Semaglutide vs Tirzepatide: Which Is Better for Weight Loss? SURMOUNT-5 Explained
In the first published head-to-head randomized trial in adults with obesity without diabetes, tirzepatide produced 20.2% weight loss versus 13.7% for semaglutide over 72 weeks. Here is what the study showed, plus side effects, heart evidence, and how clinicians say to choose.
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In the first published head-to-head randomized trial of the two drugs in adults with obesity who did not have type 2 diabetes, tirzepatide (Zepbound for weight management) produced more weight loss than semaglutide (Wegovy). At 72 weeks, people taking tirzepatide at their maximum tolerated dose lost an average of 20.2% of their body weight, compared with 13.7% for people taking semaglutide at their maximum tolerated dose [2][5]. In kilograms, that worked out to 22.8 kg lost with tirzepatide versus 15.0 kg with semaglutide [4].
That trial, called SURMOUNT-5, was published online in the New England Journal of Medicine on May 11, 2025, and in print on July 3, 2025 (Vol. 393, No. 1, pp. 26-36) [2]. It was also presented at the European Congress on Obesity (ECO) 2025 in Malaga, Spain [3][4]. But “more weight loss” is not the same as “better for everyone.” The trial’s primary and key secondary endpoints were weight change and waist circumference, and its superiority conclusion applies to those measures [2][5]; semaglutide has heart-outcome evidence that tirzepatide does not yet have in people without diabetes [4][8], and the trial had design limitations worth understanding before drawing conclusions [3].
What was SURMOUNT-5 and who was in it?
SURMOUNT-5 was a phase 3b, open-label, controlled trial in which 751 adults with obesity were randomized 1:1 to receive either tirzepatide or semaglutide, given as a once-weekly subcutaneous injection for 72 weeks [2][5]. Participants were titrated to their maximum tolerated dose: tirzepatide 10 mg or 15 mg, or semaglutide 1.7 mg or 2.4 mg [2][5]. Both groups also received a behavior support program [3]. The trial’s ClinicalTrials.gov number is NCT05822830 [2][5].
To enroll, participants needed a BMI of 30 or higher, or a BMI of 27 or higher with at least one obesity-related complication such as hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease. People with type 2 diabetes were excluded [2][4].
The average participant was 44.7 years old, and 64.7% were women [3][4]. The group was 76% White and 19% Black or African American, and 26% were Hispanic or Latino [3]. Mean baseline weight was 113 kg (106 kg in women and 126-127 kg in men), mean BMI was 39.4 kg/m2, and mean waist circumference was 118-118.3 cm [3][4].
The primary endpoint was the percentage change in weight from baseline to week 72. Key secondary endpoints included achieving weight reductions of at least 10%, 15%, 20%, and 25%, and the change in waist circumference [2][5].
The trial was funded by Eli Lilly, the maker of tirzepatide, and Lilly employees were among the authors; Lilly also provided editorial assistance acknowledged in the paper [2].
How much weight did each drug take off?
Tirzepatide produced a least-squares mean weight change of -20.2% (95% CI -21.4 to -19.1) at week 72, versus -13.7% (95% CI -14.9 to -12.6) for semaglutide, a difference that was statistically significant (P<0.001) [2][5]. In absolute terms, that was 22.8 kg lost with tirzepatide versus 15.0 kg with semaglutide [4].
Waist circumference, a marker of fat around the abdomen, fell 18.4 cm (95% CI -19.6 to -17.2) with tirzepatide versus 13.0 cm (95% CI -14.3 to -11.7) with semaglutide (P<0.001), a 5.4 cm difference [2][5][3]. The study’s conclusion was that tirzepatide was superior to semaglutide for reduction in body weight and waist circumference at week 72 [2][5].
| Measure at week 72 | Tirzepatide | Semaglutide |
|---|---|---|
| Mean percent weight change | -20.2% | -13.7% [2][5] |
| Mean weight lost | 22.8 kg | 15.0 kg [4] |
| Mean waist circumference change | -18.4 cm | -13.0 cm [2][5] |
| Systolic blood pressure change | -10.2 mmHg | -7.7 mmHg [4] |
These are averages from a trial setting with structured dose titration and behavior support. They are not a prediction of what any individual will lose, and the trial design pushed participants to their maximum tolerated doses faster than typical real-world practice [3].
What were the odds of losing 10%, 20%, or 25% of body weight?
Tirzepatide hit every weight-loss threshold tested more often than semaglutide [2][5]. The specific breakdowns come from the trial’s presentation at the European Congress on Obesity (ECO) 2025 in Malaga and from conference coverage of it [3][4]:
| Weight-loss threshold | Tirzepatide | Semaglutide |
|---|---|---|
| At least 10% | More than 80% | 60.5% [4] |
| At least 20% | Nearly 50% | 27.3% [4] |
| At least 25% | 31.6% | 16.1% [3][4] |
| At least 30% | 19.7% | 6.9% [3] |
Roughly twice as many people on tirzepatide lost at least 25% of their body weight compared with semaglutide (31.6% vs 16.1%) [3][4]. The New England Journal of Medicine abstract itself states only that tirzepatide participants were more likely to reach each threshold; the split percentages come from the ECO 2025 presentation and coverage of it [2][3][4].
How did side effects compare?
The most common adverse events in both groups were gastrointestinal, and most were mild to moderate in severity and occurred mainly during dose escalation [2][5][3].
Conference coverage reported serious adverse events in 4.8% of the tirzepatide group versus 3.5% of the semaglutide group, with no adverse events leading to death [4]. Injection-site reactions were more common with tirzepatide (8.6% vs 0.3% with semaglutide), and 14 participants reported more than five injection-site reactions each [4][3]. Vomiting went the other way: 15.0% with tirzepatide versus 21.3% with semaglutide [4]. Alopecia (hair loss) was reported in around 6% of both arms [3].
The discontinuation figures conflict between sources. Conference coverage reported that 6.1% of the tirzepatide group and 8.0% of the semaglutide group stopped treatment because of adverse events (2.7% and 5.6% for gastrointestinal events, respectively) [4]. A separate summary of the trial reported discontinuation due to adverse events at 1.6% in both groups [3]. The supplied sources do not resolve this discrepancy, so both figures are reported here rather than reconciled.
Did blood pressure and other measures improve?
Both drugs improved several cardiometabolic measures. Systolic blood pressure fell 10.2 mmHg with tirzepatide versus 7.7 mmHg with semaglutide [4]. Improvements in HbA1c, fasting glucose, fasting insulin, triglycerides, and diastolic blood pressure occurred in both groups and were numerically larger with tirzepatide [4][3]. Neither drug produced a significant change in LDL or non-HDL cholesterol [3].
These are changes in risk-factor numbers, not proof of fewer heart attacks or strokes.
Did men and women respond differently?
Yes. Women lost 23.8% of body weight with tirzepatide versus 18.0% with semaglutide, while men lost 17.8% versus 11.0% [4]. That pattern reverses what is usually seen with lifestyle changes alone, where men typically lose more weight than women, and there is no explanation for the reversal yet [3][4].
Do the open-label design and Lilly funding undermine the result?
The trial was not blinded: original drug packs and product information were used for both drugs, so participants and staff knew which drug was being given [3]. The investigators point out that the findings are consistent with prior blinded trials of each drug separately [3].
Other limitations: the maximum-tolerated-dose design means some participants stayed at semaglutide 1.7 mg or tirzepatide 10 mg rather than the top doses [2][5], and the trial capped semaglutide at 2.4 mg [2][5]. Lead investigator Louis Aronne noted that titration to the maximal tolerated dose likely happened faster and more aggressively than it would in real-world practice [3]. The funding is also worth noting: Eli Lilly, the manufacturer of tirzepatide, paid for the trial, and Lilly employees were among the authors [2].
What about the diabetes head-to-head trial, SURPASS-2?
SURPASS-2 is a different head-to-head trial in a different population. It was an open-label, 40-week phase 3 trial that randomized 1,879 patients with type 2 diabetes in a 1:1:1:1 ratio to tirzepatide 5 mg, 10 mg, or 15 mg, or semaglutide 1 mg [7]. Participants had a mean baseline HbA1c of 8.28%, a mean age of 56.6 years, and a mean weight of 93.7 kg [7].
HbA1c fell 2.01, 2.24, and 2.30 percentage points with tirzepatide 5, 10, and 15 mg respectively, versus 1.86 points with semaglutide 1 mg. The treatment differences versus semaglutide were -0.15 (P=0.02), -0.39 (P<0.001), and -0.45 (P<0.001) percentage points [7]. Tirzepatide also produced extra weight loss of 1.9, 3.6, and 5.5 kg versus semaglutide [7].
The key caveat: the comparator was semaglutide 1 mg, the diabetes dose, not the 2.4 mg weight-management dose used in SURMOUNT-5 [7]. Serious adverse events occurred in 5-7% of tirzepatide patients versus 3% of semaglutide patients, and hypoglycemia (blood glucose under 54 mg/dL) occurred in 0.6%, 0.2%, and 1.7% of the tirzepatide dose groups versus 0.4% with semaglutide [7]. SURPASS-2 was also funded by Eli Lilly (NCT03987919) [7].
Which drug has proven reduction in heart attacks and strokes?
Semaglutide does, in people with existing cardiovascular disease. The SELECT trial enrolled 17,604 patients age 45 or older with a BMI of 27 or higher, established cardiovascular disease, and no diabetes, in a double-blind, placebo-controlled design [8]. Patients received semaglutide 2.4 mg weekly or placebo [8].
A composite of cardiovascular death, nonfatal heart attack, or nonfatal stroke occurred in 6.5% of the semaglutide group (569 of 8,803) versus 8.0% of the placebo group (701 of 8,801), a hazard ratio of 0.80 (95% CI 0.72 to 0.90, P<0.001). Mean follow-up was 39.8 months [8]. Permanent discontinuation for adverse events occurred in 16.6% of the semaglutide group versus 8.2% of the placebo group (P<0.001) [8]. SELECT was funded by Novo Nordisk (NCT03574597) [8].
Tirzepatide does not yet have equivalent outcomes data in people with obesity without diabetes. Aronne noted there are no prospective outcomes data with tirzepatide yet, while calling SELECT a “very powerful” study [4]. The SURMOUNT-MMO trial of tirzepatide in obesity without diabetes is ongoing with roughly 15,000 participants and is not expected to complete until 2027 [4][3]. A tirzepatide cardiovascular outcomes trial in type 2 diabetes exists (SURPASS-CVOT, a tirzepatide-versus-dulaglutide comparison), but its results are not in the supplied sources [9]. An observational comparison of semaglutide versus tirzepatide cardiovascular outcomes in routine type 2 diabetes care also exists in the literature, but its figures are not available in the supplied sources [10].
What other approved uses distinguish the two drugs?
Tirzepatide is licensed in the US for obstructive sleep apnea, based on the SURMOUNT-OSA study (Malhotra et al, NEJM 2024;391:1193-205) [3][12]. Semaglutide is licensed in the US for adolescents [3], and it gained a US indication in 2024 for reducing major adverse cardiovascular events [4].
A semaglutide chronic kidney disease trial in type 2 diabetes (FLOW) exists, but its effect sizes are not in the supplied sources [11]. A phase 3 semaglutide trial in MASH (metabolic dysfunction-associated steatohepatitis) has been published, but its details are not in the supplied sources [15].
On approvals: oral semaglutide (Rybelsus) was approved for type 2 diabetes in 2019, and injectable semaglutide for chronic weight management in 2021 [4]. Tirzepatide was approved in 2022 as Mounjaro for type 2 diabetes and in 2023 for chronic weight management in adults with obesity or overweight plus at least one weight-related condition [4]. Tirzepatide is Zepbound (Eli Lilly) for weight management; semaglutide is Wegovy (Novo Nordisk) [4].
What do clinicians say about choosing between them?
Aronne said the choice should be individualized, and that both drugs are highly effective alongside behavior-change support [3]. He suggested that for people with class 1 obesity (BMI 30 to under 35), the weight loss achievable with semaglutide is likely sufficient, while people with higher BMIs are likely to benefit more from tirzepatide’s greater weight loss [3][4].
Access is a real constraint. David Horner, a physician not involved in the study, noted that if tirzepatide cannot be accessed, semaglutide remains a good option because roughly 15% weight loss is still enormous, particularly at the population level [4].
One possible reason for tirzepatide’s larger effect: it is a single molecule that activates both the GIP and GLP-1 receptors, while semaglutide activates only the GLP-1 receptor [3][4]. The study’s authors suggest tirzepatide’s action on GIP receptors in adipose tissue may have contributed to the greater weight reduction [3].
Two other points from the coverage: at very high levels of weight loss (25% or more of body weight), there is growing concern about loss of lean muscle, and research on muscle quality after medically induced weight loss is ongoing [4]. And waist circumference is worth tracking, since a pooled analysis of 650,000 adults (Cerhan et al, 2014) found that each 5 cm increase in waist circumference predicted 9% higher mortality in women and 7% higher mortality in men [3].
Real-world evidence on how long people stay on these drugs and what happens after discontinuation is still emerging; a published cohort study examines weight change with semaglutide or tirzepatide by discontinuation status, but its specific percentages are not available in the supplied sources [14].
If you are deciding between these medications, that is a conversation to have with your clinician, who can weigh your BMI, health conditions, heart risk, insurance coverage, and how you tolerate each drug’s side effects.
Sources
- ClinicalTrials.gov. Study record NCT05822830.
- New England Journal of Medicine. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity.
- DiabetesontheNet. Diabetes Distilled: Tirzepatide SURMOUNTs semaglutide for weight loss. July 9, 2025.
- TCTMD. Tirzepatide Tops Semaglutide for Weight Loss: SURMOUNT-5. May 12, 2025.
- PubMed. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity.
- The Lancet Diabetes & Endocrinology. Once-weekly semaglutide 7.2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial.
- PubMed. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes.
- New England Journal of Medicine. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes.
- PubMed. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes.
- PubMed. Cardiovascular outcomes of semaglutide and tirzepatide for patients with type 2 diabetes in clinical practice.
- PubMed. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes.
- PubMed. Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity.
- PubMed. A systematic review and meta-analysis of the efficacy and safety of pharmacological treatments for obesity in adults.
- PubMed. Changes in weight and glycemic control following obesity treatment with semaglutide or tirzepatide by discontinuation status.
- PubMed. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis.
Frequently asked questions
Which drug produced more weight loss in the only direct trial?
Tirzepatide did. In SURMOUNT-5, the first published head-to-head randomized trial in adults with obesity without diabetes, tirzepatide produced a mean weight change of -20.2% at 72 weeks versus -13.7% for semaglutide (P<0.001). The trial concluded tirzepatide was superior for both body weight and waist circumference.
How much weight in kilograms did people lose on each drug?
Participants on tirzepatide lost an average of 22.8 kg, versus 15.0 kg for those on semaglutide, over 72 weeks. Waist circumference fell 18.4 cm with tirzepatide versus 13.0 cm with semaglutide. These are trial averages under structured titration, not a prediction for any individual.
Do side effects differ meaningfully between the two?
Both drugs caused mostly mild-to-moderate gastrointestinal effects during dose escalation. Injection-site reactions were more common with tirzepatide (8.6% vs 0.3%), while vomiting was more common with semaglutide (21.3% vs 15.0%). Discontinuation figures conflict across sources: 6.1% vs 8.0% in one report and 1.6% in both groups in another.
Does the open-label, Lilly-funded design undermine the trial?
The trial was not blinded, since original drug packs were used, and it was funded by Eli Lilly, tirzepatide's maker. The investigators note the results are consistent with prior blinded trials of each drug. The design also titrated participants to maximum tolerated doses faster than typical real-world practice, per lead investigator Aronne.
Why did SURPASS-2 use a lower semaglutide dose?
SURPASS-2 tested tirzepatide against semaglutide 1 mg, the type 2 diabetes dose, not the 2.4 mg weight-management dose. In that 40-week trial of 1,879 patients with type 2 diabetes, HbA1c fell 2.30 points with tirzepatide 15 mg versus 1.86 points with semaglutide 1 mg. So SURPASS-2 cannot answer the weight-management dosing question.
Which drug has proven heart attack and stroke reduction?
Semaglutide. In the SELECT trial of 17,604 patients with established cardiovascular disease and no diabetes, semaglutide 2.4 mg reduced a composite of cardiovascular death, nonfatal heart attack, or nonfatal stroke by 20% versus placebo (HR 0.80, 95% CI 0.72-0.90). Comparable tirzepatide outcomes data in obesity without diabetes is not expected before 2027.
When will tirzepatide heart-outcomes data in obesity be available?
The SURMOUNT-MMO trial of tirzepatide in people with obesity but not type 2 diabetes is ongoing with approximately 15,000 participants and is not expected to complete until 2027. Until then, there are no prospective cardiovascular outcomes data with tirzepatide in this population, according to lead investigator Aronne.
Which drug is better if you have sleep apnea?
Tirzepatide is licensed in the US for obstructive sleep apnea, based on the SURMOUNT-OSA study (Malhotra et al, NEJM 2024). Semaglutide's distinguishing US approvals include use in adolescents and a 2024 indication for reducing major adverse cardiovascular events. Discuss your specific situation with your clinician.
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.