 tablets, and others are in development. See the GLP-1 pipeline.

Questions to ask your prescriber

• Given my health and goals, how relevant are the SURMOUNT-5 results to me?
• Does my heart health make semaglutide's cardiovascular evidence important in my case?
• If I am doing well on my current medicine, is there any reason to change?
• If I switch, what dose would I start on, and what side effects should I expect?
• How will we measure whether treatment is working?

When to speak to a professional

Speak to your GP, pharmacist or prescriber before starting, switching or stopping tirzepatide or semaglutide. Tell them about all the medicines you take, including contraception (the MHRA has noted tirzepatide may reduce the effectiveness of oral contraceptives in some people), and about any history of pancreatitis, gallbladder disease, kidney problems, thyroid cancer, diabetic eye disease or eating disorders. Let them know if you are pregnant, planning pregnancy or breastfeeding.

Seek urgent medical help through NHS 111, or call 999 in an emergency, if you experience:

• Severe, persistent abdominal pain, especially spreading to the back, with or without vomiting
• Pain in the upper right abdomen, fever, or yellowing of the skin or eyes
• Vomiting or diarrhoea that stops you keeping fluids down, or signs of dehydration
• Signs of a severe allergic reaction, such as swelling of the face or throat, or difficulty breathing
• Symptoms of low blood sugar if you also take insulin or a sulfonylurea

Report suspected side effects through the MHRA Yellow Card scheme. To compare regulated services, see our provider comparison. Browse more guides at /guides, or visit the weight loss injections hub.