Controlled study
SURMOUNT-5: weight change at 72 weeks
In SURMOUNT-5, adjusted mean weight change at 72 weeks was −20.2% with tirzepatide and −13.7% with semaglutide; the reported difference was −6.5 percentage points (95% CI −8.1 to −4.9).
SURMOUNT-5 had 751 randomized participants, 750 who received at least one dose and 636 evaluable participants in the registered primary outcome; these counts describe different sets.
In the SURMOUNT-5 registry, 18 of 374 tirzepatide-treated participants and 13 of 376 semaglutide-treated participants had serious adverse events during the registered 72-week window.
Weight results during 68 or 72 treatment weeks and a two-week sleep intervention answer different questions from a withdrawal comparison after initial treatment. SURMOUNT-4 provides that specific comparison for 52 weeks after randomization.
- Evidence design
- Randomized comparison
- Population
- Adults aged at least 18 years with BMI >=30 kg/m2, or BMI >=27 kg/m2 with at least one weight-related comorbidity, without type 2 diabetes. Both arms received diet and physical-activity intervention.
- Assessment period
- Baseline to week 72
- Reported units
- percentage points; participants; % change
Keep in view
- Open-label trial in adults without type 2 diabetes; group averages do not predict an individual's response.
- 751 randomized, 750 treated/mITT and 636 evaluable in the registered outcome are different denominators.
- Verification used the original abstract, registry and SAP; the full NEJM article was not accessed.
See study details — SURMOUNT-5
Study design and methods
Randomized comparison
Randomized, open-label, active-controlled superiority trial; allocation 1:1; 72 weeks; phase 3b.
Population
Adults aged at least 18 years with BMI >=30 kg/m2, or BMI >=27 kg/m2 with at least one weight-related comorbidity, without type 2 diabetes. Both arms received diet and physical-activity intervention.
- Outcome definition
- Percent change in body weight from baseline to week 72
- Assessment period
- Value
- 72
- Unit
- weeks
- Reported statistic
- least-squares mean
- Unit
- % change from baseline
- Randomized participants
- 751
- Modified intention-to-treat participants
- 750
- Estimand and analysis rules
- Name
- modified treatment-regimen estimand
- Primary estimand
- Yes
- Analysis population
- Modified intention-to-treat: all randomized participants exposed to at least one dose, analyzed as randomized. FAS contains treatment-period data from mITT with the exclusions below.
- Treatment discontinuation
- Included regardless of discontinuation for any reason.
- Other weight-management medication
- Included except nonstudy crossover to the randomized comparator drug.
- Nonstudy comparator crossover
- Data after nonstudy tirzepatide in the semaglutide arm or nonstudy semaglutide in the tirzepatide arm excluded; missing week-72 values after early discontinuation are addressed by within-arm multiple imputation using observed post-discontinuation outcomes.
- Bariatric or other weight-loss procedures
- Post-procedure data excluded; missing body weight imputed using the worst/highest pre-procedure value from baseline onward.
- Other missing data
- SAP says sporadic missing week-72 data for other reasons unrelated to early discontinuation or procedures are not imputed.
- Analysis method
- ANCOVA with treatment, sex, BMI category, baseline prediabetes and baseline body weight; Rubin combination for multiple imputations.
- Secondary estimand distinction
- Efficacy estimand assumes continuation of assigned treatment without other anti-obesity therapies and is analyzed with MMRM in EAS; do not attach that estimand to these primary estimates.
- Denominator distinctions
- 751 randomized (375/376); 750 received >=1 dose (374/376). ClinicalTrials.gov separately reports 636 evaluable participants for this primary outcome (318/318), with LS means and SE 0.59 in each arm. The 636 registry outcome denominator is not the randomized or safety population. It must not replace 750 as the mITT/FAS parent population or imply a complete-case-only analysis. Study completers are separately 319/319.
Extracted outcomes
| Outcome and group | Reported value | Assessment period | Sample and denominators | Uncertainty |
|---|---|---|---|---|
| Percent change in body weight Tirzepatide Effect estimate | -20.2 % change least-squares mean Unit: % change | Baseline to week 72 Study weeks 0–72 | Reported N: 374 — modified intention-to-treat parent population
| 95% confidence interval: -21.4 to -19.1 |
| Percent change in body weight Semaglutide Effect estimate | -13.7 % change least-squares mean Unit: % change | Baseline to week 72 Study weeks 0–72 | Reported N: 376 — modified intention-to-treat parent population
| 95% confidence interval: -14.9 to -12.6 |
| Percent change in body weight Tirzepatide minus semaglutide Effect estimate | -6.5 percentage points adjusted mean difference Unit: percentage points | Baseline to week 72 Study weeks 0–72 | Reported N: 750 — combined modified intention-to-treat parent population
| 95% confidence interval: -8.1 to -4.9 Reported p-value: <0.001 (Between-group comparison) |
| Participants with a serious adverse event Tirzepatide Descriptive result; not an effect estimate | 18 participants event count Exact numerator: 18 Unit: participants | Baseline to week 72 Study weeks 0–72 | Reported N: 374 — safety analysis population
| Confidence interval for this event was not verified; descriptive count or percentage. |
| Participants with a serious adverse event Semaglutide Descriptive result; not an effect estimate | 13 participants event count Exact numerator: 13 Unit: participants | Baseline to week 72 Study weeks 0–72 | Reported N: 376 — safety analysis population
| Confidence interval for this event was not verified; descriptive count or percentage. |
| Deaths Tirzepatide Descriptive result; not an effect estimate | 0 participants event count Exact numerator: 0 Unit: participants | Baseline to week 72 Study weeks 0–72 | Reported N: 374 — safety analysis population
| Confidence interval for this event was not verified; descriptive count or percentage. |
| Deaths Semaglutide Descriptive result; not an effect estimate | 0 participants event count Exact numerator: 0 Unit: participants | Baseline to week 72 Study weeks 0–72 | Reported N: 376 — safety analysis population
| Confidence interval for this event was not verified; descriptive count or percentage. |
Percent change in body weight — Tirzepatide: extraction context
- Outcome role
- Not specified in the consulted scope
- Scale reference
- baseline_body_weight
- Estimand and analysis rules
- Name
- modified treatment-regimen estimand
- Primary estimand
- Yes
- Analysis population
- Modified intention-to-treat: all randomized participants exposed to at least one dose, analyzed as randomized. FAS contains treatment-period data from mITT with the exclusions below.
- Treatment discontinuation
- Included regardless of discontinuation for any reason.
- Other weight-management medication
- Included except nonstudy crossover to the randomized comparator drug.
- Nonstudy comparator crossover
- Data after nonstudy tirzepatide in the semaglutide arm or nonstudy semaglutide in the tirzepatide arm excluded; missing week-72 values after early discontinuation are addressed by within-arm multiple imputation using observed post-discontinuation outcomes.
- Bariatric or other weight-loss procedures
- Post-procedure data excluded; missing body weight imputed using the worst/highest pre-procedure value from baseline onward.
- Other missing data
- SAP says sporadic missing week-72 data for other reasons unrelated to early discontinuation or procedures are not imputed.
- Analysis method
- ANCOVA with treatment, sex, BMI category, baseline prediabetes and baseline body weight; Rubin combination for multiple imputations.
- Secondary estimand distinction
- Efficacy estimand assumes continuation of assigned treatment without other anti-obesity therapies and is analyzed with MMRM in EAS; do not attach that estimand to these primary estimates.
- Extraction location
- Original article abstract; arm sample sizes cross-checked against registry participant flow
Percent change in body weight — Semaglutide: extraction context
- Outcome role
- Not specified in the consulted scope
- Scale reference
- baseline_body_weight
- Estimand and analysis rules
- Name
- modified treatment-regimen estimand
- Primary estimand
- Yes
- Analysis population
- Modified intention-to-treat: all randomized participants exposed to at least one dose, analyzed as randomized. FAS contains treatment-period data from mITT with the exclusions below.
- Treatment discontinuation
- Included regardless of discontinuation for any reason.
- Other weight-management medication
- Included except nonstudy crossover to the randomized comparator drug.
- Nonstudy comparator crossover
- Data after nonstudy tirzepatide in the semaglutide arm or nonstudy semaglutide in the tirzepatide arm excluded; missing week-72 values after early discontinuation are addressed by within-arm multiple imputation using observed post-discontinuation outcomes.
- Bariatric or other weight-loss procedures
- Post-procedure data excluded; missing body weight imputed using the worst/highest pre-procedure value from baseline onward.
- Other missing data
- SAP says sporadic missing week-72 data for other reasons unrelated to early discontinuation or procedures are not imputed.
- Analysis method
- ANCOVA with treatment, sex, BMI category, baseline prediabetes and baseline body weight; Rubin combination for multiple imputations.
- Secondary estimand distinction
- Efficacy estimand assumes continuation of assigned treatment without other anti-obesity therapies and is analyzed with MMRM in EAS; do not attach that estimand to these primary estimates.
- Extraction location
- Original article abstract; arm sample sizes cross-checked against registry participant flow
Percent change in body weight — Tirzepatide minus semaglutide: extraction context
- Outcome role
- Not specified in the consulted scope
- Scale reference
- Difference in percent change
- Estimand and analysis rules
- Name
- modified treatment-regimen estimand
- Primary estimand
- Yes
- Analysis population
- Modified intention-to-treat: all randomized participants exposed to at least one dose, analyzed as randomized. FAS contains treatment-period data from mITT with the exclusions below.
- Treatment discontinuation
- Included regardless of discontinuation for any reason.
- Other weight-management medication
- Included except nonstudy crossover to the randomized comparator drug.
- Nonstudy comparator crossover
- Data after nonstudy tirzepatide in the semaglutide arm or nonstudy semaglutide in the tirzepatide arm excluded; missing week-72 values after early discontinuation are addressed by within-arm multiple imputation using observed post-discontinuation outcomes.
- Bariatric or other weight-loss procedures
- Post-procedure data excluded; missing body weight imputed using the worst/highest pre-procedure value from baseline onward.
- Other missing data
- SAP says sporadic missing week-72 data for other reasons unrelated to early discontinuation or procedures are not imputed.
- Analysis method
- ANCOVA with treatment, sex, BMI category, baseline prediabetes and baseline body weight; Rubin combination for multiple imputations.
- Secondary estimand distinction
- Efficacy estimand assumes continuation of assigned treatment without other anti-obesity therapies and is analyzed with MMRM in EAS; do not attach that estimand to these primary estimates.
- Extraction location
- Published comparison; SURMOUNT-5 contrast CI verified in official registry
- Reported difference; not recomputed from rounded arm means.
Participants with a serious adverse event — Tirzepatide: extraction context
- Outcome role
- Descriptive safety outcome
- Extraction location
- ClinicalTrials.gov adverseEventsModule.eventGroups; baseline through week 72
- Descriptive safety result; no inference of comparative safety superiority.
Participants with a serious adverse event — Semaglutide: extraction context
- Outcome role
- Descriptive safety outcome
- Extraction location
- ClinicalTrials.gov adverseEventsModule.eventGroups; baseline through week 72
- Descriptive safety result; no inference of comparative safety superiority.
Deaths — Tirzepatide: extraction context
- Outcome role
- Descriptive safety outcome
- Extraction location
- ClinicalTrials.gov adverseEventsModule.eventGroups; baseline through week 72
- Descriptive safety result; no inference of comparative safety superiority.
Deaths — Semaglutide: extraction context
- Outcome role
- Descriptive safety outcome
- Extraction location
- ClinicalTrials.gov adverseEventsModule.eventGroups; baseline through week 72
- Descriptive safety result; no inference of comparative safety superiority.
What the curated evidence supports
- In SURMOUNT-5, adjusted mean weight change at 72 weeks was −20.2% with tirzepatide and −13.7% with semaglutide; the reported difference was −6.5 percentage points (95% CI −8.1 to −4.9).
- SURMOUNT-5 had 751 randomized participants, 750 who received at least one dose and 636 evaluable participants in the registered primary outcome; these counts describe different sets.
- In the SURMOUNT-5 registry, 18 of 374 tirzepatide-treated participants and 13 of 376 semaglutide-treated participants had serious adverse events during the registered 72-week window.
- Weight results during 68 or 72 treatment weeks and a two-week sleep intervention answer different questions from a withdrawal comparison after initial treatment. SURMOUNT-4 provides that specific comparison for 52 weeks after randomization.
Limitations
- Open-label trial in adults without type 2 diabetes; group averages do not predict an individual's response.
- 751 randomized, 750 treated/mITT and 636 evaluable in the registered outcome are different denominators.
- Verification used the original abstract, registry and SAP; the full NEJM article was not accessed.
Verification scope
Verified through 2026-11-04 within the consulted scope.
- Bibliographic metadata checked
- Yes
- Original article abstract consulted
- Yes
- Full-text consultation
- Not consulted
- Official trial registry consulted
- Yes
- Statistical analysis plan consulted
- Yes
- Verification boundary
- Verification is limited to the specific fields and sources consulted; it is not a full systematic appraisal or GRADE rating.
Source record
Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (2025). The New England journal of medicine.
Source identifiers
- Article DOI: 10.1056/NEJMoa2416394
- PubMed record 40353578
- Trial registration: NCT05822830
- Structured registry: NCT05822830
- Statistical analysis plan: NCT05822830 · SAP_001.pdf