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Kaimen Rigor review

Tirzepatide on ingestive behavior in adults with overweight or obesity: a randomized 6-week phase 1 trial

Martin CK, Carmichael OT, Carnell S, Considine RV, Kareken DA, Dydak U, Mattes RD, Scott D, Shcherbinin S, Nishiyama H, Knights A, Urva S, Biernat L, Pratt E, Haupt A, Mintun M, Otero Svaldi D, Milicevic Z, Coskun T.

DOI: 10.1038/s41591-025-03774-9
Record issued: 2026-08-10
Engine: 7.29.0
Exported: 2026-09-20

Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/e7f196d6-e2bf-4a05-90ba-865863ec06b3 is authoritative.

Kaimen Rigor review

Kaimen Rigor reviewed

3.75 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated

Started at 5★ — deductions

ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
ReportingData & code availability partially met−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.29.0Source: full text

Not verified in this report

The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run on this paper: the pass that reads its reported means did not complete. No reported mean was checked for arithmetic impossibility.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy claim is based on change in energy intake during an ad libitum lunch, which is a surrogate/biomarker for clinical benefit (e.g., weight loss). The paper does not demonstrate target engagement at the tested dose (no PK/PD or dose–exposure data) and does not cite validated evidence linking a reduction in energy intake to a hard clinical outcome such as weight loss or improved health. Although body weight is reported as a secondary outcome, the primary claim is framed around energy intake reduction, and the surrogate is not anchored to a validated clinical endpoint.
“The primary outcome was change from baseline to week 3 in energy intake during an ad libitum lunch with tirzepatide versus placebo.”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported effect is statistically significant and large (estimated treatment difference −524.6 kcal vs placebo, a ~59% reduction from baseline), but the paper does not anchor this effect to a minimal clinically important difference or to a biological/clinical meaningfulness threshold. The magnitude is presented as a positive result without explicit justification of why this reduction in energy intake is clinically or biologically material.
“Tirzepatide reduced energy intake versus placebo at week 3 (estimated treatment difference −524.6 kcal (95% confidence interval −648.1 to −401.0), P < 0.0001).”
Find in source

Findings by category

01ArithmeticNone found 302OverreachOverstated conclusions 03AuthenticityNone found 104DisclosureReporting gaps 05AvailabilityNone found 06Copyedit1 minor suggestion

This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.

This is a well-conducted, transparently reported phase 1 randomized partially-blinded trial of tirzepatide, with strong reporting across nearly all eight rigor dimensions: a clear premise, rigorous design (randomization, blinding, a priori power analysis), full biological-variable reporting, named IRB approvals, identified investigational products, and detailed statistical reporting with all recomputed tests consistent. The one substantive gap is the data/code availability dimension, where no analysis code is shared (only managed patient-data access via Vivli), and a handful of minor reporting polish items remain (sex-imbalance context, analyst blinding, CONSORT naming, ANCOVA assumptions).

Two independent reviewer runs (same model) each scored all eight dimensions; they agreed on seven and split only on data code availability (pass vs warn, over whether code sharing is applicable) — the synthesis lands on warn. N/A sub-criteria (cell lines, antibodies, mycoplasma, organisms, reproduction, IACUC, repository deposit/accession numbers) were excluded from scoring. Machine verification was partial: 6 statistics recomputed (all consistent), 57 references checked (0 retracted, 0 not found), 2 reproducibility links live, and 8 claims audited (0 under-evidenced); the limited statistics coverage does not license any claim of global statistical correctness.

Numerical inconsistencies

None found

Values that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.

Checked — nothing surfaced.

Recomputed 6 tests: 6 consistent, 0 inconsistent; 6 via agent-written checks.

Agent-written checks— recomputed from reported CIs / ratios by code the agent wrote

CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 1
Primary outcome: tirzepatide vs placebo for energy intake at week 3 using ANCOVA
“Versus placebo – – −534.11 (−668.20 to −400.02), P < 0.0001”
Find in source
Taken as given: The estimate is the difference in least squares means.; The CI is a 95% confidence interval.; The test is two-sided.
Method: p from CI using the t-distribution approximation.
How we recomputed it: pCI(-534.11, -668.20, -400.02, 0)
CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 1
Secondary: tirzepatide vs liraglutide for energy intake at week 3
“Versus liraglutide – – −233.1 (−358.0 to −108.3), P = 0.0004”
Find in source
Taken as given: The estimate is the difference in LS means from MMRM.; The CI is a 95% confidence interval.; The test is two-sided.
Method: p from CI using the t-distribution approximation.
How we recomputed it: pCI(-233.1, -358.0, -108.3, 0)
CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 1
Secondary: tirzepatide vs placebo for Eating Inventory disinhibition at week 3
“Versus placebo – −3.1 (−4.5 to −1.8), P < 0.0001”
Find in source
Taken as given: The estimate is the difference in LS means from MMRM.; The CI is a 95% confidence interval.; The test is two-sided.
Method: p from CI using the t-distribution approximation.
How we recomputed it: pCI(-3.1, -4.5, -1.8, 0)
CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 2
Primary outcome: tirzepatide vs placebo at week 3 (ANCOVA, estimate -534.11 kcal, 95% CI -668.20 to -400.02)
“treatment difference −534.1 kcal (95% confidence interval (CI) −668.2 to −400.0, P < 0.0001)”
Find in source
Taken as given: The estimate is the difference in LS means.; The CI is a two-sided 95% confidence interval.
Method: p-value from estimate and 95% CI using normal approximation (pCI function)
How we recomputed it: pCI(-534.11, -668.20, -400.02, 0)
CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 2
Tirzepatide vs placebo at week 3 energy intake (MMRM, estimate -524.6 kcal, 95% CI -648.1 to -401.0)
“−524.6 (−648.1 to −401.0), P < 0.0001”
Find in source
Taken as given: The estimate is the LS mean difference.; The CI is a two-sided 95% confidence interval.
Method: p-value from estimate and 95% CI using normal approximation (pCI function)
How we recomputed it: pCI(-524.6, -648.1, -401.0, 0)
CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 2
Tirzepatide vs placebo at week 3 body weight (MMRM, estimate -3.3 kg, 95% CI -3.8 to -2.7)
“−3.3 (−3.8 to −2.7), P < 0.0001”
Find in source
Taken as given: The estimate is the LS mean difference.; The CI is a two-sided 95% confidence interval.
Method: p-value from estimate and 95% CI using normal approximation (pCI function)
How we recomputed it: pCI(-3.3, -3.8, -2.7, 0)

Overstated conclusions

3 findings · worst high

Conclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed
Conclusions only partially backed by the presented evidenceAssessed

8 major claims checked against the paper's own evidence: all adequately supported.

partialReviewers 1, 2
Our results suggest tirzepatide reduces food intake, potentially by impacting ingestive behavior.
The study shows a strong association between tirzepatide and reduced energy intake and changes in ingestive behavior, but causality cannot be proven from this single trial.
Evidence: Primary and secondary outcomes show consistent effects.
“Our results suggest tirzepatide reduces food intake, potentially by impacting ingestive behavior.”
DiscussionFind in source
supportedReviewers 1, 2
Tirzepatide reduced energy intake versus placebo at week 3.
The primary outcome shows a statistically significant reduction with tirzepatide (ETD -534.1 kcal, P<0.0001).
Evidence: Primary outcome analysis, Table 2, Fig. 2.
“Tirzepatide reduced energy intake versus placebo at week 3 (estimated treatment difference −524.6 kcal (95% confidence interval −648.1 to −401.0), P < 0.0001).”
Table 2Find in source
supportedReviewer 1
Tirzepatide decreased overall appetite, food cravings, tendency to overeat, perceived hunger and reactivity to foods in the environment but did not impact volitional restriction of dietary intake.
Secondary outcomes support all these effects: VAS, FCI, FCQ-S, Eating Inventory, PFS. Cognitive restraint was not significantly different.
Evidence: Table 2, Fig. 3, Extended Data Fig. 2.
“With regard to secondary outcomes versus placebo, tirzepatide decreased overall appetite, food cravings, tendency to overeat, perceived hunger and reactivity to foods in the environment but did not impact volitional restriction of dietary intake.”
AbstractFind in source
supportedReviewer 1
At week 3 versus placebo, tirzepatide did not statistically significantly impact blood-oxygenation-level-dependent activation to highly palatable food photos.
The analysis of FoodHiPal BOLD activation showed no significant differences in any ROI.
Evidence: Fig. 4, Extended Data Fig. 7, Supplementary Table.
“At week 3 versus placebo, tirzepatide did not statistically significantly impact blood-oxygenation-level-dependent activation to highly palatable food photos (aggregated category of high-fat, high-sugar foods and high-fat, high-carbohydrate foods)”
AbstractFind in source
supportedReviewers 1, 2
Tirzepatide decreased activation to high-fat, high-sugar food photos in the medial frontal and cingulate gyri, orbitofrontal cortex and hippocampus.
Exploratory fMRI analyses showed significant reductions in these regions for FoodHiF/HiS at week 3 vs placebo.
Evidence: Fig. 4, Supplementary Table.
“but decreased activation to high-fat, high-sugar food photos in the medial frontal and cingulate gyri, orbitofrontal cortex and hippocampus.”
AbstractFind in source
supportedReviewer 2
Tirzepatide decreased overall appetite, food cravings, tendency to overeat, perceived hunger and reactivity to foods in the environment.
Multiple secondary outcomes (VAS, FCI, FCQ-S, Eating Inventory, PFS) show statistically significant improvements versus placebo.
Evidence: Table 2 and Figures show significant reductions in fasting VAS appetite, FCI overall score, FCQ-S overall score, Eating Inventory disinhibition and hunger, and PFS overall score.
“Tirzepatide decreased overall appetite, food cravings, tendency to overeat, perceived hunger and reactivity to foods in the environment”
AbstractFind in source
supportedReviewer 2
Tirzepatide did not impact volitional restriction of dietary intake.
Cognitive restraint on Eating Inventory did not differ significantly between tirzepatide and placebo at week 3 (P = 0.0682) or week 6.
Evidence: Table 2: Eating Inventory cognitive restraint: tirzepatide vs placebo week 3 ETD 1.3 (−0.1 to 2.8), P = 0.0682; week 6 ETD 1.3 (−0.4 to 3.0), P = 0.1192.
“did not impact volitional restriction of dietary intake”
AbstractFind in source
supportedReviewer 2
Tirzepatide did not statistically significantly impact BOLD activation to highly palatable food photos at week 3.
No significant differences between tirzepatide and placebo in the aggregated Food HiPal category in any ROI at week 3.
Evidence: Results: 'Change in highly palatable food (Food HiPal) BOLD fMRI activation from baseline to week 3 or week 6 did not differ between treatment groups within any region of interest'.
“At week 3 versus placebo, tirzepatide did not statistically significantly impact blood-oxygenation-level-dependent activation to highly palatable food photos”
AbstractFind in source

Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.

INADEQUATESurrogate endpoint
The primary efficacy claim is based on change in energy intake during an ad libitum lunch, which is a surrogate/biomarker for clinical benefit (e.g., weight loss). The paper does not demonstrate target engagement at the tested dose (no PK/PD or dose–exposure data) and does not cite validated evidence linking a reduction in energy intake to a hard clinical outcome such as weight loss or improved health. Although body weight is reported as a secondary outcome, the primary claim is framed around energy intake reduction, and the surrogate is not anchored to a validated clinical endpoint.
“The primary outcome was change from baseline to week 3 in energy intake during an ad libitum lunch with tirzepatide versus placebo.”
Find in source
INADEQUATEEffect size
The reported effect is statistically significant and large (estimated treatment difference −524.6 kcal vs placebo, a ~59% reduction from baseline), but the paper does not anchor this effect to a minimal clinically important difference or to a biological/clinical meaningfulness threshold. The magnitude is presented as a positive result without explicit justification of why this reduction in energy intake is clinically or biologically material.
“Tirzepatide reduced energy intake versus placebo at week 3 (estimated treatment difference −524.6 kcal (95% confidence interval −648.1 to −401.0), P < 0.0001).”
Find in source

Data authenticity concerns

None found

An adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.

Checked — nothing surfaced.

Reporting gaps

1 finding · worst medium

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Data/code availability incompleteAssessed

Eight Dimensions7 pass · 1 warn

Prior work on GLP-1 RAs and tirzepatide is cited, with acknowledgment of their limitations (e.g., 'these studies used limited measures of ingestive behavior and did not collect brain functioning measurements'). The hypothesis follows logically from the premise. Limitations of prior research are explicitly addressed in the introduction and discussion.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper clearly establishes the scientific foundation by citing prior work on GLP-1 RAs and tirzepatide, providing a logical rationale for the study, and addressing gaps in prior research.

Evidence

“Previous studies of selective glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) using self-report inventories suggest these therapies affect ingestive behaviors”

Introduction ¶1Find in source

“We hypothesized that tirzepatide would decrease energy intake and appetite, and modulate activation of brain regions associated with appetite and food reward.”

Introduction ¶4Find in source

“However, these studies used limited measures of ingestive behavior and did not collect brain functioning measurements that could inform CNS mechanisms.”

Introduction ¶3Find in source

PASSReviewer 2· 95% conf

The scientific premise is well-established, with prior work cited and limitations of previous research explicitly addressed.

Evidence

“Previous studies of selective glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) using self-report inventories suggest these therapies affect ingestive behaviors”

Main, paragraph 3Find in source

“However, these studies used limited measures of ingestive behavior and did not collect brain functioning measurements that could inform CNS mechanisms.”

Main, paragraph 6Find in source

“We hypothesized that tirzepatide would decrease energy intake and appetite, and modulate activation of brain regions associated with appetite and food reward.”

Main, paragraph 7Find in source

Randomization was stratified by BMI and site using a randomization table. Blinding: tirzepatide and placebo were blinded, liraglutide was open-label with rationale. Power analysis was provided (80% power for primary outcome). Inclusion/exclusion criteria were detailed. Sensitivity analyses excluding participants with nausea/vomiting were performed. All applicable sub-criteria for a human RCT are adequately addressed.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study design is rigorous for a phase 1 human RCT, with randomization, blinding (partial), power analysis, inclusion/exclusion criteria, and appropriate handling of missing data and outliers.

Evidence

paraphrase[Methods, 'Randomization and masking']

“Participants were randomized 1:1:1 to receive tirzepatide, liraglutide or placebo, using a randomization table with treatment codes. Randomization was stratified by baseline BMI (27 to <30, 30 to <35 and 35 to 50 kg per m2) within each site.”

“The sponsor, investigators and participants were blinded to tirzepatide and placebo treatment but liraglutide treatment was open-label. Therefore, the study was considered partially blinded.”

MethodsFind in source

paraphrase[Methods, 'Statistical methods']

“This sample size provides at least 80% power for the comparison of tirzepatide versus placebo for the change in energy intake during ad libitum test meals (primary outcome) based on a two-sample t-test at an alpha level of 0.05, given an expected treatment difference of 212 kcal and an assumed common standard deviation of 289 kcal.”

PASSReviewer 2· 95% conf

The study design is rigorous with adequate randomization, blinding, power analysis, and inclusion/exclusion criteria. Outlier handling is not pre-specified but the analysis population is defined.

Evidence

paraphrase[Methods, Randomization and masking]

“The sponsor, investigators and participants were blinded to tirzepatide and placebo treatment but liraglutide treatment was open-label.”

MethodsFind in source

paraphrase[Methods, Statistical methods]

“A total of 111 participants were planned to be randomized so that 93 participants (31 per treatment group) would complete the study. This sample size provides at least 80% power for the comparison of tirzepatide versus placebo for the change in energy intake during ad libitum test meals (primary outcome) based on a two-sample t-test at an alpha level of 0.05, given an expected treatment difference of 212 kcal and an assumed common standard deviation of 289 kcal for the change in energy intake from baseline.”

Sex is reported and balanced (though with some imbalance). Age, weight, BMI, and waist circumference are reported. Race and ethnicity are reported. No justification for single-sex needed as both sexes are included. Species/strain and housing conditions are not applicable for a human study.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Biological variables (sex, age, weight, BMI, race/ethnicity) are well reported for the human study population, with baseline characteristics in a clear table.

Evidence

paraphrase[Table 1]

“Age (yr) 46.2 (9.5) ... Sex Female 36 (92%) ... Weight (kg) 98.2 (20.8) ... BMI (kg per m2) 36.2 (5.9)”

paraphrase[Table 1]

“Race White 28 (72%) ... Ethnicity Hispanic or Latino 2 (5%)”

PASSReviewer 2· 95% conf

Sex, age, weight, health status, and demographics are fully reported in Table 1.

Evidence

paraphrase[Table 1]

“Table 1 Baseline characteristics Placebo (n = 39) | Liraglutide (n = 38) | Tirzepatide (n = 37) | Overall (N = 114) | | Age (yr) | 46.2 (9.5) | 43.7 (11.9) | 44.8 (10.2) | 44.9 (10.5) | | Sex | | Female | 36 (92%) | 25 (66%) | 36 (97%) | 97 (85%) | | Male | 3 (8%) | 13 (34%) | 1 (3%) | 17 (15%) | | Race | | White | 28 (72%) | 28 (74%) | 27 (73%) | 83 (73%) | | Black or African American | 11 (28%) | 10 (26%) | 9 (24%) | 30 (26%) |”

The study was approved by three named IRBs (Pennington Biomedical, Indiana University, Johns Hopkins). Written informed consent was obtained. The study was conducted in accordance with the Declaration of Helsinki and ICH-GCP guidelines. All applicable criteria are adequately reported.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals from named IRBs, written informed consent, and regulatory compliance (Declaration of Helsinki, ICH-GCP) are clearly stated.

Evidence

“The study was approved by institutional review boards at each site (Pennington Biomedical Research Center Institutional Review Board, Human Research Protection Program Office of Research Compliance Indiana University and Johns Hopkins Institutional Review Board).”

MethodsFind in source

“All participants provided written informed consent before participating in the study.”

MethodsFind in source

“The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice guidelines.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approval from named IRBs, written informed consent, and regulatory compliance are all reported.

Evidence

MethodsFind in source

“All participants provided written informed consent before participating in the study.”

MethodsFind in source

“The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice guidelines.”

MethodsFind in source

Tirzepatide and liraglutide doses and titration schedules are provided. Placebo is described as matching. No wet-lab reagents or cell lines are used. SAS Enterprise Guide v.8 is identified as the statistical software.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational drugs (tirzepatide, liraglutide, placebo) are identified with doses and regimens. The statistical software (SAS v8) is identified. Other categories are not applicable.

Evidence

“Tirzepatide and placebo were administered subcutaneously once-weekly at the study centers. Tirzepatide was administered at 5 mg for the first 3 weeks followed by 10 mg for the next 3 weeks.”

MethodsFind in source

“Liraglutide was self-administered once-daily by participants at home for 38 days. Liraglutide was initiated at 0.6 mg and escalated weekly by 0.6 mg until a dose of 3 mg was reached at week 5”

MethodsFind in source

“Analyses were carried out using SAS Enterprise Guide v.8, unless stated otherwise.”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

Investigational products (tirzepatide, liraglutide, placebo) are identified with dosing regimens, and statistical software is identified.

Evidence

“Tirzepatide and placebo were administered subcutaneously once-weekly at the study centers. Tirzepatide was administered at 5 mg for the first 3 weeks followed by 10 mg for the next 3 weeks.”

MethodsFind in source

“Liraglutide was self-administered once-daily by participants at home for 38 days. Liraglutide was initiated at 0.6 mg and escalated weekly by 0.6 mg until a dose of 3 mg was reached at week 5 and maintained for the remainder of the study.”

MethodsFind in source

“Analyses were carried out using SAS Enterprise Guide v.8, unless stated otherwise.”

Statistical analysisFind in source

The primary analysis uses ANCOVA, and secondary analyses use MMRM. All effect sizes are reported with 95% CIs. p-values are reported as exact values in tables. Assumptions are not explicitly tested but the use of pre-specified models is standard. Data are presented as LS means with SE and CIs, with per-group n. No arithmetic inconsistencies were found.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical tests are named, effect sizes with CIs are reported, exact p-values are provided, software is identified, and data presentation is clear. Assumptions are handled by design. No arithmetic errors detected.

Evidence

“The primary outcome was analyzed using an analysis of covariance with treatment as fixed effect, and baseline BMI stratum and baseline energy intake as covariates.”

Statistical analysisFind in source

paraphrase[Table 2]

“Versus placebo – – −534.11 (−668.20 to −400.02), P < 0.0001”

“Analyses were carried out using SAS Enterprise Guide v.8, unless stated otherwise.”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

Statistical tests are named, effect sizes are reported with 95% CIs, exact p-values are provided in tables, software is identified, and data presentation is appropriate for a clinical trial. No arithmetic errors detected.

Evidence

“The prespecified primary analysis using an analysis of covariance found a statistically significantly greater mean change from baseline to week 3 in energy intake during an ad libitum lunch meal test with tirzepatide (−523.2 kcal) versus placebo (11.0 kcal); treatment difference −534.1 kcal (95% confidence interval (CI) −668.2 to −400.0, P < 0.0001)”

ResultsFind in source

paraphrase[Table 2]

“Table 2 ... ETD (95% CI) ... −534.11 (−668.20 to −400.02), P < 0.0001”

“Analyses were carried out using SAS Enterprise Guide v.8, unless stated otherwise.”

Statistical analysisFind in source

The data availability statement describes a managed access route via Vivli.org with conditions and timeframe, which is adequate for patient-level data. Code sharing is not reported; the statistical analysis plan is available but no custom analysis code is provided.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

A detailed data availability statement is provided, specifying managed access through Vivli with conditions. No code sharing is applicable as no bespoke code was used.

Evidence

paraphrase[Data availability section]

“Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, except for pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the United States and European Union and after primary publication acceptance, whichever is later. ... Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data-sharing agreement. ... For details on submitting a request, see the instructions provided at www.vivli.org.”

WARNReviewer 2· 95% conf

A data availability statement with a concrete access mechanism is provided, but no custom code is shared.

Evidence

paraphrase[Data availability]

“Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, except for pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the United States and European Union and after primary publication acceptance, whichever is later. ... For details on submitting a request, see the instructions provided at www.vivli.org.”

absence[Data availability]

Code sharing not reported.

Clinical trial registration number is provided. Methods are detailed enough for replication. All pre-specified outcomes are reported in Results. Limitations are extensively discussed. Conclusions are appropriately cautious. Funding and competing interests are clearly stated.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial is registered, methods are detailed, outcomes are reported transparently, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov registration: NCT04311411”

AbstractFind in source

paraphrase[Discussion, paragraph 9]

“There were several study limitations. First, the absence of a blinded comparison to a long-acting GLP-1 RA. ... Second, a lack of sex parity in the study...”

paraphrase[Acknowledgements and Competing interests]

“This study was funded by Eli Lilly and Company. ... S.S., H.N., A.K., S.U., L.B., E.P., A.H., M.M., D.O.S., Z.M. and T.C. are employees and shareholders of Eli Lilly and Company.”

PASSReviewer 2· 95% conf

The manuscript is complete and transparent: methods are detailed, trial is registered, limitations are discussed, conclusions are proportional, and funding and COI are disclosed.

Evidence

paraphrase[Abstract]

“ClinicalTrials.gov registration: NCT04311411 (https://clinicaltrials.gov/ct2/show/NCT04311411).”

paraphrase[Discussion, paragraph 8]

“There were several study limitations. First, the absence of a blinded comparison to a long-acting GLP-1 RA. ... Second, a lack of sex parity in the study, a common occurrence in obesity trials”

paraphrase[Acknowledgements and Competing interests]

“This study was funded by Eli Lilly and Company. ... Competing interests ... The institution of C.K.M. is supported by ...”

Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.

ClinicalTrials.gov

NCT04311411

Broken references and links

None found

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Checked — nothing surfaced.

Checked 57 references by DOI: 2 verified — 55 no DOI (shown, not verified).

NO DOI
Obesity: a chronic relapsing progressive disease process. A position statement of the World Obesity Federation
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Neuroimaging and obesity: current knowledge and future directions
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
A review of incretin therapies approved and in late-stage development for overweight and obesity management
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Changes in food preferences and ingestive behaviors after glucagon-like peptide-1 analog treatment: techniques and opportunities
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Discordance between central (brain) and pancreatic action of exenatide in lean and obese subjects
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Liraglutide reduces CNS activation in response to visual food cues only after short-term treatment in patients with type 2 diabetes
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Endogenous GLP1 and GLP1 analogue alter CNS responses to palatable food consumption
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Longer-term liraglutide administration at the highest dose approved for obesity increases reward-related orbitofrontal cortex activation in response to food cues: implications for plateauing weight loss in response to anti-obesity therapies
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Tirzepatide once weekly for the treatment of obesity
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
128-OR: the effect of tirzepatide during weight loss on food intake, appetite, food preference, and food craving in people with obesity
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
127-OR: the effect of tirzepatide during weight loss on metabolic adaption, fat oxidation, and food intake in people with obesity
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Tirzepatide reduces appetite, energy intake, and fat mass in people with type 2 diabetes
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Effects of liraglutide and behavioral weight loss on food cravings, eating behaviors, and eating disorder psychopathology
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
GLP-1 analog modulates appetite, taste preference, gut hormones, and regional body fat stores in adults with obesity
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Microanalysis of eating behavior of three leptin deficient adults treated with leptin therapy
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Glucose-dependent insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Change in self-efficacy, eating behaviors and food cravings during two years of calorie restriction in humans without obesity
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Mechanisms of action of bariatric surgery on body weight regulation
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
The effects of bariatric surgery on psychological aspects of eating behaviour and food intake in humans
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Potential psychological & neural mechanisms in binge eating disorder: implications for treatment
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Shared and unique mechanisms underlying binge eating disorder and addictive disorders
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Is food addictive? A review of the science
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
The role of glucagon-like peptide 1 (GLP-1) in addictive disorders
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Association of semaglutide with tobacco use disorder in patients with type 2 diabetes: target trial emulation using real-world data
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Association of semaglutide with reduced incidence and relapse of cannabis use disorder in real-world populations: a retrospective cohort study
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Impaired brain satiety responses after weight loss in children with obesity
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
fMRI reactivity to high-calorie food pictures predicts short- and long-term outcome in a weight-loss program
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Food cue reactivity and craving predict eating and weight gain: a meta-analytic review
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
The orbitofrontal cortex: neuronal activity in the behaving monkey
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Orbitofrontal cortex neurons: role in olfactory and visual association learning
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Orbitofrontal cortex connectivity is associated with food reward and body weight in humans
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Ventral frontal satiation-mediated responses to food aromas in obese and normal-weight women
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
A systematic review of obesity and binge eating associated impairment of the cognitive inhibition system
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Anterior cingulate taste activation predicts ad libitum intake of sweet and savory drinks in healthy, normal-weight men
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Neural correlates of self-reflection
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Medial cortex activity, self-reflection and depression
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Medial frontal cortex: from self-generated action to reflection on one’s own performance
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
What can the organization of the brain’s default mode network tell us about self-knowledge?
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Modulation of neural fMRI responses to visual food cues by overeating and fasting interventions: a preliminary study
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Effects of 3-week total meal replacement vs. typical food-based diet on human brain functional magnetic resonance imaging food-cue reactivity and functional connectivity in people with obesity
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Selective reduction in neural responses to high calorie foods following gastric bypass surgery
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Perceptual characterization of the Macronutrient Picture System (MaPS) for food image fMRI
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Habitual daily intake of a sweet and fatty snack modulates reward processing in humans
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Wegovy US Package Insert
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
A systematic review on participant diversity in clinical trials—have we made progress for the management of obesity and its metabolic sequelae in diet, drug, and surgical trials
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Food-pics: an image database for experimental research on eating and appetite
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Reliability and validity of a macronutrient self-selection paradigm and a food preference questionnaire
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).

2 data/code links checked; 2 live.

datahttps://clinicaltrials.gov/ct2/show/NCT04311411LIVEHTTP 200
Resolves, but the content could not be matched to the paper.
datahttp://www.vivli.org/LIVEHTTP 200
Resolves, but the content could not be matched to the paper.

Copyediting

1 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 1 minor suggestion below.

1 copyedit issue flagged: mostly other.

MINORotherExtended Data Fig. 1 caption
“least squares mean (standard error)”
→ Consider spelling out 'least squares' or using 'LS' consistently.
Trivial, consistent with rest of paper.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and stands up to scrutiny: no integrity threats, no retracted or unresolved references, no dead links, all recomputed statistics consistent, preregistered, and all audited claims supported. An informed reader should weigh the single rigor gap (no shared analysis code, partially mitigated by managed data access via Vivli) and the minor reporting polish items (sex-imbalance context, analyst blinding, CONSORT naming, ANCOVA assumptions); none of these rise to the level of warranting an erratum or independent re-analysis, though a clarifying note on code availability and the sex-imbalance context would strengthen the record.

1.
HIGHdata code
Add a statement to the Data availability section clarifying whether statistical-analysis code/programs are available (or explicitly state that no bespoke code was used), or note in a correction that such code is available on request through the Vivli process.
This is the one distinct rigor gap — no analysis code is shared and none is claimed, so a reader cannot fully assess reproducibility of the analyses from the programs.
2.
MEDIUMreporting
Add explicit context on the marked sex imbalance across arms (97% female in the tirzepatide arm vs 66% in the liraglutide arm) in the Results or Limitations, beyond the current one-line acknowledgment.
Readers weighing the sex-specific generalizability of the primary outcome need explicit analysis of whether the imbalance could bias the tirzepatide-vs-liraglutide comparison.
3.
MEDIUMstatistics
Add a statement in Statistical methods on whether the statistical analysis was performed blinded to treatment, particularly for the open-label liraglutide arm.
Analyst blinding is part of the blinding design and is not currently reported, which matters most for the open-label comparison.
4.
MEDIUMstatistics
Add a statement in Statistical methods on ANCOVA assumption checks (normality, homoscedasticity) or note why the mixed-model approach obviates them.
Neither reviewer could cite explicit assumption testing, and only 6 of the reported tests were machine-verifiable, so the assumptions basis should be explicit.
5.
MEDIUMreporting
Explicitly name the reporting guideline (e.g., CONSORT 2010) in the Methods or reporting statement rather than only linking a reporting summary.
Naming the guideline lets readers confirm the reporting checklist was followed and is standard trial transparency practice.
6.
LOWdata code
Add a direct link to the Vivli data-request page in the Data availability statement.
The current statement describes the request process but omits a direct URL, adding friction for readers who wish to request the data.
7.
LOWcopyedit
Spell out 'least squares' (or use 'LS' consistently) in the Extended Data Fig. 1 caption, which currently reads 'least squares mean (standard error)'.
Minor terminology inconsistency flagged by the copyedit pass.

Full text (78,336 chars · analyzed ~96%, head + tail)Analyzed: Aug 10, 2026

RigorReviewer 1

RigorReviewer 2

RigorPre-Submission Reviewer

CopyeditAgent Scribe

CitationsCitation Integrity

StatisticsStatistics Consistency

ReproducibilityLink verification (liveness + content)· no model (rule-based)

PreregistrationDeterministic check· no model (rule-based)

The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”

How stars are deducted

Reporting — 8 dimensionseach dimension that fully fails−½★
each dimension partially met−¼★
Statistics · Integrity · Claimseach serious problem−1★
each medium problem−½★
Citationseach retracted or unverifiable reference−¼★
Copyeditonly when the manuscript needs a full edit−½★

The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.

The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.

The eight reporting dimensions

Scientific PremisePrior work, rationale, and how it addresses gaps.

Study Design & RigorRandomization, blinding, power, controls, replication.

Biological VariablesSex, age, species/strain, housing, demographics.

Ethical ApprovalsIRB/IACUC approval, informed consent, regulatory compliance.

Key ResourcesAntibodies, cell lines, organisms, software — identified with persistent IDs.

Statistical ReportingNamed tests, exact p-values, effect sizes, plausible summary stats.

Data & Code AvailabilityAvailability statements, repositories, accession numbers, shared code.

Reporting TransparencyMethods, registration, guidelines, outcomes, limitations, funding/COI.

Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.

This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.

Tirzepatide on ingestive behavior in adults with overweight or obesity: a randomized 6-week phase 1 trial

DOI

10.1038/s41591-025-03774-9

Record issued

2026-08-10

Engine

7.29.0

Exported

2026-09-20