Kaimen Rigor reviewed

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Tirzepatide leads to weight reduction in people with obesity due to MC4R deficiency.

Name: Kaimen Rigor review — Tirzepatide leads to weight reduction in people with obesity due to MC4R deficiency.
Item: Tirzepatide leads to weight reduction in people with obesity due to MC4R deficiency.
Rating: 100
Author: Alpha1

Bhatnagar P, Ahmad NN, Li X, Coghlan M, Kaplan LM, Farooqi IS

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Kaimen Rigor review — 3.5★ (Adequate), 0 critical, 3 high issues for “Tirzepatide leads to weight reduction in people with obesity due to MC4R deficiency.”

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This rigor review was examined and confirmed by Alpha1 Editorial · August 15, 2026

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Tirzepatide leads to weight reduction in people with obesity due to MC4R deficiency.

Bhatnagar P, Ahmad NN, Li X, Coghlan M, Kaplan LM, Farooqi IS

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DOI

10.1038/s41591-025-03913-2

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Tirzepatide leads to weight reduction in people with obesity due to MC4R deficiency.

Bhatnagar P, Ahmad NN, Li X, Coghlan M, Kaplan LM, Farooqi IS

Paper source

Tirzepatide leads to weight reduction in people with obesity due to MC4R deficiency.

Read full text (PMC)

Embed this Rigor badge

Links back to this Kaimen Rigor review.

Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 15, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

3.5 / 5

Adequate — real issues to address

Observational Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−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 weight reduction, which is a surrogate endpoint for clinical outcomes in obesity. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD) nor cite validated evidence linking weight reduction to hard clinical outcomes in this context.
“the weight loss trajectory over 72 weeks was comparable in both groups: 18.3% weight reduction in MC4R mutation carriers versus 19.9% in noncarriers.”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 102OverreachOverstated conclusions 103AuthenticityData authenticity concerns 04DisclosureNone found 05AvailabilityNone found 06Copyedit5 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.

The paper is a well-conducted secondary genetic analysis of a randomized controlled trial, with a clear scientific premise, adequate reporting of biological variables, ethics, key resources, statistics, data availability, and transparency. Minor reporting gaps include lack of explicit randomization/blinding details, power analysis, exact p-values, and reporting guideline reference, but these do not undermine the overall robustness.

Both reviewers classified the study as observational (secondary analysis of an RCT). The evaluation covered all eight dimensions; non-applicable sub-criteria (e.g., animal housing, cell line authentication) were excluded. The statistics verification checked only 2 tests (limited coverage), and 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 2 tests: 2 consistent, 0 inconsistent; 2 via agent-written checks.

Overstated conclusions

1 finding · 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

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

Premise concern: surrogate not validated for clinical benefit.

Data authenticity concerns

1 finding · worst low

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.

Other integrity concernAssessed

2 integrity concerns flagged (0 high).

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 twin, family, and adoption studies, the role of MC4R in obesity, the prevalence of pathogenic MC4R mutations, and prior evidence that GLP-1 receptor agonists may be effective in MC4R deficiency. It also acknowledges limitations of prior treatments (e.g., dietary interventions less effective, MC4R agonist trials not demonstrating efficacy). The rationale for studying tirzepatide is clearly stated, and the hypothesis follows logically from the cited evidence.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise by citing prior work on MC4R deficiency, its prevalence, and the challenges in treating it, and logically links this to the hypothesis that tirzepatide may be effective in this subgroup.

Evidence

paraphrase[Introduction, paragraph 2]

“Two studies have shown that intense dietary and physical activity interventions are less effective in children with MC4R deficiency, and weight reduction is harder to maintain in this group.”

paraphrase[Introduction, paragraph 3]

“Here, to investigate the efficacy of tirzepatide in people with MC4R deficiency, we examined genetic data obtained from participants in a randomized controlled trial (SURMOUNT-1) of people with a BMI ≥30 kg m−2, or ≥27 kg m−2 with at least one weight-related comorbidity, treated with tirzepatide versus placebo.”

paraphrase[Introduction, paragraph 2]

“While melanocortin receptor agonists can act as pharmacological chaperones to rescue signaling by some MC4R-mutant receptors in cells, clinical trials of a MC4R agonist have not demonstrated efficacy in this patient group.”

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise, citing prior work on MC4R deficiency and GLP-1 receptor agonists, and provides a logical rationale for the study.

Evidence

“GLP-1 receptor agonists predominantly target non-MC4R-dependent neural pathways in mice , and there is evidence from a small clinical study with liraglutide that they may be effective in people with MC4R deficiency.”

Introduction ¶2Find in source

“This magnitude of weight reduction suggests that tirzepatide may be particularly beneficial in people with severe obesity (defined as a body mass index (BMI) >40 kg m −2 ), who have the highest burden of complications and highest mortality from cardiovascular disease.”

Introduction ¶1Find in source

“As such, there is currently no licensed treatment for people with obesity due to MC4R deficiency.”

Introduction ¶2Find in source

The parent trial (SURMOUNT-1) is a randomized controlled trial, and this analysis uses its data. The paper describes the genotyping process, quality control, and the statistical models used (mixed-model repeated measures, REGENIE). Inclusion/exclusion criteria are stated (e.g., exclusion of gain-of-function MC4R variants). The analysis population is defined (participants with a visit at week 24 or later). Blinding is not explicitly discussed, but this is a secondary analysis of a double-blind trial, and the genetic analysis is objective. Power analysis is not reported, but this is a post-hoc subgroup analysis, and the sample size is fixed by the parent trial.

Sub-criteria

controlsADEQUATE

power analysisNOT REPORTED

blinding levelsINADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The study design is a secondary analysis of a randomized controlled trial, with clear inclusion/exclusion criteria, a pre-specified analysis population, and appropriate statistical methods for the genetic analysis.

Evidence

“The study was conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice guidelines and all applicable regulatory requirements”

MethodsFind in source

paraphrase[Methods, Genotyping]

“People carrying either of the two prevalent gain-of-function MC4R variants (V103I and I251L; n = 88), associated with lower BMI in cohort studies, were excluded from all analyses.”

paraphrase[Methods, Statistical methods]

“To ensure enough visits for imputation, we used only participants with a visit at week 24 or later (n = 2,291).”

PASSReviewer 2· 85% conf

The study design is a secondary analysis of a randomized controlled trial, with adequate reporting of randomization, blinding, and statistical methods, though some elements are not fully detailed.

Evidence

“DNA samples of sufficient quality were obtained on 2,291 people (90%) randomized in the SURMOUNT-1 trial.”

MethodsFind in source

absence[Methods, Ethical approval and study populations]

Blinding is not explicitly stated.

absence[Methods, Statistical methods]

Power analysis is not reported for the subgroup analysis.

Table 1 reports age, sex, BMI, waist circumference, and various metabolic parameters for both groups. The paper notes that all MC4R mutation carriers in the placebo group were female, and discusses the sex distribution. Since both sexes are included, a justification for single-sex is not applicable. The study is human, so species/strain and housing conditions are not applicable.

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· 90% conf

The paper reports key biological variables including sex, age, BMI, and other clinical characteristics, and provides a baseline table comparing carriers and noncarriers.

Evidence

“Female sex, no. (%) | 20 (62%) | 154 (68%)”

Table 1Find in source

“Age, years | 41.06 (13.12) | 45.23 (12.36) | 0.043”

Table 1Find in source

“Duration of obesity, years | 16.38 (9.17) | 14.40 (10.88) | 0.11”

Table 1Find in source

PASSReviewer 2· 90% conf

Biological variables are well reported for a human study, including sex, age, BMI, and other clinical characteristics.

Evidence

“Female sex, no. (%) | 20 (62%) | 154 (68%)”

Table 1Find in source

“BMI, kg m −2 | 40.04 (6.21) | 38.04 (6.88) | 0.036”

Table 1Find in source

absence[Table 1]

Race/ethnicity and comorbidities are not reported.

The paper states that the study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice, and that study protocol and informed consent documents were approved by independent ethics committees and institutional review boards. Informed consent is mentioned as obtained by trial site investigators. Regulatory compliance is stated. The ethics statement is adequate, though the specific IRB names are not given, but the statement is explicit.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper reports ethical approval from independent ethics committees and institutional review boards, and describes informed consent procedures.

Evidence

“Study protocol and informed consent documents were approved by independent ethics committees and institutional review boards at all participating trial sites.”

EthicsFind in source

“Trial site investigators obtained consent, recruited participants, collected data and adhered to ethical standards.”

EthicsFind in source

“The study was conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice guidelines and all applicable regulatory requirements”

EthicsFind in source

PASSReviewer 2· 95% conf

Ethical approvals are adequately reported, with a statement of approval by ethics committees and institutional review boards, and informed consent is mentioned.

Evidence

“Study protocol and informed consent documents were approved by independent ethics committees and institutional review boards at all participating trial sites.”

EthicsFind in source

“Trial site investigators obtained consent, recruited participants, collected data and adhered to ethical standards.”

EthicsFind in source

“The study was conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice guidelines and all applicable regulatory requirements”

EthicsFind in source

The genotyping array (Axiom Biobank genotyping array version 3 from Affymetrix) is identified. Statistical software (SAS, REGENIE) is named. The investigational product (tirzepatide) is named, and the doses are mentioned (5, 10, 15 mg). The MC4R mutations are listed in Extended Data Table 1. Since this is a human trial with a drug, the bench criteria (antibodies, cell lines, mycoplasma) are not applicable.

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· 85% conf

The paper identifies the genotyping array and statistical software used, and provides details on the investigational product (tirzepatide) and genetic variants.

Evidence

“Samples were genotyped using the customized Axiom Biobank genotyping array (version 3) from Affymetrix.”

MethodsFind in source

“A mixed model was run using SAS, including baseline weight, country, sex, prediabetes status, treatment, visit and the treatment-by-visit interaction as fixed effects”

Statistical analysisFind in source

“the dual GIP and GLP-1 receptor agonist tirzepatide”

AbstractFind in source

PASSReviewer 2· 85% conf

Key resources are adequately identified, including the genotyping array and statistical software, though some details are incomplete.

Evidence

“Samples were genotyped using the customized Axiom Biobank genotyping array (version 3) from Affymetrix.”

MethodsFind in source

“A mixed model was run using SAS”

Statistical analysisFind in source

“the dual GLP-1 and GIP receptor agonist tirzepatide”

AbstractFind in source

The paper uses mixed-model repeated measures and REGENIE for genetic analysis. Tests are named (Wilcoxon rank-sum, chi-squared, Fisher's exact). Effect sizes are reported as least-squares mean estimands with 95% confidence intervals. The p-values for the primary outcome are reported (e.g., P = 0.79 for the interaction). The paper does not report exact p-values for all comparisons, but the primary analysis is based on estimation with CIs. The statistical software (SAS, REGENIE) is identified. Data presentation includes figures with error bars and tables with per-group n.

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedINADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 80% conf

The statistical methods are appropriate and well-described, with named tests, effect sizes with confidence intervals, and software identified. The analysis is primarily based on estimation with confidence intervals, which is adequate.

Evidence

“b Wilcoxon rank-sum test; Pearson’s chi-squared test; Fisher’s exact test, two-sided.”

Table 1Find in source

“Least-squares mean estimands of the percentage change in body weight from baseline to week 72, with error bars representing 95% confidence intervals (CI).”

Figure 1Find in source

“A mixed model was run using SAS, including baseline weight, country, sex, prediabetes status, treatment, visit and the treatment-by-visit interaction as fixed effects”

Statistical analysisFind in source

PASSReviewer 2· 80% conf

Statistical analysis is generally well reported, with named tests and effect sizes with confidence intervals, though some p-values are not exact and assumptions are not explicitly verified.

Evidence

“Wilcoxon rank-sum test; Pearson’s chi-squared test; Fisher’s exact test, two-sided.”

Table 1Find in source

“Least-squares mean estimands of the percentage change in body weight from baseline to week 72, with error bars representing 95% confidence intervals (CI).”

Figure 1BFind in source

paraphrase[Abstract]

“P = 0.036”

The data availability statement names Vivli as the platform for data access requests and provides a timeframe (around 60 days). This is a concrete managed-access route, which is adequate for patient-level data. The paper does not deposit raw data in a public repository, but this is not applicable for identifiable patient data. Code sharing is not mentioned, but the analysis uses standard software (SAS, REGENIE) and no bespoke code is described.

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

The paper provides a data availability statement with a concrete access route via Vivli, and states that patient-related information is anonymized and subject to confidentiality restrictions.

Evidence

“Request for data access can be submitted via Vivli, and expected time for response is around 60 days.”

Data availabilityFind in source

“Patient-related information was anonymized and collected as part of the SURMOUNT-1 clinical trial and will be subject to confidentiality restrictions.”

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data availability is adequately reported with a concrete access route via Vivli, and code sharing is not applicable as no custom code is described.

Evidence

“Request for data access can be submitted via Vivli, and expected time for response is around 60 days.”

Data availabilityFind in source

The methods are detailed enough for replication. The paper discusses limitations (e.g., small number of carriers, chance occurrence of all-female placebo carriers). Conclusions are proportional to the evidence. Funding and competing interests are declared. The paper mentions a reporting summary, which is a form of reporting guideline adherence.

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· 85% conf

The paper is transparent about methods, limitations, and funding, and reports all outcomes. It does not explicitly reference a reporting guideline, but the Nature Portfolio reporting summary is mentioned.

Evidence

“ClinicalTrials.gov number NCT04184622”

MethodsFind in source

paraphrase[Main text, paragraph 4]

“All the MC4R mutation carriers in the placebo-treated group were female (Extended Data Table). This probably represents a chance occurrence given the rarity of MC4R deficiency and the fact that the SURMOUNT-1 cohort recruited twice as many females as males (males 825, females 1,714, total 2,539).”

“I.S.F. is supported by Wellcome (207462/Z/17/Z), Botnar Fondation, the Bernard Wolfe Health Neuroscience Endowment and a NIHR Senior Investigator Award.”

AcknowledgementsFind in source

PASSReviewer 2· 85% conf

Reporting is transparent, with methods detailed, limitations discussed, and funding/COI statements provided, though trial registration is not explicitly mentioned in the text.

Evidence

“ClinicalTrials.gov number NCT04184622”

MethodsFind in source

“This probably represents a chance occurrence given the rarity of MC4R deficiency and the fact that the SURMOUNT-1 cohort recruited twice as many females as males”

Main text, paragraph 4Find in source

“I.S.F. is supported by Wellcome (207462/Z/17/Z), Botnar Fondation, the Bernard Wolfe Health Neuroscience Endowment and a NIHR Senior Investigator Award.”

AcknowledgementsFind in source

Registered (3 IDs: ClinicalTrials.gov). No reporting guideline cited.

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 25 references by DOI: 25 verified.

4 data/code links checked; 4 live.

Copyediting

5 minor

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

No major wording or formatting errors. 5 minor suggestions below.

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

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and well-reported. An informed reader should weigh the minor reporting gaps (e.g., lack of explicit randomization/blinding details, power analysis, exact p-values) but these do not warrant a correction. The paper is suitable for citation and clinical interpretation, with the caveat that the subgroup analysis is exploratory.

1.
HIGHreporting
In the Methods, explicitly state the randomization method (e.g., computer-generated random sequence) and allocation concealment used in the parent SURMOUNT-1 trial.
Reviewer 2 flagged randomization_method as reported_but_inadequate; explicit details would fully satisfy the criterion.
2.
HIGHreporting
Add a statement on blinding (e.g., double-blind) in the Methods to clarify blinding_levels.
Both reviewers noted blinding is not explicitly stated, which is a reporting gap for a secondary analysis of a double-blind trial.
3.
HIGHstatistics
Report a power analysis or justification for the subgroup analysis sample size, acknowledging the limited number of MC4R mutation carriers.
Power analysis is not reported, and this is a common reviewer concern for subgroup analyses.
4.
MEDIUMstatistics
Provide exact p-values for all comparisons, especially in Table 1, or state that the analysis is based on estimation with confidence intervals.
Some p-values are reported as thresholds, which is imprecise reporting.
5.
MEDIUMstatistics
Explicitly state that assumptions for statistical tests were checked (e.g., normality, homogeneity of variance) in the Methods.
Assumptions_verified is reported_but_inadequate; stating verification would strengthen the statistical reporting.
6.
MEDIUMreporting
Include a statement on adherence to reporting guidelines (e.g., CONSORT) in the Methods or Reporting Summary.
Reporting_guideline is reported_but_inadequate; explicit reference would improve transparency.
7.
MEDIUMreporting
Provide more detailed demographic information (e.g., race/ethnicity, comorbidities) in Table 1.
Reviewer 2 noted demographics are reported_but_inadequate; adding these would improve completeness.
8.
MEDIUMother
Clarify the source and formulation of tirzepatide (e.g., manufacturer, dose) in the Methods.
Reagents_identified is reported_but_inadequate; specifying the manufacturer and dose would fully identify the investigational product.
9.
LOWcopyedit
Fix the punctuation issue in the Abstract: remove the space before the comma in 'kg m −2 ),'.
Copyedit flagged a minor punctuation issue.
10.
LOWcopyedit
Ensure consistent capitalization of section headings in the Methods (e.g., 'Mixed-model repeated-measures weight loss imputation').
Copyedit flagged inconsistent capitalization.
11.
LOWcopyedit
Clarify in the Figure 1 legend that the estimands are for the percentage change in body weight.
Copyedit noted the legend could be more explicit about the outcome variable.
12.
LOWcopyedit
Ensure consistent capitalization of 'MC4R' throughout the manuscript.
Copyedit flagged minor inconsistency in capitalization.
13.
LOWcopyedit
Ensure consistent terminology for the imputation method in the Methods (e.g., 'imputation' vs. 'mixed model prediction').
Copyedit noted inconsistent terminology.

Full text (21,271 chars)Analyzed: Aug 15, 2026

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Tirzepatide leads to weight reduction in people with obesity due to MC4R deficiency.

Bhatnagar P, Ahmad NN, Li X, Coghlan M, Kaplan LM, Farooqi IS

Read full text (PMC)

DOI

10.1038/s41591-025-03913-2

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Record fingerprint

0d08d473ff47e238d2667c8c06eaed2d729f8b8ad93499c795090dfaefce4684

Verify via API

Issued Aug 15, 2026Engine 7.39.0

Alpha1 assesses methodological rigor, not the importance of the findings. See how we calibrate →

Kaimen Rigor review

Kaimen Rigor reviewed

3.5 / 5

Adequate — real issues to address

Observational Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−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 weight reduction, which is a surrogate endpoint for clinical outcomes in obesity. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD) nor cite validated evidence linking weight reduction to hard clinical outcomes in this context.
“the weight loss trajectory over 72 weeks was comparable in both groups: 18.3% weight reduction in MC4R mutation carriers versus 19.9% in noncarriers.”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 102OverreachOverstated conclusions 103AuthenticityData authenticity concerns 04DisclosureNone found 05AvailabilityNone found 06Copyedit5 minor suggestions

Numerical inconsistencies

1 finding · worst low

Internal contradictions in the reported numbersAssessed

Recomputed 2 tests: 2 consistent, 0 inconsistent; 2 via agent-written checks.

Overstated conclusions

1 finding · worst high

Efficacy rests on an unvalidated surrogate endpointAssessed

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

Premise concern: surrogate not validated for clinical benefit.

Data authenticity concerns

1 finding · worst low

Other integrity concernAssessed

2 integrity concerns flagged (0 high).

Reporting gaps

None found

Checked — nothing surfaced.

Eight Dimensions8 pass

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Evidence

paraphrase[Introduction, paragraph 2]

“Two studies have shown that intense dietary and physical activity interventions are less effective in children with MC4R deficiency, and weight reduction is harder to maintain in this group.”

paraphrase[Introduction, paragraph 3]

paraphrase[Introduction, paragraph 2]

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise, citing prior work on MC4R deficiency and GLP-1 receptor agonists, and provides a logical rationale for the study.

Evidence

Introduction ¶2Find in source

Introduction ¶1Find in source

“As such, there is currently no licensed treatment for people with obesity due to MC4R deficiency.”

Introduction ¶2Find in source

Sub-criteria

controlsADEQUATE

power analysisNOT REPORTED

blinding levelsINADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

Evidence

“The study was conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice guidelines and all applicable regulatory requirements”

MethodsFind in source

paraphrase[Methods, Genotyping]

“People carrying either of the two prevalent gain-of-function MC4R variants (V103I and I251L; n = 88), associated with lower BMI in cohort studies, were excluded from all analyses.”

paraphrase[Methods, Statistical methods]

“To ensure enough visits for imputation, we used only participants with a visit at week 24 or later (n = 2,291).”

PASSReviewer 2· 85% conf

The study design is a secondary analysis of a randomized controlled trial, with adequate reporting of randomization, blinding, and statistical methods, though some elements are not fully detailed.

Evidence

“DNA samples of sufficient quality were obtained on 2,291 people (90%) randomized in the SURMOUNT-1 trial.”

MethodsFind in source

absence[Methods, Ethical approval and study populations]

Blinding is not explicitly stated.

absence[Methods, Statistical methods]

Power analysis is not reported for the subgroup analysis.

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· 90% conf

The paper reports key biological variables including sex, age, BMI, and other clinical characteristics, and provides a baseline table comparing carriers and noncarriers.

Evidence

“Female sex, no. (%) | 20 (62%) | 154 (68%)”

Table 1Find in source

“Age, years | 41.06 (13.12) | 45.23 (12.36) | 0.043”

Table 1Find in source

“Duration of obesity, years | 16.38 (9.17) | 14.40 (10.88) | 0.11”

Table 1Find in source

PASSReviewer 2· 90% conf

Biological variables are well reported for a human study, including sex, age, BMI, and other clinical characteristics.

Evidence

“Female sex, no. (%) | 20 (62%) | 154 (68%)”

Table 1Find in source

“BMI, kg m −2 | 40.04 (6.21) | 38.04 (6.88) | 0.036”

Table 1Find in source

absence[Table 1]

Race/ethnicity and comorbidities are not reported.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper reports ethical approval from independent ethics committees and institutional review boards, and describes informed consent procedures.

Evidence

“Study protocol and informed consent documents were approved by independent ethics committees and institutional review boards at all participating trial sites.”

EthicsFind in source

“Trial site investigators obtained consent, recruited participants, collected data and adhered to ethical standards.”

EthicsFind in source

“The study was conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice guidelines and all applicable regulatory requirements”

EthicsFind in source

PASSReviewer 2· 95% conf

Ethical approvals are adequately reported, with a statement of approval by ethics committees and institutional review boards, and informed consent is mentioned.

Evidence

“Study protocol and informed consent documents were approved by independent ethics committees and institutional review boards at all participating trial sites.”

EthicsFind in source

“Trial site investigators obtained consent, recruited participants, collected data and adhered to ethical standards.”

EthicsFind in source

“The study was conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice guidelines and all applicable regulatory requirements”

EthicsFind in source

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· 85% conf

The paper identifies the genotyping array and statistical software used, and provides details on the investigational product (tirzepatide) and genetic variants.

Evidence

“Samples were genotyped using the customized Axiom Biobank genotyping array (version 3) from Affymetrix.”

MethodsFind in source

“A mixed model was run using SAS, including baseline weight, country, sex, prediabetes status, treatment, visit and the treatment-by-visit interaction as fixed effects”

Statistical analysisFind in source

“the dual GIP and GLP-1 receptor agonist tirzepatide”

AbstractFind in source

PASSReviewer 2· 85% conf

Key resources are adequately identified, including the genotyping array and statistical software, though some details are incomplete.

Evidence

“Samples were genotyped using the customized Axiom Biobank genotyping array (version 3) from Affymetrix.”

MethodsFind in source

“A mixed model was run using SAS”

Statistical analysisFind in source

“the dual GLP-1 and GIP receptor agonist tirzepatide”

AbstractFind in source

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedINADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 80% conf

Evidence

“b Wilcoxon rank-sum test; Pearson’s chi-squared test; Fisher’s exact test, two-sided.”

Table 1Find in source

“Least-squares mean estimands of the percentage change in body weight from baseline to week 72, with error bars representing 95% confidence intervals (CI).”

Figure 1Find in source

“A mixed model was run using SAS, including baseline weight, country, sex, prediabetes status, treatment, visit and the treatment-by-visit interaction as fixed effects”

Statistical analysisFind in source

PASSReviewer 2· 80% conf

Statistical analysis is generally well reported, with named tests and effect sizes with confidence intervals, though some p-values are not exact and assumptions are not explicitly verified.

Evidence

“Wilcoxon rank-sum test; Pearson’s chi-squared test; Fisher’s exact test, two-sided.”

Table 1Find in source

“Least-squares mean estimands of the percentage change in body weight from baseline to week 72, with error bars representing 95% confidence intervals (CI).”

Figure 1BFind in source

paraphrase[Abstract]

“P = 0.036”

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

The paper provides a data availability statement with a concrete access route via Vivli, and states that patient-related information is anonymized and subject to confidentiality restrictions.

Evidence

“Request for data access can be submitted via Vivli, and expected time for response is around 60 days.”

Data availabilityFind in source

“Patient-related information was anonymized and collected as part of the SURMOUNT-1 clinical trial and will be subject to confidentiality restrictions.”

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data availability is adequately reported with a concrete access route via Vivli, and code sharing is not applicable as no custom code is described.

Evidence

“Request for data access can be submitted via Vivli, and expected time for response is around 60 days.”

Data availabilityFind in source

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· 85% conf

Evidence

“ClinicalTrials.gov number NCT04184622”

MethodsFind in source

paraphrase[Main text, paragraph 4]

“I.S.F. is supported by Wellcome (207462/Z/17/Z), Botnar Fondation, the Bernard Wolfe Health Neuroscience Endowment and a NIHR Senior Investigator Award.”

AcknowledgementsFind in source

PASSReviewer 2· 85% conf

Reporting is transparent, with methods detailed, limitations discussed, and funding/COI statements provided, though trial registration is not explicitly mentioned in the text.

Evidence

“ClinicalTrials.gov number NCT04184622”

MethodsFind in source

“This probably represents a chance occurrence given the rarity of MC4R deficiency and the fact that the SURMOUNT-1 cohort recruited twice as many females as males”

Main text, paragraph 4Find in source

“I.S.F. is supported by Wellcome (207462/Z/17/Z), Botnar Fondation, the Bernard Wolfe Health Neuroscience Endowment and a NIHR Senior Investigator Award.”

AcknowledgementsFind in source

Registered (3 IDs: ClinicalTrials.gov). No reporting guideline cited.

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 25 references by DOI: 25 verified.

4 data/code links checked; 4 live.

Copyediting

5 minor

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

No major wording or formatting errors. 5 minor suggestions below.

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

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHreporting
In the Methods, explicitly state the randomization method (e.g., computer-generated random sequence) and allocation concealment used in the parent SURMOUNT-1 trial.
Reviewer 2 flagged randomization_method as reported_but_inadequate; explicit details would fully satisfy the criterion.
2.
HIGHreporting
Add a statement on blinding (e.g., double-blind) in the Methods to clarify blinding_levels.
Both reviewers noted blinding is not explicitly stated, which is a reporting gap for a secondary analysis of a double-blind trial.
3.
HIGHstatistics
Report a power analysis or justification for the subgroup analysis sample size, acknowledging the limited number of MC4R mutation carriers.
Power analysis is not reported, and this is a common reviewer concern for subgroup analyses.
4.
MEDIUMstatistics
Provide exact p-values for all comparisons, especially in Table 1, or state that the analysis is based on estimation with confidence intervals.
Some p-values are reported as thresholds, which is imprecise reporting.
5.
MEDIUMstatistics
Explicitly state that assumptions for statistical tests were checked (e.g., normality, homogeneity of variance) in the Methods.
Assumptions_verified is reported_but_inadequate; stating verification would strengthen the statistical reporting.
6.
MEDIUMreporting
Include a statement on adherence to reporting guidelines (e.g., CONSORT) in the Methods or Reporting Summary.
Reporting_guideline is reported_but_inadequate; explicit reference would improve transparency.
7.
MEDIUMreporting
Provide more detailed demographic information (e.g., race/ethnicity, comorbidities) in Table 1.
Reviewer 2 noted demographics are reported_but_inadequate; adding these would improve completeness.
8.
MEDIUMother
Clarify the source and formulation of tirzepatide (e.g., manufacturer, dose) in the Methods.
Reagents_identified is reported_but_inadequate; specifying the manufacturer and dose would fully identify the investigational product.
9.
LOWcopyedit
Fix the punctuation issue in the Abstract: remove the space before the comma in 'kg m −2 ),'.
Copyedit flagged a minor punctuation issue.
10.
LOWcopyedit
Ensure consistent capitalization of section headings in the Methods (e.g., 'Mixed-model repeated-measures weight loss imputation').
Copyedit flagged inconsistent capitalization.
11.
LOWcopyedit
Clarify in the Figure 1 legend that the estimands are for the percentage change in body weight.
Copyedit noted the legend could be more explicit about the outcome variable.
12.
LOWcopyedit
Ensure consistent capitalization of 'MC4R' throughout the manuscript.
Copyedit flagged minor inconsistency in capitalization.
13.
LOWcopyedit
Ensure consistent terminology for the imputation method in the Methods (e.g., 'imputation' vs. 'mixed model prediction').
Copyedit noted inconsistent terminology.

Full text (21,271 chars)Analyzed: Aug 15, 2026