In the SURMOUNT-5 head-to-head clinical trial in adults with obesity without type 2 diabetes, tirzepatide produced a larger mean weight reduction than semaglutide over 72 weeks of treatment (-20.2% versus -13.7%). At Longevity Benchmark, we examine how published trial data compares to public discussion so readers understand what clinical evidence actually demonstrates before speaking with a clinician.

Weight loss is not the entire comparison between these two therapies. Semaglutide is the only molecule of the two with a published cardiovascular outcomes trial in adults with overweight or obesity without diabetes. Both therapies represent distinct pharmacological classes with separate trial programs, unique manufacturer affiliations, and differing clinical profiles.

The Verdict

The published trial evidence demonstrates documented differences between semaglutide and tirzepatide across primary clinical endpoints. In direct head-to-head evaluation in adults with obesity without diabetes (SURMOUNT-5), tirzepatide achieved a statistically significant greater mean weight loss at 72 weeks (-20.2% versus -13.7%) and a larger reduction in waist circumference (-18.4 cm versus -13.0 cm). In patients with type 2 diabetes (SURPASS-2), tirzepatide produced larger reductions in HbA1c and body weight than semaglutide 1 mg. Conversely, semaglutide has completed a dedicated cardiovascular outcomes trial (SELECT) in patients with overweight or obesity without diabetes, reporting a hazard ratio of 0.80 (95% CI 0.72 to 0.90, P<0.001) for primary cardiovascular events, whereas an equivalent published cardiovascular outcomes trial for tirzepatide is not available. Both medications share common gastrointestinal adverse events, primarily occurring during dose escalation, and both carry a boxed warning in their United States prescribing information regarding thyroid C-cell tumours observed in rodents. The clinical comparison between semaglutide and tirzepatide involves balancing the magnitude of weight and glycemic reductions against the breadth of long-term cardiovascular endpoint data, personal tolerability, and approved brand indications. The decision of which medication to initiate, continue, or adjust belongs strictly to the reader and their prescribing healthcare provider.

Semaglutide vs Tirzepatide, Side by Side

AttributeSemaglutideTirzepatide
Receptor target GLP-1 receptor agonist Dual GIP and GLP-1 receptor agonist
Manufacturer Novo Nordisk Eli Lilly
United States brand names Ozempic (type 2 diabetes), Wegovy (chronic weight management), Rybelsus (type 2 diabetes) Mounjaro (type 2 diabetes), Zepbound (chronic weight management)
Head-to-head weight change (SURMOUNT-5) -13.7% least-squares mean weight change at week 72 -20.2% least-squares mean weight change at week 72
Placebo-controlled weight change -14.9% mean weight change at week 68 in STEP 1 -15.0% (5 mg), -19.5% (10 mg), and -20.9% (15 mg) at week 72 in SURMOUNT-1
HbA1c reduction in type 2 diabetes (SURPASS-2) -1.86 percentage points with 1 mg dose at week 40 -2.01 (5 mg), -2.24 (10 mg), and -2.30 (15 mg) percentage points at week 40
Published cardiovascular outcomes trial Completed and published (SELECT trial) No equivalent published cardiovascular outcomes trial available
Most common adverse events Gastrointestinal events, primarily nausea, diarrhea, and vomiting Gastrointestinal events, primarily nausea, diarrhea, and vomiting
Administration frequency Once weekly subcutaneous injection (Ozempic, Wegovy) or oral tablet (Rybelsus) Once weekly subcutaneous injection (Mounjaro, Zepbound)

What the Head to Head Trial Measured

In the SURMOUNT-5 clinical trial, tirzepatide demonstrated a statistically significant greater mean weight loss than semaglutide over 72 weeks of treatment.

The SURMOUNT-5 study (published in 2025, NCT05822830) represents the only published head-to-head randomized trial comparing semaglutide and tirzepatide directly in adults with obesity. Conducted as a phase 3b, open-label trial, SURMOUNT-5 enrolled 751 adults who had obesity but did not have type 2 diabetes. Participants were randomized in a 1:1 ratio to receive the maximum tolerated dose of tirzepatide (either 10 mg or 15 mg) or the maximum tolerated dose of semaglutide (either 1.7 mg or 2.4 mg), administered once weekly for 72 weeks.

The primary end point in SURMOUNT-5 was the percent change in body weight from baseline to week 72. At the completion of the 72-week evaluation period, the least-squares mean weight change was -20.2% (95% CI -21.4 to -19.1) among participants receiving tirzepatide, compared to -13.7% (95% CI -14.9 to -12.6) among participants receiving semaglutide, yielding a statistically significant difference (P<0.001).

Secondary outcomes in the trial aligned with the primary weight loss finding. In SURMOUNT-5, the reduction in waist circumference reached -18.4 cm with tirzepatide compared to -13.0 cm with semaglutide (P<0.001). Participants assigned to tirzepatide were also more likely to achieve categorical weight loss reductions of at least 10%, 15%, 20%, and 25% over the 72 weeks. The trial utilized an open-label design, meaning participants and investigators were aware of the assigned study drug. Eli Lilly funded the trial.

  • Mean weight change. Least-squares mean weight change was -20.2% with tirzepatide compared to -13.7% with semaglutide at week 72 in SURMOUNT-5 (P<0.001).
  • Waist circumference change. Participants in SURMOUNT-5 achieved a mean reduction in waist circumference of -18.4 cm on tirzepatide compared to -13.0 cm on semaglutide (P<0.001).
  • Dosing protocol. SURMOUNT-5 evaluated maximum tolerated weekly doses of 10 mg or 15 mg for tirzepatide versus 1.7 mg or 2.4 mg for semaglutide.
  • Trial population. SURMOUNT-5 evaluated 751 adults with obesity but without type 2 diabetes in an open-label design funded by Eli Lilly.

The Two Mechanisms Are Not the Same Drug Class

Semaglutide and tirzepatide belong to distinct pharmacological classes defined by their specific receptor binding profiles.

Semaglutide acts at the GLP-1 receptor. It is a GLP-1 receptor agonist. Novo Nordisk manufactures semaglutide for subcutaneous injection and oral tablet administration.

Tirzepatide acts at both the GIP and GLP-1 receptors. It is classified as a dual GIP and GLP-1 receptor agonist. Eli Lilly manufactures tirzepatide for subcutaneous injection.

Both molecules share a weekly subcutaneous injection schedule for their primary injectable formulations, but their receptor targets distinguish them into separate drug classes. Sibling research examining how incretin therapies interact with the central nervous system can be found in our overview of GLP-1 and the brain, as well as our review on insulin resistance and weight loss.

What the Placebo-Controlled Trials Showed Separately

Before direct head-to-head research was published, clinical benchmarks for semaglutide and tirzepatide were established in separate placebo-controlled trials.

Comparing separate placebo-controlled studies requires caution because the trials enrolled different patient populations, used differing study lengths, and followed unique protocols. The SURMOUNT-1 trial evaluated tirzepatide over 72 weeks, whereas the STEP 1 trial evaluated semaglutide over 68 weeks. Cross-trial comparisons cannot replace direct head-to-head trials, but the individual results provide context on how each drug performed against placebo.

In the SURMOUNT-1 trial (published in 2022, NCT04184622), investigators evaluated tirzepatide in 2,539 adults with a body mass index of 30 or greater, or 27 or greater with a weight-related complication, excluding individuals with diabetes. At baseline, participants had a mean body weight of 104.8 kg and a mean body mass index of 38.0. Over 72 weeks of double-blind treatment, mean weight change was -15.0% with 5 mg tirzepatide, -19.5% with 10 mg tirzepatide, -20.9% with 15 mg tirzepatide, and -3.1% with placebo. A weight reduction of 5% or more was achieved by 85% (5 mg), 89% (10 mg), and 91% (15 mg) of tirzepatide participants, compared to 35% on placebo. Reductions of 20% or more were achieved by 50% in the 10 mg arm and 57% in the 15 mg arm, compared to 3% in the placebo group. Eli Lilly funded the study.

In the STEP 1 trial (published in 2021, NCT03548935), semaglutide 2.4 mg was evaluated against placebo in 1,961 adults with a body mass index of 30 or greater, or 27 or greater with a weight-related coexisting condition, without diabetes. Over 68 weeks alongside a lifestyle intervention, participants receiving semaglutide achieved a mean weight change of -14.9% compared to -2.4% for placebo, reflecting a treatment difference of -12.4 percentage points (95% CI -13.4 to -11.5, P<0.001) and an absolute weight reduction of -15.3 kg versus -2.6 kg. A weight reduction of 5% or more was reached by 86.4% on semaglutide versus 31.5% on placebo; 10% or more was reached by 69.1% versus 12.0%; and 15% or more was reached by 50.5% versus 4.9%. Novo Nordisk funded the study.

These published percentages represent group averages across thousands of trial participants. The trials do not predict an individual outcome for any specific patient. Related research on how weight changes over time is covered in our guide to the weight-loss plateau to understand how weight changes evolve over time.

Blood Sugar Where the Comparison Was Run in Diabetes

In adults diagnosed with type 2 diabetes, the comparative glycemic and weight effects of semaglutide and tirzepatide were examined directly in the SURPASS-2 clinical trial.

The SURPASS-2 trial (published in 2021, NCT03987919) was a 40-week, open-label study enrolling 1,879 patients with type 2 diabetes. At baseline, the study population had a mean glycated hemoglobin (HbA1c) of 8.28%, a mean age of 56.6 years, and a mean body weight of 93.7 kg. The trial evaluated three doses of tirzepatide (5 mg, 10 mg, and 15 mg) administered once weekly in comparison to semaglutide 1 mg administered once weekly.

The primary outcome was the change in HbA1c from baseline to week 40. Mean reductions in HbA1c were -2.01 percentage points with tirzepatide 5 mg, -2.24 percentage points with tirzepatide 10 mg, and -2.30 percentage points with tirzepatide 15 mg, compared to -1.86 percentage points with semaglutide 1 mg. The differences versus semaglutide were -0.15 percentage points (95% CI -0.28 to -0.03, P=0.02) for 5 mg, -0.39 percentage points (95% CI -0.51 to -0.26, P<0.001) for 10 mg, and -0.45 percentage points (95% CI -0.57 to -0.32, P<0.001) for 15 mg.

Body weight reductions in SURPASS-2 also showed statistically significant differences favoring tirzepatide. The treatment differences versus semaglutide 1 mg were -1.9 kg for 5 mg, -3.6 kg for 10 mg, and -5.5 kg for 15 mg (P<0.001 for all three comparisons). Eli Lilly funded the SURPASS-2 trial. To understand how glycemic biomarkers reflect metabolic function, see our guide on A1c vs fasting glucose and the assessment of fasting insulin levels.

Where the Evidence Is Uneven

Published cardiovascular outcomes evidence is uneven between semaglutide and tirzepatide because only semaglutide has completed a dedicated cardiovascular trial in non-diabetic populations.

The cardiovascular outcomes profile of semaglutide 2.4 mg was evaluated in the SELECT trial (published in 2023, NCT03574597). SELECT enrolled 17,604 patients aged 45 years or older with preexisting cardiovascular disease and a body mass index of 27 or greater, but without diabetes. Over a mean follow-up of 39.8 months, the primary composite cardiovascular end point occurred in 6.5% of patients in the semaglutide group compared to 8.0% of patients in the placebo group.

The SELECT trial reported a hazard ratio of 0.80 (95% CI 0.72 to 0.90, P<0.001) for the primary cardiovascular end point. Adverse events leading to permanent discontinuation of the study medication occurred in 16.6% of the semaglutide group compared to 8.2% of the placebo group (P<0.001). Novo Nordisk funded the SELECT trial.

No equivalent published cardiovascular outcomes trial for tirzepatide is available. Because an equivalent trial has not been published for tirzepatide in this population, the two medications cannot be compared on published cardiovascular outcome data on equal terms. This asymmetry means that clinical evidence for semaglutide covers long-term cardiovascular endpoints in adults with overweight or obesity without diabetes, while tirzepatide currently lacks equivalent published endpoint data.

Side Effects as the Trials Reported Them

Gastrointestinal symptoms represent the most frequently reported adverse events for both semaglutide and tirzepatide across published clinical trials.

In clinical trials of both molecules, gastrointestinal events were mostly mild to moderate in severity and occurred primarily during dose escalation. The trials reported specific frequencies of these events during direct and placebo-controlled comparisons.

  • Nausea rates. In the SURPASS-2 trial, nausea was reported in 17% to 22% of participants across tirzepatide doses and 18% of participants receiving semaglutide 1 mg.
  • Diarrhea rates. In SURPASS-2, diarrhea occurred in 13% to 16% of participants across tirzepatide doses and 12% of participants receiving semaglutide 1 mg.
  • Vomiting rates. In SURPASS-2, vomiting was observed in 6% to 10% of participants on tirzepatide across doses and 8% on semaglutide 1 mg.
  • Hypoglycemia incidence. In SURPASS-2, hypoglycemia (blood glucose below 54 mg/dL) occurred in 0.6% on tirzepatide 5 mg, 0.2% on 10 mg, 1.7% on 15 mg, and 0.4% on semaglutide 1 mg.
  • Serious adverse events. In SURPASS-2, serious adverse events were reported in 5% to 7% of tirzepatide patients and 3% of semaglutide patients.
  • Discontinuation rates. In STEP 1, 4.5% of participants receiving semaglutide discontinued treatment due to gastrointestinal events versus 0.8% on placebo. In SURMOUNT-1, adverse events led to treatment discontinuation in 4.3% (5 mg), 7.1% (10 mg), and 6.2% (15 mg) of tirzepatide groups compared to 2.6% on placebo.
  • Boxed warning. The approved United States prescribing information for the injectable formulations of both medications carries a boxed warning regarding thyroid C-cell tumours observed in rodents. Readers should consult the prescribing information for the exact warning language and the full contraindications list.

What the Brand Names Mean

Semaglutide and tirzepatide are marketed under distinct brand names that designate specific approved uses and formulations.

Semaglutide is sold in the United States under three brand names manufactured by Novo Nordisk: Ozempic (injectable formulation for type 2 diabetes), Wegovy (injectable formulation for chronic weight management), and Rybelsus (oral tablet formulation for type 2 diabetes). Both Ozempic and Wegovy are taken once weekly by subcutaneous injection.

Tirzepatide is sold in the United States under two brand names manufactured by Eli Lilly: Mounjaro (injectable formulation for type 2 diabetes) and Zepbound (injectable formulation for chronic weight management). Both Mounjaro and Zepbound are taken once weekly by subcutaneous injection. The diabetes brand against the weight-management brand is compared directly in Mounjaro vs Wegovy.

Costs, insurance coverage, copay assistance programs, and pharmacy availability are subject to commercial variables outside what this page can verify. Specific prescribing details and product specifications should be confirmed in the prescribing information for Ozempic, Wegovy, Mounjaro, or Zepbound. Readers evaluating individual brand formulations can review our comparison of Zepbound vs Wegovy, Ozempic vs Wegovy, or compounded vs brand semaglutide, as well as dietary planning in our guide to nutrient-dense foods on GLP-1 therapies.

Frequently Asked Questions

Is tirzepatide better than semaglutide for weight loss?

In the only published head-to-head trial in adults with obesity without diabetes, SURMOUNT-5, tirzepatide produced a larger mean weight reduction than semaglutide over 72 weeks of treatment (-20.2% versus -13.7%). Tirzepatide participants also achieved a greater reduction in waist circumference (-18.4 cm versus -13.0 cm) and were more likely to reach weight loss thresholds of 10%, 15%, 20%, and 25%. However, individual responses vary across clinical trials, and weight loss magnitude is only one factor among clinical considerations. Deciding whether one therapy is clinically preferable requires an individualized evaluation with a licensed healthcare provider.

Has anyone compared semaglutide and tirzepatide directly?

Yes, semaglutide and tirzepatide have been directly compared in two major published trials. In the SURMOUNT-5 trial, 751 adults with obesity without type 2 diabetes received maximum tolerated doses of either tirzepatide or semaglutide for 72 weeks, with tirzepatide achieving a -20.2% mean weight reduction compared to -13.7% for semaglutide. In the SURPASS-2 trial, 1,879 adults with type 2 diabetes were randomized to tirzepatide (5 mg, 10 mg, or 15 mg) or semaglutide 1 mg for 40 weeks. Tirzepatide demonstrated greater reductions in both HbA1c and body weight across all three evaluated doses.

Is tirzepatide a GLP-1?

Tirzepatide is a dual GIP and GLP-1 receptor agonist, meaning it acts at both the GIP receptor and the GLP-1 receptor. Semaglutide is a GLP-1 receptor agonist that acts at the GLP-1 receptor alone. While both medications involve GLP-1 receptor activity and share a weekly subcutaneous injection schedule for their primary injectable formulations, their pharmacological classification differs based on tirzepatide's dual receptor binding profile. Both drug classes require a prescription from a licensed clinician.

Why does semaglutide have a cardiovascular trial and tirzepatide does not?

The SELECT trial published results in 2023 demonstrating that semaglutide 2.4 mg reduced primary composite cardiovascular events in adults with preexisting cardiovascular disease and overweight or obesity without diabetes, reporting a hazard ratio of 0.80 (95% CI 0.72 to 0.90, P<0.001). No equivalent published cardiovascular outcomes trial for tirzepatide is currently available. Because published cardiovascular outcomes trials have not been reported on equal terms for both medications, clinical evidence regarding long-term cardiovascular event reduction remains uneven between the two therapies.

Are the side effects different between the two?

Gastrointestinal adverse events represent the most commonly reported side effects for both semaglutide and tirzepatide in clinical studies. In the head-to-head SURPASS-2 trial in type 2 diabetes, reported nausea rates were 17% to 22% for tirzepatide and 18% for semaglutide 1 mg; diarrhea rates were 13% to 16% for tirzepatide and 12% for semaglutide; and vomiting rates were 6% to 10% for tirzepatide and 8% for semaglutide. Both medications carry boxed warnings in their approved United States prescribing information regarding thyroid C-cell tumours observed in rodents.

Do the trial percentages mean I would lose that much?

No, trial percentages reflect average outcomes observed across study populations and do not predict individual weight loss results. In the SURMOUNT-5 trial, participants on tirzepatide achieved an average weight change of -20.2% compared to -13.7% on semaglutide over 72 weeks. In the STEP 1 trial, semaglutide 2.4 mg produced an average weight loss of -14.9% at week 68, while SURMOUNT-1 showed average reductions of -15.0% to -20.9% across tirzepatide doses at week 72. Individual responses depend on personal clinical factors evaluated by a healthcare professional.

Who paid for these trials?

Each major clinical trial was funded by the pharmaceutical company that manufactures one of the evaluated medications. Eli Lilly, the manufacturer of tirzepatide, funded the SURMOUNT-5 head-to-head trial, the SURMOUNT-1 placebo-controlled trial, and the SURPASS-2 active-comparator trial. Novo Nordisk, the manufacturer of semaglutide, funded the STEP 1 placebo-controlled trial and the SELECT cardiovascular outcomes trial.

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