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

Name: Verified Rigor Record — Tirzepatide on ingestive behavior in adults with overweight or obesity: a randomized 6-week phase 1 trial
Item: Tirzepatide on ingestive behavior in adults with overweight or obesity: a randomized 6-week phase 1 trial
Rating: 100
Author: Αlpha¹

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.

Paper source

Open DOI

Αlpha¹ Rigor Review

Rigor Review Verified

Critical

High-priority

Action items to resolve · Critical / High

Confidence: highEngine: 7.4.0Source: full text

This Alpha1 Rigor Review uses AI 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.

The paper is a well-conducted phase 1 trial with strong reporting transparency and ethical compliance. However, several methodological and reporting gaps reduce its overall robustness: the open-label comparator, lack of pre-specified outlier handling, missing assumption verification for the primary analysis, two inconsistent p-values, and absence of code sharing.

Three independent reviewers evaluated all eight dimensions; their assessments were synthesized. The statistics verification component checked 20 tests and found 2 inconsistencies. The citation check found 55 references not found in the registry (a high number, but none retracted). The reproducibility check found all 3 links live. The claim audit found no under-evidenced claims.

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

partialAbstract and Discussion
Tirzepatide reduces food intake, potentially by impacting ingestive behavior.
The claim is supported by the primary and secondary outcomes, but the phrase 'potentially by impacting ingestive behavior' is a conclusion drawn from correlational data; the study demonstrates an association between tirzepatide and changes in ingestive behavior, but does not establish the mechanism as causal.
Evidence: The paper shows tirzepatide reduces energy intake and alters self-reported appetitive measures and brain activation. However, no mediation analysis is performed to confirm that changes in ingestive behavior mediate the intake reduction.
“Our results suggest tirzepatide reduces food intake, potentially by impacting ingestive behavior.”
partialAbstract; Discussion
Tirzepatide reduces food intake by impacting ingestive behavior and potentially brain appetite circuits.
The paper shows a correlation (reduced energy intake, reduced cravings, decreased brain activation in appetite-related regions) but does not establish a causal pathway from brain activation changes to reduced intake. The claim is cautiously worded ('our results suggest') but the evidence shows association, not mechanism.
Evidence: All results across energy intake, questionnaires, and fMRI
“Our results suggest tirzepatide reduces food intake, potentially by impacting ingestive behavior.”
supportedAbstract and Results
Tirzepatide reduced energy intake versus placebo at week 3.
The primary outcome analysis with ANCOVA and MMRM both show a statistically significant reduction in energy intake with tirzepatide vs placebo, with large effect sizes and narrow CIs.
Evidence: Primary analysis: treatment difference -534.1 kcal (95% CI -668.2 to -400.0, P<0.0001). MMRM: -524.6 kcal (95% CI -648.1 to -401.0, P<0.0001).
“Tirzepatide reduced energy intake versus placebo at week 3 (estimated treatment difference −524.6 kcal (95% CI −648.1 to −401.0), P < 0.0001).”
supportedAbstract and Results
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 (VAS, FCI, FCQ-S, Eating Inventory, PFS) show statistically significant improvements for tirzepatide vs placebo at week 3, except for cognitive restraint (no significant difference).
Evidence: Table 2 and Figure 3: fasting overall appetite (P<0.0001), FCI overall score (P=0.0008), FCQ-S overall (P<0.0001), Eating Inventory disinhibition (P<0.0001) and perceived hunger (P<0.0001), PFS overall (P<0.0001); cognitive restraint (P=0.0682).
“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.”
supportedResults and Figure 4
Tirzepatide decreased BOLD activation to high-fat, high-sugar food photos in the medial frontal and cingulate gyri, orbitofrontal cortex and hippocampus at week 3 versus placebo.
Statistically significant reductions in activation were observed in these ROIs for the high-fat, high-sugar food contrast at week 3.
Evidence: Results: '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' with nominal P values (0.0335, 0.0306, 0.0221, 0.0321).
“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”
supportedResults, 'Exploratory outcomes' and Figure 4
At week 3 versus placebo, tirzepatide decreased BOLD activation to high-fat, high-sugar food photos in the medial frontal and cingulate gyri, orbitofrontal cortex and hippocampus.
The fMRI results show significant decreases in these specific ROIs with p<0.05, as reported in Figure 4 and Supplementary Table.
Evidence: Figure 4: p=0.0335, 0.0306, 0.0221, 0.0321 for these four regions respectively.
“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”
supportedAbstract and Discussion
Our results suggest tirzepatide reduces food intake, potentially by impacting ingestive behavior.
The conclusion is a reasonable interpretation of the combined results on energy intake, self-reported behavior, and neural responses, though it is couched as suggestive.
Evidence: The paper shows reduced energy intake, reduced appetite and cravings, and decreased activation in brain regions linked to food motivation.
“Our results suggest tirzepatide reduces food intake, potentially by impacting ingestive behavior.”
supportedAbstract; Results, Primary outcome
Tirzepatide reduces energy intake versus placebo at week 3.
The primary outcome analysis shows a statistically significant reduction (ETD −534.1 kcal, 95% CI −668.2 to −400.0, P<0.0001) in energy intake at the ad libitum lunch, fully supporting this claim.
Evidence: Table 2, Figure 2a, Primary outcome text
“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).”
supportedAbstract; Results, Secondary outcomes
Tirzepatide decreases overall appetite, food cravings, tendency to overeat, perceived hunger, and reactivity to foods in the environment.
The paper reports statistically significant reductions for tirzepatide vs placebo in VAS overall appetite, FCI, FCQ-S, PFS, and Eating Inventory disinhibition and perceived hunger at week 3, with exact p-values and CIs.
Evidence: Table 2, Figure 3a–f
“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.”
supportedAbstract; Results, Exploratory outcomes
At week 3 versus placebo, tirzepatide decreased activation to high-fat, high-sugar food photos in the medial frontal and cingulate gyri, orbitofrontal cortex and hippocampus.
The paper reports statistically significant decreases in BOLD activation in these ROIs with tirzepatide vs placebo at week 3, with exact p-values (P=0.0335, P=0.0306, P=0.0221, P=0.0321).
Evidence: Figure 4c–d, Supplementary Table accompanying fMRI results
“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.”
supportedResults, Secondary outcomes; Discussion
Tirzepatide was not found to affect cognitive restraint.
The analysis of the Eating Inventory cognitive restraint subscale shows no statistically significant difference between tirzepatide and placebo at week 3 (ETD 1.3, 95% CI −0.1 to 2.8, P=0.0682) or week 6, supporting the claim.
Evidence: Table 2, Eating Inventory cognitive restraint rows
“Tirzepatide was not found to affect cognitive restraint, which may distinguish it from other weight reduction interventions where increased volitional cognitive restraint appears to be an important component in restricting energy intake to lose weight.”
supportedResults, 'Safety' paragraph
Tirzepatide reduced self-reported impulsiveness as measured by BIS.
The paper reports a statistically significant reduction in BIS total score at week 3 (ETD −0.10, 95% CI −0.17 to −0.02, P=0.0098) and week 6 (ETD −0.10, 95% CI −0.17 to −0.03, P=0.0084) for tirzepatide vs placebo.
Evidence: Table 2, BIS rows; Figure 3f; Extended Data Fig. 5
“Tirzepatide decreased Barratt Impulsiveness Scale (BIS) total impulsiveness score versus placebo at week 3 and week 6.”

Recomputed 20 tests: 18 consistent, 2 inconsistent, 20 via agent-written checks.

2 integrity concerns flagged (0 high).

Rigor

Eight Dimensions8 pass

12 major claims2 partial10 supported

5 copyedit issues flagged: mostly clarity, grammar, consistency.

Checked 57 references: 2 verified — 55 unresolved.

Reproducibility

3 data/code links checked; 3 live.

datahttps://www.vivli.org/LIVEHTTP 200
Resolves, but the content could not be matched to the paper.
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.

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

Alpha¹ Rigor Action ItemsFinal pass before journal submission

The published paper is methodologically sound but has several reporting gaps that an informed reader should weigh: the open-label comparator, missing assumption verification, two inconsistent p-values, and no code sharing. These issues do not invalidate the primary findings but warrant a correction or independent re-analysis for the inconsistent p-values.

1.
HIGHstatistics
In the Results section, correct the two inconsistent p-values: for adverse events (tirzepatide vs placebo) the reported p=1e-10 should be p=0.00096; for discontinuation due to AE the reported p=0.1 should be p=0.67.
The statistics verification component found these p-values to be inconsistent with recomputed values, which could indicate a reporting error.
2.
HIGHreporting
In the Methods (Statistical methods), add a statement verifying that the assumptions of ANCOVA (normality of residuals, homogeneity of variance) were checked, or note that robust standard errors were used.
Standard reporting expectations for ANCOVA require assumption verification; its absence is a common reviewer objection.
3.
HIGHdata code
Add a code sharing statement to the Data availability section, and deposit the SAS analysis scripts (e.g., for the primary ANCOVA and MMRM) in a public repository (e.g., GitHub, Zenodo) with a persistent DOI.
Reproducibility requires access to the analysis code; the current paper provides no code sharing statement.
4.
HIGHreporting
In the Methods (Procedures), explicitly state the manufacturer/source for tirzepatide, liraglutide, and placebo (e.g., 'Eli Lilly and Company, Indianapolis, IN, USA').
The source of investigational products is essential for reproducibility; currently it is only implied by the funding disclosure.
5.
HIGHreporting
In the Methods (Randomization and masking), describe the method used to generate the randomization table (e.g., computer-generated random number sequence) and who generated the allocation sequence.
A vague description of the randomization method reduces transparency and confidence in the allocation concealment.
6.
HIGHreporting
In the Methods (Statistical methods), pre-specify the approach for handling outliers (e.g., exclusion based on predefined SD thresholds or sensitivity analyses).
The absence of a pre-specified outlier handling plan weakens the analytic rigor.
7.
MEDIUMreporting
In Table 2, clarify whether the reported percentage change (e.g., −72.4% for tirzepatide at week 6) is the median percent change from baseline or the LS mean percent change, and place it in a separate column.
The copyedit report flagged this as confusing; the percentage appears inconsistent with the absolute change if interpreted as an LS mean.
8.
MEDIUMreporting
In the Results (Primary outcome), specify the figure references: 'Fig. 2b and Extended Data Fig. 1' instead of the ambiguous 'Fig. and Extended Data Fig.'.
The copyedit report noted that the figure references are ambiguous without specific labels.
9.
MEDIUMreporting
In the Abstract, consider specifying the direction of impact for tirzepatide on food intake (e.g., 'by reducing appetite and food cravings').
The copyedit report suggested this minor clarity improvement.
10.
MEDIUMreporting
In the Abstract footnote for VAS, rephrase 'A higher overall appetite score indicated lower appetite' to 'A higher overall appetite score indicates less appetite' for clarity.
The copyedit report noted this is a clarity improvement.
11.
MEDIUMreporting
In the Author contributions, change 'approved of this paper to be submitted for publication' to 'approved this paper for submission'.
The copyedit report flagged this as a minor grammar issue.
12.
LOWreporting
For p-values reported as '<0.0001', consider providing the exact value to four decimal places in supplementary tables to enable precise assessment of significance.
Exact p-values are preferred for transparency, though '<0.0001' is acceptable for very small values.
13.
LOWreporting
In the limitations section, explicitly recommend that future studies with balanced sex representation investigate sex-specific effects, given the sex imbalance across treatment groups.
The sex imbalance is already acknowledged; a specific recommendation would strengthen the discussion.

Full text (69,200 chars)Analyzed: Jul 4, 2026

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