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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: 2026-08-15
Engine: 7.39.0
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/f95b78ea-fe66-4a75-adf8-cb2e9a58eec8 is authoritative.

Kaimen Rigor review

Kaimen Rigor reviewed

3.5 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy claim is based on reduction in energy intake during an ad libitum lunch meal test, which is a surrogate for weight loss and clinical benefit. The paper does not provide evidence linking this surrogate to hard clinical outcomes, nor does it demonstrate target engagement at the tested dose (e.g., PK/PD data).
“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 a reduction in energy intake of 524.6 kcal at week 3, which is a large absolute change but is not anchored to a minimal clinically important difference or to long-term weight loss outcomes. The paper does not establish that this magnitude of reduction in a single meal translates to meaningful clinical benefit.
“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

101ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 05AvailabilityNone found 06Copyedit6 minor suggestions

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 and well-reported phase 1 randomized clinical trial of tirzepatide in adults with overweight or obesity. The paper demonstrates strong scientific premise, rigorous design, adequate reporting of biological variables, ethics, key resources, statistics, data availability, and transparency. Minor reporting gaps include lack of explicit reporting guideline adherence, some internal inconsistencies in reported values, and a few copyedit issues.

Both reviewers classified the study as interventional, and this was adopted. The evaluation covered all eight dimensions; several sub-criteria were marked not applicable for a human clinical trial (e.g., replicate distinction, iacuc statement, cell line authentication). The statistics verification recomputed only 4 tests (all consistent); the paper's full statistical analysis was not independently verified. The citation check found no retracted or unresolved references.

Numerical inconsistencies

1 finding · worst low

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.

Internal contradictions in the reported numbersAssessed

Recomputed 4 tests: 4 consistent, 0 inconsistent; 4 via agent-written checks.

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

CONSISTENTreported p < .001 · recomputed p = <.001Reviewers 1, 2
Primary outcome: tirzepatide vs placebo energy intake change at week 3 (ANCOVA)
“treatment difference −534.11 (95% CI −668.20 to −400.02), P < 0.0001”
Find in source
Taken as given: The estimate is the treatment difference in least squares mean change from baseline.; The 95% CI is two-sided and based on a normal approximation.; The p-value is from the same ANCOVA model.
Method: p-value derived from the estimate and 95% CI using a normal approximation (pCI function).
How we recomputed it: pCI(-534.11, -668.20, -400.02, 0)
CONSISTENTreported p < .001 · recomputed p = <.001Reviewers 1, 2
Secondary outcome: tirzepatide vs placebo energy intake change at week 3 (MMRM)
“−524.6 (−648.1 to −401.0), P < 0.0001”
Find in source
Taken as given: The estimate is the treatment difference in least squares mean change from baseline from MMRM.; The 95% CI is two-sided and based on a normal approximation.; The p-value is from the same MMRM model.
Method: p-value derived from the estimate and 95% CI using a normal approximation (pCI function).
How we recomputed it: pCI(-524.6, -648.1, -401.0, 0)
CONSISTENTreported p < .001 · recomputed p = <.001Reviewers 1, 2
Secondary outcome: tirzepatide vs liraglutide energy intake change at week 3 (MMRM)
“−233.1 (−358.0 to −108.3), P = 0.0004”
Find in source
Taken as given: The estimate is the treatment difference in least squares mean change from baseline from MMRM.; The 95% CI is two-sided and based on a normal approximation.; The p-value is from the same MMRM model.
Method: p-value derived from the estimate and 95% CI using a normal approximation (pCI function).
How we recomputed it: pCI(-233.1, -358.0, -108.3, 0)
CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 1
Secondary outcome: tirzepatide vs placebo body weight change at week 3 (MMRM)
“−3.3 (−3.8 to −2.7), P < 0.0001”
Find in source
Taken as given: The estimate is the treatment difference in least squares mean change from baseline from MMRM.; The 95% CI is two-sided and based on a normal approximation.; The p-value is from the same MMRM model.
Method: p-value derived from the estimate and 95% CI using a normal approximation (pCI function).
How we recomputed it: pCI(-3.3, -3.8, -2.7, 0)

lowinternal contradiction
The abstract reports a treatment difference of −524.6 kcal for the primary outcome, while the Results section reports −534.1 kcal for the same comparison. This may be due to different statistical models (ANCOVA vs MMRM) but is not clearly explained.
Abstract: 'estimated treatment difference −524.6 kcal (95% confidence interval −648.1 to −401.0)' ; Results: 'treatment difference −534.1 kcal (95% confidence interval (CI) −668.2 to −400.0)'
Abstractreviewer’s wording

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

9 major claims checked against the paper's own evidence: 2 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.

partialReviewers 1, 2
Tirzepatide reduces food intake, potentially by impacting ingestive behavior.
The study shows tirzepatide reduces energy intake and alters ingestive behavior and brain activity, but the causal pathway from brain changes to behavior is not directly tested; the claim is appropriately cautious ('potentially').
Evidence: The paper presents evidence of reduced energy intake, changes in appetite/craving questionnaires, and fMRI changes, but does not establish a causal link between brain activation changes and intake reduction.
“Our results suggest tirzepatide reduces food intake, potentially by impacting ingestive behavior.”
DiscussionFind in source
partialReviewer 2
Tirzepatide decreases BOLD fMRI activation to high-fat, high-sugar food photos in specific brain regions.
The paper reports significant decreases in several ROIs at week 3, but these are not adjusted for multiple comparisons and are not sustained at week 6 versus placebo, so the claim is only partially supported.
Evidence: Figure 4 shows significant decreases in medial frontal gyrus, cingulate gyrus, hippocampus, and orbitofrontal cortex at week 3, but no differences at week 6 versus placebo.
“At week 3, with tirzepatide versus placebo, high-fat, high-sugar food (Food HiF/HiS ) activation decreased within medial frontal gyrus, cingulate gyrus, hippocampus and orbitofrontal cortex (Fig. and Supplementary Table ).”
ResultsFind in source
supportedReviewer 1
Tirzepatide reduced energy intake versus placebo at week 3.
The primary outcome analysis (ANCOVA) shows a statistically significant reduction with tirzepatide vs placebo (treatment difference −534.1 kcal, 95% CI −668.2 to −400.0, P < 0.0001).
Evidence: Table 2 and Figure 2a show the primary analysis results.
“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).”
AbstractFind in source
supportedReviewer 1
Tirzepatide decreased overall appetite, food cravings, tendency to overeat, perceived hunger, and reactivity to foods in the environment.
Secondary outcomes from questionnaires (VAS, FCI, FCQ-S, Eating Inventory, PFS) show statistically significant reductions with tirzepatide vs placebo at week 3, as reported in Table 2 and Figure 3.
Evidence: Table 2 and Figure 3 show significant differences for VAS overall appetite, FCI, FCQ-S, Eating Inventory disinhibition and hunger, and PFS.
“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
Tirzepatide did not statistically significantly impact BOLD activation to highly palatable food photos at week 3 versus placebo.
The paper reports no significant difference for the aggregated Food HiPal category, which is consistent with the presented results.
Evidence: Figure 4b shows no significant differences for Food HiPal in any ROI.
“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) 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 1
Tirzepatide decreased activation to high-fat, high-sugar food photos in specific brain regions at week 3 versus placebo.
The paper reports statistically significant reductions in BOLD activation for Food HiF/HiS in medial frontal gyrus, cingulate gyrus, hippocampus, and orbitofrontal cortex at week 3 vs placebo, with p-values provided.
Evidence: Figure 4d and Supplementary Table show significant p-values for these regions.
“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) 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 reduces energy intake versus placebo at week 3.
The primary outcome analysis shows a statistically significant reduction in energy intake with tirzepatide compared to placebo, with a large effect size and narrow confidence interval.
Evidence: Primary outcome: ANCOVA treatment difference −534.1 kcal (95% CI −668.2 to −400.0), P < 0.0001.
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).
Resultsreviewer’s wording
supportedReviewer 2
Tirzepatide decreases overall appetite, food cravings, tendency to overeat, perceived hunger, and reactivity to foods in the environment.
Multiple secondary outcomes show statistically significant improvements with tirzepatide versus placebo, with consistent effects across several measures.
Evidence: Table 2 and Figure 3 show significant reductions in VAS overall appetite, FCI, FCQ-S, PFS, Eating Inventory disinhibition and perceived hunger.
“Tirzepatide decreased fasting overall appetite as assessed by visual analog scale (VAS) at week 3 versus placebo (Table , Fig. and Extended Data Fig. ).”
ResultsFind in source
supportedReviewer 2
Tirzepatide does not impact volitional restriction of dietary intake (cognitive restraint).
The paper reports no statistically significant difference in cognitive restraint between tirzepatide and placebo at week 3, which is consistent with the claim.
Evidence: Table 2: Eating Inventory cognitive restraint change at week 3 versus placebo: 1.3 (−0.1 to 2.8), P = 0.0682.
“There was no statistically significant difference for change in cognitive restraint at week 3 between tirzepatide and placebo.”
ResultsFind 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 reduction in energy intake during an ad libitum lunch meal test, which is a surrogate for weight loss and clinical benefit. The paper does not provide evidence linking this surrogate to hard clinical outcomes, nor does it demonstrate target engagement at the tested dose (e.g., PK/PD data).
“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 a reduction in energy intake of 524.6 kcal at week 3, which is a large absolute change but is not anchored to a minimal clinically important difference or to long-term weight loss outcomes. The paper does not establish that this magnitude of reduction in a single meal translates to meaningful clinical benefit.
“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

None found

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.

Checked — nothing surfaced.

Eight Dimensions8 pass

The introduction cites prior studies on GLP-1 RAs and tirzepatide, noting their effects on ingestive behavior and brain activity, and identifies gaps such as limited measures and lack of brain functioning measurements. The rationale linking the premise to the study's objectives is logical, and the hypothesis follows from the cited evidence. Limitations of prior research (e.g., limited measures, no CNS data) are explicitly addressed as gaps the current study aims to fill.

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 its scientific premise by citing prior work on GLP-1 receptor agonists and tirzepatide, providing a logical rationale for the study, and addressing limitations of prior research.

Evidence

paraphrase[Introduction, paragraphs 1-3]

“Previous studies of selective glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) using self-report inventories suggest these therapies affect ingestive behaviors, while functional magnetic resonance imaging (fMRI) studies using food cues show involvement of central nervous system (CNS) mechanisms.”

“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

“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

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with prior work cited and a logical rationale linking GLP-1/GIP receptor agonism to ingestive behavior and CNS mechanisms.

Evidence

paraphrase[Introduction, paragraph 1-2]

“A 72-week phase 3 study in adults with obesity demonstrated that once-weekly tirzepatide produced weight reduction of up to 20.9%, compared to 3.1% with placebo.”

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

Introduction ¶2Find 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 ¶3Find in source

Randomization method is described (randomization table with treatment codes, stratified by BMI), and the unit of randomization is the participant. Blinding is partially described: tirzepatide and placebo are blinded, liraglutide is open-label with a rationale. A power analysis is provided (111 participants planned for 80% power). Inclusion/exclusion criteria are detailed in the supplementary information. Outlier handling is not explicitly reported, but sensitivity analyses excluding participants with nausea/vomiting are described. Controls (placebo and active comparator) are appropriate. Independent replication is not applicable for a phase 1 trial. For a human RCT, replicate_distinction and controls (as wet-lab concepts) are not applicable.

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingINADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The study design is rigorous for a phase 1 trial, with adequate randomization, blinding (partially), a power analysis, and pre-specified inclusion/exclusion criteria. Some elements like outlier handling and independent replication are not applicable or not reported.

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]

“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.”

PASSReviewer 2· 90% conf

The trial design is rigorous: randomized, partially blinded, with a prespecified primary outcome, power analysis, and clear inclusion/exclusion criteria.

Evidence

MethodsFind in source

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

MethodsFind in source

“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.”

Statistical analysisFind in source

Sex is reported in Table 1 (92% female in placebo, 66% in liraglutide, 97% in tirzepatide). Age, weight, BMI, and waist circumference are reported as mean (SD). Race and ethnicity are also reported. Since both sexes were enrolled, sex_justified is not applicable. Species/strain/source and housing conditions are not applicable for a human trial. Demographics are adequately reported.

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 are well reported for a human trial: sex, age, weight, BMI, race, ethnicity, and waist circumference are provided in baseline demographics. Sex justification is not applicable as both sexes were enrolled.

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%) |”

PASSReviewer 2· 90% conf

Sex, age, weight, BMI, and demographics are reported; sex imbalance is acknowledged and discussed.

Evidence

“Sex was self-reported by participants.”

Table 1Find in source

“There was also an imbalance in sex across treatment groups, with more males in the liraglutide group (34%) compared to the other groups (<10% in each).”

LimitationsFind in source

The methods state that the study was approved by institutional review boards at each site (Pennington Biomedical Research Center IRB, Indiana University HRPP, Johns Hopkins IRB). Written informed consent was obtained from all participants. Regulatory compliance with the Declaration of Helsinki and ICH-GCP is explicitly stated. The trial is registered at ClinicalTrials.gov.

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 are adequately reported: the study was approved by named IRBs at each site, informed consent was obtained, and compliance with the Declaration of Helsinki and ICH-GCP is 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

Ethics 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

The investigational products are identified: tirzepatide (5 mg then 10 mg), liraglutide (titrated to 3 mg), and placebo, all administered subcutaneously. The software used for analysis is identified (SAS Enterprise Guide v.8). Antibodies, cell lines, mycoplasma testing, and organisms are not applicable for this human clinical trial. Reagents are not applicable beyond the investigational products.

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

Key resources are adequately identified: the investigational products (tirzepatide, liraglutide, placebo) are named with dosing regimens, and software (SAS Enterprise Guide v.8) is identified. Other resource types (antibodies, cell lines, etc.) are not applicable.

Evidence

paraphrase[Methods, Procedures]

“Tirzepatide was administered at 5 mg for the first 3 weeks followed by 10 mg for the next 3 weeks. 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.”

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

Statistical analysisFind in source

PASSReviewer 2· 90% conf

The investigational products (tirzepatide, liraglutide, placebo) are identified with dosing regimens; software is identified.

Evidence

paraphrase[Methods, Procedures]

“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 MMRMs, both named. Effect sizes with 95% CIs are reported throughout. Exact p-values are provided for the primary outcome and many secondary outcomes (e.g., P < 0.0001, P = 0.0004). Software is identified (SAS Enterprise Guide v.8). Data presentation includes individual data points in figures and per-group n. Assumptions verification is not explicitly stated, but for a clinical trial using standard methods (ANCOVA, MMRM), this is acceptable. Mathematical plausibility checks are not applicable for continuous outcomes with large N.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedINADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical analysis is rigorous: tests are named, effect sizes with confidence intervals are reported, software is identified, and data presentation is adequate. Assumptions verification is not explicitly reported but is acceptable for a clinical trial using standard methods. Exact p-values are provided for primary and many secondary analyses.

Evidence

paraphrase[Methods, Statistical methods]

“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. ... Changes in efficacy parameters from baseline to week 3 and week 6 and changes from week 3 to week 6 were analyzed using a MMRMs with treatment, baseline BMI stratum, time point (of measurement) and treatment-by-time-point interaction as fixed effects, baseline value as a covariate and participant as a random effect.”

“treatment difference −534.1 kcal (95% confidence interval (CI) −668.2 to −400.0, P < 0.0001)”

ResultsFind in source

“Versus placebo | – | −291.4 (−412.1 to −170.8), P < 0.0001 | −524.6 (−648.1 to −401.0), P < 0.0001”

Table 2Find in source

PASSReviewer 2· 85% conf

Statistical tests are named, effect sizes with CIs are reported, and the analysis is appropriate for a clinical trial; exact p-values are provided for many comparisons.

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

“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).”

AbstractFind in source

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

Table 2Find in source

The data availability statement is detailed: it explains that data cannot be shared publicly due to sponsor obligations but provides a managed-access route via Vivli (www.vivli.org) with conditions (proposal approval, data-sharing agreement). This is reported_and_adequate for a clinical trial with patient-level data. Repository deposit and accession numbers are not applicable for patient-level data. Code sharing is not applicable as no custom code is mentioned.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data availability is adequately described: a data availability statement is present, and a managed-access route via Vivli is provided with conditions. Code sharing is not applicable as no custom code is mentioned.

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.”

PASSReviewer 2· 90% conf

A detailed data availability statement describes managed access via Vivli, which is adequate for individual patient data.

Evidence

paraphrase[Data availability]

“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. Data and documents, including the study protocol, statistical analysis plan, clinical study report and blank or annotated case report forms, will be provided in a secure data-sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.”

Methods are detailed enough for replication (dosing, assessments, statistical methods). The trial is registered at ClinicalTrials.gov (NCT04311411). Limitations are discussed in detail (e.g., open-label liraglutide, sex imbalance, multiple comparisons, short duration). Conclusions are proportional to the evidence, acknowledging limitations. Funding sources and competing interests are disclosed. A specific reporting guideline (e.g., CONSORT) is not explicitly referenced, but the paper follows standard clinical trial reporting.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Reporting transparency is high: methods are detailed, the trial is registered, limitations are discussed, conclusions are proportional, and funding/COI are disclosed. A reporting guideline is not explicitly referenced but the paper follows standard clinical trial reporting.

Evidence

paraphrase[Abstract and Methods]

“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... Third, this study was principally designed to detect treatment effect of the primary outcome. Since type 1 error rate adjustments were not made for multiple comparisons...”

paraphrase[Acknowledgements and Competing interests]

“This study was funded by Eli Lilly and Company. ... Competing interests ... 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· 90% conf

The trial is registered, methods are detailed, limitations are discussed, and funding/COI are disclosed.

Evidence

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

AbstractFind in source

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

LimitationsFind in source

“This study was funded by Eli Lilly and Company.”

AcknowledgementsFind in source

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 56 references by DOI: 2 verified — 54 no DOI (shown, not verified).

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

6 minor

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

No major wording or formatting errors. 6 minor suggestions below.

6 copyedit issues flagged: mostly consistency, clarity, other.

MINORconsistencyTable 2, Change at week 3 (primary analysis of covariance) row
“Change at week 3 (primary analysis of covariance) | 11.0 (49.1) | – | −523.2 (52.8)”
→ The '–' for liraglutide in the primary analysis row is inconsistent with the MMRM row below where liraglutide data are provided. Consider adding a note that the primary analysis only compared tirzepatide vs placebo.
The primary analysis only compares tirzepatide vs placebo, so the dash is correct, but a footnote would clarify.
MINORclarityResults, Secondary outcomes, paragraph 1
“Tirzepatide decreased fasting overall appetite as assessed by visual analog scale (VAS) at week 3 versus placebo (Table , Fig. and Extended Data Fig. ).”
→ The table, figure, and extended data figure references are empty. Ensure they are populated with correct numbers.
Likely a formatting issue in the provided text.
MINORconsistencyTable 2, Change at week 3 row (MMRM)
“Change at week 3 | −7.9 (44.7) (1.9%) | −299.3 (46.2) (−31.5%) | −532.4 (48.3) (−59.1%)”
→ The percentage change for placebo is 1.9% (increase) while the absolute change is negative (-7.9 kcal). This seems inconsistent. Verify the calculation.
The percentage change is calculated relative to baseline mean (893.1 kcal), so -7.9/893.1 ≈ -0.9%, not +1.9%. This may be a typo.
MINORconsistencyAbstract
“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).”
→ Ensure the primary analysis result is consistently reported as −534.1 kcal in the abstract or clarify the difference between the two values.
The abstract reports −524.6 kcal while the Results section reports −534.1 kcal for the primary analysis; this may be due to different models (ANCOVA vs MMRM) but should be clarified.
MINORclarityTable 2
“Change at week 3 (primary analysis of covariance) | 11.0 (49.1) | – | −523.2 (52.8)”
→ Clarify that the values are least squares means (standard error) to avoid confusion with raw means.
The table footnote indicates LS mean (SE) but the header could be more explicit.
MINORotherData availability
“For details on submitting a request, see the instructions provided at www.vivli.org (10.1007/s40615-022-01487-0) .”
→ Remove the extraneous DOI that appears to be incorrectly placed.
The DOI appears to be a reference to a different paper and is likely a formatting error.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and generally well-reported. An informed reader should weigh the minor internal inconsistencies (e.g., abstract vs. results primary outcome value, percentage change in Table 2) and the lack of explicit reporting guideline adherence. These do not undermine the main conclusions but warrant clarification, possibly via an erratum or author note.

1.
HIGHstatistics
Reconcile the primary outcome treatment difference reported in the Abstract (−524.6 kcal) with the Results section (−534.1 kcal) and clarify whether the difference is due to different statistical models (ANCOVA vs MMRM).
The internal contradiction between the abstract and results for the primary outcome could confuse readers and may warrant an erratum.
2.
HIGHstatistics
Verify and correct the percentage change for placebo in Table 2 (reported as +1.9% while the absolute change is −7.9 kcal), ensuring the calculation is consistent with the baseline mean.
The percentage change appears inconsistent with the absolute change and may be a typo that could mislead interpretation.
3.
HIGHreporting
Explicitly state adherence to a reporting guideline (e.g., CONSORT 2010) in the Methods or Reporting Summary, and consider providing a CONSORT flow diagram in the main text.
Both reviewers flagged the lack of an explicit reporting guideline reference, which is a standard expectation for clinical trials and improves transparency.
4.
MEDIUMcopyedit
Populate the empty table/figure references in the Results section (e.g., 'Table , Fig. and Extended Data Fig. ') with the correct numbers.
Broken cross-references reduce clarity and professionalism.
5.
MEDIUMcopyedit
Remove the extraneous DOI (10.1007/s40615-022-01487-0) from the Data availability section, as it appears to be a formatting error.
The DOI is unrelated to the data availability statement and could confuse readers.
6.
MEDIUMreporting
Add a footnote to Table 2 clarifying that the primary analysis only compared tirzepatide vs placebo, explaining the dash for liraglutide.
The dash for liraglutide in the primary analysis row is correct but could be misinterpreted without a note.
7.
MEDIUMstatistics
Clarify in the Statistical methods section whether assumptions for ANCOVA/MMRM (e.g., normality, homoscedasticity) were verified, or note that robust methods were used.
Reviewer 1 flagged assumptions verification as inadequate; explicit reporting would strengthen the statistical analysis description.
8.
MEDIUMstatistics
Report exact p-values for all secondary analyses in the main text or tables, rather than only as thresholds like 'P < 0.0001'.
Exact p-values improve transparency and allow readers to assess the strength of evidence.
9.
MEDIUMreporting
Include the full inclusion and exclusion criteria in the main Methods text rather than only in supplementary information.
Full criteria in the main text improve accessibility and reproducibility.
10.
LOWreporting
Provide a rationale for the choice of 5 mg/10 mg tirzepatide doses in the Methods section.
Justifying the dose selection would strengthen the study design description.
11.
LOWreporting
Discuss the potential impact of the open-label liraglutide arm on blinding and bias more explicitly in the limitations.
The open-label design is a known limitation; a more explicit discussion would be helpful.
12.
LOWdata code
Consider depositing the full study protocol and statistical analysis plan in a public repository (e.g., ClinicalTrials.gov already has registration, but linking the full protocol would be beneficial).
Full protocol availability enhances transparency and reproducibility.

Full text (78,336 chars · analyzed ~96%, head + tail)Analyzed: Aug 15, 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

2026-08-15

Engine

7.39.0

Exported

2026-09-20