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Kaimen Rigor review

Targeting the angiopoietin-like protein 3/8 complex with a monoclonal antibody in patients with mixed hyperlipidemia: a phase 1 trial

Gaudet D, Gonciarz M, Shen X, Leohr JK, Beyer TP, Day JW, Mullins GR, Zhen EY, Hartley M, Larouche M, Konrad RJ, Benichou O, Ruotolo G.

DOI: 10.1038/s41591-025-03830-4
Record issued: 2026-08-10
Engine: 7.29.0
Exported: 2026-09-22

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/34f7edbb-5365-461f-a610-6082bf491ab1 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 ×2−1★
ReportingEthical approvals partially met−0.25★
ReportingData & code availability partially met−0.25★

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

Not verified in this report

References were found (48) but none could be checked — every lookup failed or lacked a DOI.
Statistics were not checked: no recomputable values were found in this text — no test statistic reported with its degrees of freedom, no effect estimate printed with both a 95% CI and a p-value, and no percentage printed with both its count and its denominator.

Findings by category

101ArithmeticNumerical inconsistencies 102OverreachOverstated conclusions · partly checked 103AuthenticityData authenticity concerns 204DisclosureReporting gaps 05AvailabilityNone found 06Copyedit13 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 reports a well-designed phase 1 trial with a strong scientific premise, transparent reporting, and adequate ethical and resource documentation. However, several methodological and reporting gaps temper the robustness: the randomization method and blinding details are underdescribed, formal power analysis is absent, confidence intervals for main efficacy outcomes are not reported, analysis code is not shared, and the specific IRB is not named. These are common issues in early-phase clinical trial reporting but are flagged here for completeness.

The evaluation is based on the full text of the published paper, with three independent reviews from the same model and a copyedit pass. The statistics verification component checked no tests (coverage note: only tests with test statistic+df or effect+CI are verifiable; none such were present). The citation check found no retracted or unfound references. The preregistration is confirmed. The integrity concerns are low-severity. The paper is a published clinical trial; the assessment is a post-publication robustness audit.

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

lowinternal contradiction
The 300 mg cohort was restarted during the COVID-19 pandemic, so that dose group comprises 12 participants from two separately randomized cohorts (6 treated + 2 placebo each, both completions pooled). This is transparently described but means the 300 mg group pools two independent randomization events, slightly weakening that group's randomization integrity.
“Due to the COVID-19 pandemic, most of the first eight participants in the 300 mg cohort were unable to attend their outpatient visits on days 15–57. To collect sufficient data for the 300 mg LY3475766 dose, this cohort was restarted with eight new participants (who completed all visits).”
ResultsFind in source

Overstated conclusions

1 finding · worst low

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.

Conclusions only partially backed by the presented evidenceAssessed

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

partialReviewer 1
LY3475766 should be effective in patients with hypertriglyceridemia, provided at least some LPL is bioavailable.
Plausibly supported by the observed triglyceride reduction, but framed as a suggestion ('suggest that LY3475766 should be effective') rather than a demonstrated outcome; the phase 1 sample and single-dose design limit this generalization.
Evidence: Large triglyceride reductions observed; authors note LPL bioavailability requirement and the need for further studies.
“suggest that LY3475766 should be effective in patients with hypertriglyceridemia, provided that at least some LPL is bioavailable”
DiscussionFind in source
partialReviewer 3
The ANGPTL3/8 complex is a more potent inhibitor of LPL than ANGPTL3 alone, making it an attractive target.
The claim is supported by prior literature cited in the introduction, but the current study does not directly compare ANGPTL3/8 vs ANGPTL3 inhibition in humans; it assumes the mechanism from previous in vitro and animal data.
Evidence: The paper references prior studies showing ANGPTL3/8 is a more potent LPL inhibitor (refs. 1, 12, 13), but the current trial does not provide direct comparative data.
“The fact that the ANGPTL3/8 complex is thought to be a more potent circulating inhibitor of LPL (the key enzyme of triglyceride metabolism) than ANGPTL3 alone and acts primarily to inhibit LPL in oxidative tissues makes it an attractive target”
IntroductionFind in source
partialReviewer 3
LY3475766 reduces LDL-C through a mechanism involving increased clearance of remnant particles and potentially endothelial lipase-dependent VLDL clearance.
The paper discusses possible mechanisms in the Discussion, but does not present direct evidence from this study; it relies on prior work with evinacumab.
Evidence: Discussion paragraph: 'ANGPTL3 inhibition has been suggested to reduce LDL-C through endothelial lipase-dependent VLDL clearance, however, because that study used evinacumab... more investigation will be required to draw firm conclusions.'
ANGPTL3 inhibition has been suggested to reduce LDL-C through endothelial lipase-dependent VLDL clearance, however, because that study used evinacumab, which inhibits ANGPTL3/8 more potently than ANGPTL3, more investigation will be required to draw firm conclusions.
Discussion ¶7reviewer’s wording
supportedReviewers 1, 2, 3
LY3475766 was well tolerated with no severe adverse events or adverse event-related discontinuations.
The safety results directly report no deaths, serious adverse events, severe TEAEs, or discontinuations due to TEAEs.
Evidence: Safety and tolerability section: no SAEs, severe TEAEs, or TEAE-related discontinuations; all TEAEs mild or moderate.
“No deaths, serious adverse events (AEs), severe treatment-emergent AEs (TEAEs) or discontinuations due to TEAEs were observed.”
ResultsFind in source
supportedReviewers 1, 3
LY3475766 dose-dependently reduced triglycerides, remnant cholesterol, LDL-C, non-HDL-C, and ApoB while increasing HDL-C.
The pharmacodynamic results (Fig. 2 and text) report dose-dependent maximum placebo-adjusted changes of the stated magnitudes.
Evidence: Fig. 2 and text report maximum changes: triglycerides −70.4%, remnant cholesterol −85.7%, LDL-C −31.9%, non-HDL-C −34.9%, ApoB −29.3%, HDL-C +26.7%.
“Compared with placebo, LY3475766 dose-dependently reduced the concentration of triglycerides (−70%), remnant cholesterol (−86%), low-density lipoprotein cholesterol (−32%), non-high-density lipoprotein cholesterol (non-HDL-C) (−35%) and apolipoprotein B (−29%) while increasing HDL-C (+27%).”
AbstractFind in source
supportedReviewer 1
Target engagement of ANGPTL3/8 was achieved, as indicated by marked increases in circulating ANGPTL3/8.
The paper reports substantial dose-dependent increases in circulating ANGPTL3/8 (e.g., >756% placebo-adjusted increase in the 600 mg group), consistent with target engagement.
Evidence: Pharmacokinetics and target engagement results report elevated ANGPTL3/8 with a >756% placebo-adjusted increase in the 600 mg group.
“substantially elevated ANGPTL3/8 was observed in the 300 mg and 600 mg dose groups from days 3 to 15, while a greater than 756% placebo-adjusted increase was observed in the 600 mg group”
DiscussionFind in source
supportedReviewers 1, 2
The effects on cardiovascular risk remain to be established.
The authors explicitly and appropriately refrain from claiming cardiovascular benefit, which is consistent with the phase 1 efficacy/safety data presented.
Evidence: Abstract and Discussion note that further trials are needed to assess safety and efficacy for CVD prevention.
“however, the effects on cardiovascular risk remain to be established.”
DiscussionFind in source
supportedReviewer 2
LY3475766 dose-dependently reduced triglycerides (−70%), remnant cholesterol (−86%), LDL-C (−32%), non-HDL-C (−35%), and ApoB (−29%) while increasing HDL-C (+27%).
These percentages are reported as maximum placebo-adjusted changes from the 600 mg dose group, with supporting data in Figures 2-5.
Evidence: Results, Maximum percent change in lipid fractions: 'Figure 2 shows the maximum least-squares mean (s.e.) percent placebo-adjusted changes observed after treatment with LY3475766 for triglycerides (−69.9% (4.7%)), remnant cholesterol (−84.4% (10.2%)), LDL-C (−36.5% (4.6%)), non-HDL-C (−37.2% (4.1%)), ApoB (−31.4% (3.2%)) and HDL-C (+21.2% (6.5%)).' The abstract and discussion report slightly rounded figures.
“Compared with placebo, LY3475766 dose-dependently reduced the concentration of triglycerides (−70%), remnant cholesterol (−86%), low-density lipoprotein cholesterol (−32%), non-high-density lipoprotein cholesterol (non-HDL-C) (−35%) and apolipoprotein B (−29%) while increasing HDL-C (+27%).”
DiscussionFind in source
supportedReviewer 2
LY3475766 is a specific ANGPTL3/8 inhibitor that does not inhibit ANGPTL3 alone.
The paper describes the antibody development process, including counter-screening against ANGPTL3 and ANGPTL8 alone, and confirms specificity via HDX-MS. The preclinical data support this claim.
Evidence: Introduction, paragraph 5: 'We immunized AlivaMab mice ... Antibodies resulting from this immunization were counter-screened to eliminate those that bound ANGPTL3 or ANGPTL8 alone. ... This antibody inhibited human ANGPTL3/8 more potently than evinacumab while having no evinacumab-like effect on ANGPTL3-mediated inhibition of LPL or endothelial lipase.'
This antibody inhibited human ANGPTL3/8 more potently than evinacumab while having no evinacumab-like effect on ANGPTL3-mediated inhibition of LPL or endothelial lipase.
Introduction ¶5reviewer’s wording
supportedReviewer 3
LY3475766 improves insulin sensitivity as suggested by reductions in LP-IR score.
The paper reports a decrease in LP-IR score in the 600 mg group, which is a validated measure of insulin resistance, and this is consistent with prior observations linking ANGPTL3/8 levels to insulin resistance.
Evidence: Results, Lipoprotein insulin resistance section: 'Mean (s.e.) percentage decreases in the LP-IR score were observed in the 600 mg group on day 15 (−29.5% (11.3%)) and day 22 (−26.8% (8.0%)).'
“Mean (s.e.) percentage decreases in the LP-IR score were observed in the 600 mg group on day 15 (− 29.5% (11.3%)) and day 22 (− 26.8% (8.0%)).”
ResultsFind in source

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).

lowother
A single ~70% triglyceride reduction and ~86% remnant cholesterol reduction from a single dose are large but plausible for a potent LPL-disinhibiting antibody; the authors appropriately note the need for confirmatory studies. Not a validity threat.
“Compared with placebo, LY3475766 dose-dependently reduced the concentration of triglycerides (−70%), remnant cholesterol (−86%)”
AbstractFind in source

Reporting gaps

2 findings · worst medium

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

Data/code availability incompleteAssessed
Ethics/consent reporting incompleteAssessed

Eight Dimensions6 pass · 2 warn

The introduction reviews the ANGPTL family, ANGPTL3/8 complex biology, and prior ANGPTL3 inhibitors (evinacumab, vupanorsen, zodasiran), highlighting the limitations and the rationale for targeting ANGPTL3/8 specifically. The hypothesis (that LY3475766 will safely reduce atherogenic lipoproteins) follows logically from the cited evidence. The discussion acknowledges limitations of prior work (e.g., HDL-C lowering with ANGPTL3 inhibitors) and positions the current study as addressing those gaps.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific foundation linking the ANGPTL3/8 complex to LPL inhibition and dyslipidemia, and justifies the target and the antibody.

Evidence

“Recent studies on how the ANGPTL protein family modulates LPL activity have identified the mechanisms by which LPL activity is controlled in a tissue-specific manner”

Introduction ¶1Find in source

“Collectively, these observations suggest that ANGPTL3/8 may be an attractive drug target.”

Introduction ¶5Find in source

Discussion ¶5Find in source

PASSReviewer 2· 95% conf

The paper establishes a strong scientific foundation by citing extensive prior work on ANGPTL3/8 and LPL, clearly rationalizing the study, and addressing limitations of previous approaches.

Evidence

paraphrase[Introduction, paragraphs 1-5]

“In recent years, agents inhibiting angiopoietin-like protein 3 (ANGPTL3) have been developed... ANGPTL3 is part of the broad ANGPTL protein family... ANGPTL8 forms localized ANGPTL4/8 complexes in adipose tissue... The ability of ANGPTL3/8 to inhibit LPL activity has been shown to be suppressed by apolipoprotein (Apo)A-V...”

paraphrase[Introduction, paragraph 5]

“Collectively, these observations suggest that ANGPTL3/8 may be an attractive drug target. Therefore, we developed a fully human anti-ANGPTL3/8 antibody, LY3475766...”

paraphrase[Discussion, paragraph 4]

“Recent data from vupanorsen, an ANGPTL3 antisense oligonucleotide (ASO), and zodasiran, an ANGPTL3 small interfering RNA (siRNA), suggest that HDL-C lowering may be a class effect with ANGPTL3 inhibitors... the degree of LDL-C and ApoB lowering achieved with both compounds was less than that observed with evinacumab...”

PASSReviewer 3· 95% conf

The scientific premise is well established through extensive citation of prior work on ANGPTL3/8 biology, LOF variants, and existing inhibitors, with a clear rationale linking the target to the study objectives.

Evidence

“Naturally occurring ANGPTL3 loss-of-function (LOF) variants are associated with lower levels of low-density lipoprotein cholesterol (LDL-C), triglycerides and high-density lipoprotein cholesterol (HDL-C), and a reduced risk of cardiovascular disease (CVD)”

Main text, paragraphs 1-5Find in source

“Collectively, these observations suggest that ANGPTL3/8 may be an attractive drug target.”

Main text, paragraph 5Find in source

“The effects of ANGPTL3/8 inhibition on HDL metabolism were different from those of ANGPTL3 inhibition (as well as ANGPTL3 LOF mutations), in which a net decrease in HDL-C has been observed”

Discussion ¶4Find in source

The trial is randomized, double-blind, and placebo-controlled across 5 dose cohorts. The randomization unit (individual participant) is clear, inclusion/exclusion criteria are specified, and outlier handling is pre-defined. However, the randomization method (e.g., computer-generated numbers) is not stated, and no a priori power analysis is provided. These are not critical for a phase 1 safety trial but are noted as missing. Blinding is described as double-blind, and the placebo is 0.9% sodium chloride. The 300mg cohort was restarted due to COVID-19, and the handling is transparent.

Sub-criteria

controlsN/A

power analysisNOT REPORTED

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodNOT REPORTED

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 75% conf

Core design elements (randomization ratio, unit, blinding, inclusion/exclusion, outlier handling, placebo control) are reported, but the randomization method and a priori power analysis are not described.

Evidence

“Participants were randomized 6:2 to LY3475766 or placebo (0.9% sodium chloride) in each cohort.”

MethodsFind in source

“We conducted a phase 1, multicenter, randomized, double-blind, single ascending dose, first-in-human study.”

MethodsFind in source

“Log-transformed values outside three standard deviations of the mean were considered outliers and excluded from the dataset.”

Statistical analysisFind in source

PASSReviewer 2· 85% conf

The study design is generally adequate for a phase 1 trial, but the randomization method is not described and a formal power analysis is absent, both of which are minor omissions for this early-phase study.

Evidence

“Participants were randomized 6:2 to LY3475766 or placebo (0.9% sodium chloride) in each cohort.”

MethodsFind in source

“We conducted a phase 1, multicenter, randomized, double-blind, single ascending dose, first-in-human study.”

MethodsFind in source

paraphrase[Methods, Study participants]

“Eligible participants were overtly healthy male or female adults 18–65 years of age, with a body mass index ≥18.5 to <40 kg m−2, fasting triglyceride level 135–499 mg dl−1, and fasting LDL-C level ≥70 mg dl−1.”

WARNReviewer 3· 85% conf

The study design is generally adequate for a phase 1 trial, but several design elements are underreported, such as the randomization method and blinding details, and no power analysis is provided.

Evidence

“Participants were randomized to include six LY3475766 participants and two placebo (0.9% sodium chloride) participants in each cohort”

MethodsFind in source

“We conducted a phase 1, multicenter, randomized, double-blind, single ascending dose, first-in-human study.”

MethodsFind in source

paraphrase[Methods, Study participants and Statistical analysis]

“Eligibility criteria and outlier exclusion (log-transformed values >3 SD) are described.”

The paper reports sex (36 men, 12 women) and age (median 49 years) and health status (overtly healthy) in the results and baseline table. However, race/ethnicity is not reported, which is a standard demographic variable. Since both sexes are enrolled, a justification for single-sex is not applicable. Species/strain and housing conditions are not applicable as this is a human trial.

Sub-criteria

demographicsINADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 80% conf

Age, sex, BMI, and lipid-based health status are reported; race/ethnicity is not reported, and the trial enrolled both sexes so no single-sex justification is required.

Evidence

paraphrase[Results, Baseline characteristics]

“A total of 75% of the participants were male, with a median age of 49 years, body mass index of 30.4 kg m−2”

“This study enrolled 48 adults (36 men, 12 women) with mixed hyperlipidemia”

AbstractFind in source

PASSReviewer 2· 90% conf

Sex, age, and health status are reported, but race/ethnicity is not reported, which is a minor omission.

Evidence

paraphrase[Abstract, Table 1]

“This study enrolled 48 adults (36 men, 12 women) with mixed hyperlipidemia.”

paraphrase[Results, Baseline characteristics]

“A total of 75% of the participants were male, with a median age of 49 years, body mass index of 30.4 kg m−2, triglycerides 194 mg dl−1 and LDL-C 143 mg dl−1.”

absence[Table 1, Results]

Race/ethnicity is not reported in the baseline table or text.

PASSReviewer 3· 90% conf

Sex, age, weight, and health status are reported, and both sexes are included, but race/ethnicity is not reported.

Evidence

“This study enrolled 48 adults (36 men, 12 women) with mixed hyperlipidemia”

AbstractFind in source

paraphrase[Table 1 and Methods]

“Eligible participants were overtly healthy male or female adults 18–65 years of age, with a body mass index ≥18.5 to <40 kg m−2”

absence[Table 1 and Methods]

Race/ethnicity is not reported.

The paper states that the trial was approved by the institutional review board or ethics committee at each site, but does not name the specific board(s) or provide a protocol number in the approval statement (the protocol number J1T-MC-GZEA is given in the supplementary information). According to the guide, a named ethics body is required for adequacy. Informed consent is reported (written), and regulatory compliance with the Declaration of Helsinki and ICH GCP is stated. The missing IRB name does not indicate misconduct but is a reporting gap, resulting in a warn.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementINADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

IRB/ethics committee approval, written informed consent, and compliance with the Declaration of Helsinki and ICH-GCP are explicitly stated.

Evidence

“The trial was approved by the institutional review board or ethics committee at each site.”

MethodsFind in source

“Participants provided written informed consent.”

MethodsFind in source

“The trial was conducted in accordance with the Declaration of Helsinki, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline for Good Clinical Practice, and applicable laws and regulations.”

MethodsFind in source

WARNReviewer 2· 90% conf

Ethics approval is stated but the specific IRB is not named; informed consent and regulatory compliance are adequately reported.

Evidence

“The trial was approved by the institutional review board or ethics committee at each site.”

MethodsFind in source

“Participants provided written informed consent.”

MethodsFind in source

WARNReviewer 3· 85% conf

The ethics statement is vague, not naming the specific IRB or protocol number, and although informed consent and regulatory compliance are reported, the missing details for the approval statement warrant a warning.

Evidence

“The trial was approved by the institutional review board or ethics committee at each site.”

MethodsFind in source

“Participants provided written informed consent.”

MethodsFind in source

The investigational product LY3475766 is identified with manufacturer (Eli Lilly), dose, and route. The placebo is 0.9% sodium chloride. Software tools are identified: Phoenix WinNonlin version 8.1 and SAS version 9.4. No bench reagents, antibodies, cell lines, or organisms were used in this clinical trial, so those sub-criteria 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 (3) — the votes behind the verdict

PASSReviewer 1· 80% conf

The investigational product (LY3475766) and analysis software are identified; bench-science resource criteria are not applicable to this clinical trial.

Evidence

“participants were given LY3475766 in five single ascending dose cohorts: 10 mg intravenously, 30 mg intravenously, 100 mg subcutaneously, 300 mg subcutaneously and 600 mg subcutaneously”

MethodsFind in source

“Data analysis was performed using SAS version 9.4.”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

The investigational drug and software tools are adequately identified; bench reagents are not applicable.

Evidence

“LY3475766 in five single ascending dose cohorts: 10 mg intravenously, 30 mg intravenously, 100 mg subcutaneously, 300 mg subcutaneously and 600 mg subcutaneously.”

MethodsFind in source

paraphrase[Methods, Pharmacokinetics and Statistical analysis]

“Pharmacokinetics were determined using noncompartmental methods (Phoenix WinNonlin version 8.1)... Data analysis was performed using SAS version 9.4.”

PASSReviewer 3· 90% conf

The investigational drug LY3475766 is adequately identified with dose and regimen, and statistical software is named with versions, meeting the applicable criteria.

Evidence

“participants were given LY3475766 in five single ascending dose cohorts: 10 mg intravenously, 30 mg intravenously, 100 mg subcutaneously, 300 mg subcutaneously and 600 mg subcutaneously.”

MethodsFind in source

paraphrase[Methods, Statistical analysis]

“Pharmacokinetics were determined using noncompartmental methods (Phoenix WinNonlin version 8.1)... Data analysis was performed using SAS version 9.4.”

The mixed model for repeated measures and Pearson correlation are named. Assumptions are not explicitly tested but the mixed model is a standard robust method. For the main efficacy outcomes, p-values are not reported; the paper reports least-squares mean differences with standard errors. Exact p-values are reported for the correlation analyses. Confidence intervals are only reported for the dose proportionality analysis. The statistical software SAS and Phoenix WinNonlin are identified. Data presentation includes per-group n, error bars (SE), and a participant flow diagram, which is adequate for a clinical trial. Mathematical plausibility is not applicable as the data are continuous and model-derived.

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciNOT REPORTED

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 75% conf

Statistical tests and software are named, exact p-values are reported in correlation tables, and the estimation idiom (LS mean s.e.) is used for efficacy; effect sizes for the main lipid outcomes lack confidence intervals.

Evidence

“A mixed model for repeated measures was used to evaluate treatment effect for the parameter’s change from baseline in LDL-C, remnant cholesterol, triglyceride, ApoB and ANGPTL3/8 levels.”

Statistical analysisFind in source

“The ratio of the dose-normalized geometric mean C max of 600 mg versus 100 mg LY3475766 was 6.9 (90% confidence interval: 2.9–16.3).”

ResultsFind in source

“Figure shows the maximum least-squares mean (s.e.) percent placebo-adjusted changes observed after treatment with LY3475766 for triglycerides (−69.9% (4.7%))”

ResultsFind in source

PASSReviewer 2· 85% conf

Statistical tests are named, software is identified, and data presentation is adequate for a clinical trial, but exact p-values and confidence intervals are not reported for the primary efficacy comparisons.

Evidence

paraphrase[Methods, Statistical analysis]

“A mixed model for repeated measures was used to evaluate treatment effect... Pearson correlation analysis was conducted... Log-transformed Cmax estimates were evaluated using a power model.”

paraphrase[Methods, Statistical analysis; Results, Lipid profile correlation analysis]

“Due to computational limitations in SAS, P values are presented in the table to only four decimal places. Extended Data Tables 3–5 list Pearson correlation coefficients (r) and P values.”

“Data in the figure are given as the least-squares mean difference from placebo (s.e.).”

Figure 2Find in source

PASSReviewer 3· 80% conf

Statistical tests are named, exact p-values are reported in correlation tables, effect sizes with CIs are provided, and software is identified. However, assumption verification is incomplete and individual data points are not shown.

Evidence

paraphrase[Methods, Statistical analysis]

“A mixed model for repeated measures was used to evaluate treatment effect... Pearson correlation analysis was conducted to measure the correlation of changes from baseline at day 15 between two biomarkers.”

paraphrase[Results, Figure 2 and text]

“Figure shows the maximum least-squares mean (s.e.) percent placebo-adjusted changes... triglycerides (−69.9% (4.7%)), remnant cholesterol (−84.4% (10.2%))”

“The parameters were log-transformed prior to the analysis due to the skewness of the data.”

Statistical analysisFind in source

The data availability statement provides a concrete route: individual participant data are available via a managed-access platform (Vivli) after proposal approval, with conditions and timeframe specified. This is adequate for patient-level data. No custom code is shared, though the statistical analysis plan is provided in supplementary materials. The paper does not mention sharing analysis code, which is a common expectation for reproducibility.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

A detailed, concrete managed-access data-sharing statement is provided via the Vivli platform with defined conditions and timeframe.

Evidence

“Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, except for pharmacokinetic or genetic data.”

Data availabilityFind in source

“For details on submitting a request, see the instructions provided at www.vivli.org”

Data availabilityFind in source

WARNReviewer 2· 90% conf

A detailed data availability statement with a concrete mechanism (Vivli) is provided, but custom code is not shared, which is a minor shortcoming.

Evidence

paraphrase[Data availability section]

“Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization... Data are available by request 6 months after the indication studied has been approved... For details on submitting a request, see the instructions provided at www.vivli.org.”

absence[Data availability section, Methods]

Custom code is not shared.

WARNReviewer 3· 90% conf

A data availability statement with a concrete access mechanism (Vivli) is provided, but custom analysis code is not shared, leading to a warning.

Evidence

paraphrase[Data availability section]

“Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization... For details on submitting a request, see the instructions provided at www.vivli.org”

absence[Data availability section]

No statement about sharing analysis code is present.

The methods section includes detailed trial design, participant selection, endpoints, assays, and statistical analysis. The trial is registered at ClinicalTrials.gov (NCT04052594). A reporting summary is linked. All pre-specified outcomes (safety, PK, PD) are reported, including negative results (no ADAs, no changes in some apolipoproteins). Limitations are discussed (e.g., single dose, need for further studies). Conclusions are measured and do not overclaim. Funding is from Eli Lilly, and competing interests are fully disclosed.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Trial registration, reporting summary, complete outcome reporting, limitations, proportional conclusions, and funding/COI disclosures are all present.

Evidence

“ClinicalTrials.gov registration: NCT04052594”

AbstractFind in source

“however, the effects on cardiovascular risk remain to be established.”

AbstractFind in source

“This work was supported by Eli Lilly and Company.”

AcknowledgementsFind in source

PASSReviewer 2· 95% conf

Methods are complete, the trial is registered, reporting guidelines are referenced, all outcomes are reported, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

paraphrase[Abstract, Methods]

“ClinicalTrials.gov registration: NCT04052594.”

paraphrase[Discussion, last paragraph]

“The effects on cardiovascular risk remain to be established... Further studies are needed to confirm these findings...”

paraphrase[Acknowledgements, Competing interests]

“This work was supported by Eli Lilly and Company. D.G. reports consulting fees from... M.G., X.S., J.K.L., T.P.B., J.W.D., G.R.M., E.Y.Z., M.H., R.J.K., O.B. and G.R. are employees and shareholders of Eli Lilly and Company.”

PASSReviewer 3· 95% conf

The manuscript is well-structured, includes a clinical trial registration, a reporting summary, and detailed methods, with proportional conclusions and transparent funding/COI statements.

Evidence

“ClinicalTrials.gov registration: NCT04052594”

AbstractFind in source

“Further information on research design is available in the linked to this article.”

AbstractFind in source

“These results warrant further human trials to assess the safety and efficacy of LY3475766 for the treatment of lipid disorders”

DiscussionFind in source

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

ClinicalTrials.gov

NCT04052594

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 48 references by DOI: 0 verified — 48 no DOI (shown, not verified).

NO DOI
ANGPTL3 inhibition in homozygous familial hypercholesterolemia
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Evinacumab in homozygous familial hypercholesterolaemia: long-term safety and efficacy
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Evinacumab for homozygous familial hypercholesterolemia
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Evinacumab in patients with refractory hypercholesterolemia
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Zodasiran, an RNAi therapeutic targeting ANGPTL3, for mixed hyperlipidemia
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
New insights into angiopoietin-like proteins in lipid metabolism and cardiovascular disease risk
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
An updated ANGPTL3-4-8 model as a mechanism of triglyceride partitioning between fat and oxidative tissues
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Physiological regulation of lipoprotein lipase
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Lipoprotein lipase and its regulators: an unfolding story
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Lipoprotein lipase is active as a monomer
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Angiopoietin-like proteins and postprandial partitioning of fatty acids
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
The regulation of triacylglycerol metabolism and lipoprotein lipase activity
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Decoding the role of angiopoietin-like protein 4/8 complex-mediated plasmin generation in the regulation of LPL activity
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
ANGPTL8 has both endocrine and autocrine effects on substrate utilization
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Angiopoietin-like protein 4/8 complex-mediated plasmin generation leads to cleavage of the complex and restoration of LPL activity
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
ANGPTL8 requires ANGPTL3 to inhibit lipoprotein lipase and plasma triglyceride clearance
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
ApoA5 lowers triglyceride levels via suppression of ANGPTL3/8-mediated LPL inhibition
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Hypertriglyceridemia in Apoa5-/- mice results from reduced amounts of lipoprotein lipase in the capillary lumen
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
APOA5 deficiency causes hypertriglyceridemia by reducing amounts of lipoprotein lipase in capillaries
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
ANGPTL8 protein-truncating variant associated with lower serum triglycerides and risk of coronary disease
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
An anti-ANGPTL3/8 antibody decreases circulating triglycerides by binding to a LPL-inhibitory leucine zipper-like motif
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
New, novel lipid-lowering agents for reducing cardiovascular risk: beyond statins
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Angiopoietin-like 3 inhibition of endothelial lipase is not modulated by angiopoietin-like 8
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Effect of vupanorsen on non-high-density lipoprotein cholesterol levels in statin-treated patients with elevated cholesterol: TRANSLATE-TIMI 70
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Genetic mimicry analysis reveals the specific lipases targeted by the ANGPTL3-ANGPTL8 complex and ANGPTL4
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Plozasiran, an RNA interference agent targeting APOC3, for mixed hyperlipidemia
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Plozasiran (ARO-APOC3) for severe hypertriglyceridemia: the SHASTA-2 randomized clinical trial
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Volanesorsen and triglyceride levels in familial chylomicronemia syndrome
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Exploring the association between low-density lipoprotein subfractions and major adverse cardiovascular outcomes: a comprehensive review
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Affinity capture elution bridging assay: a novel immunoassay format for detection of anti-therapeutic protein antibodies
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
The novel apolipoprotein A5 is present in human serum, is associated with VLDL, HDL, and chylomicrons, and circulates at very low concentrations compared with other apolipoproteins
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Lipoprotein insulin resistance index, a high-throughput measure of insulin resistance, is associated with incident type II diabetes mellitus in the Prevention of Renal and Vascular End-Stage Disease study
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
A novel, high-sensitivity and drug-tolerant sandwich immunoassay for the quantitative measurement of circulating proteins
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).

3 data/code links checked; 3 live.

datahttps://clinicaltrials.gov/study/NCT04052594LIVEHTTP 200
Resolves, but the content could not be matched to the paper.
datahttps://clinicaltrials.gov/ct2/show/NCT04052594LIVEHTTP 200
Resolves, but the content could not be matched to the paper.
datahttp://www.vivli.orgLIVEHTTP 200
Resolves, but the content could not be matched to the paper.

Copyediting

13 minor

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

No major wording or formatting errors. 13 minor suggestions below.

13 copyedit issues flagged: mostly typo, clarity, punctuation.

MINORtypoAbstract
“making ANPTL3/8 an attractive target”
→ making ANGPTL3/8 an attractive target
Misspelling of ANGPTL3/8.
MINORclarityResults, Pharmacokinetics and target engagement
“Assessment of the area under the operating curve of LY3475766 was not conducted”
→ Assessment of the area under the concentration-time curve (AUC) of LY3475766 was not conducted
'operating curve' is likely a typo for 'concentration-time curve'.
MINORpunctuationResults, Effects on triglyceride-rich lipoproteins
“mean (s.e.) percentage change from baseline, −52.1 (6.3%)”
→ mean (s.e.) percentage change from baseline, −52.1% (6.3%)
Missing percentage sign on the point estimate.
MINORconsistencyTable 1 title
“Baseline characteristics of healthy participants with dyslipidemia”
→ Baseline characteristics of participants with mixed hyperlipidemia
Labeling participants 'healthy' while they have dyslipidemia is inconsistent with the abstract's 'mixed hyperlipidemia'.
MINORtypoAbstract, first sentence
“making ANPTL3/8 an attractive target”
→ making ANGPTL3/8 an attractive target
Missing 'G' in ANGPTL3/8.
MINORclarityMethods, Pharmacokinetics and pharmacodynamics
“The only change observed was a modest increase in ANGPTL3 level.”
→ The only change observed was a modest increase in ANGPTL3 level (Extended Data Fig. 2).
The reference to the figure is missing in the main text.
MINORconsistencyResults, Effects on triglyceride-rich lipoproteins
“mean (s.e.) percentage change from baseline, −70.4% (5.8%)”
→ Consider using 'least-squares mean (s.e.)' consistently as in other sections.
The text uses 'mean (s.e.)' here but 'least-squares mean (s.e.)' elsewhere.
MINORpunctuationMethods, Statistical analysis
“The Pearson correlation test used was a two-sided test in which the null hypothesis was H0: rho = 0.”
→ The Pearson correlation test was two-sided, testing the null hypothesis H0: ρ = 0.
Minor phrasing improvement.
MINORclarityDiscussion, paragraph 5
“The question of differentiating between the clinical impacts of inhibiting a therapeutic target such as ANGPTL3 at the production site in the liver and the ANGPTL3/8 complex in the bloodstream remains up for debate.”
→ The question of whether the clinical impacts differ between inhibiting ANGPTL3 at the production site in the liver versus inhibiting the ANGPTL3/8 complex in the bloodstream remains an open question.
Slightly awkward phrasing.
MINORconsistencyFigure 2 legend
“Data in the legend are given as the least-squares mean difference from baseline (s.e.). Data in the figure are given as the least-squares mean difference from placebo (s.e.).”
→ Clarify that the legend shows change from baseline and the figure shows placebo-adjusted change.
This is clear but could be confusing; consider adding a note.
MINORtypoAbstract
“ANPTL3/8”
→ ANGPTL3/8
Missing 'G' in ANGPTL3/8.
MINORgrammarResults, Participant disposition
“The 300 mg dose group included 12 participants treated with LY3475766 due to restarting during the COVID-19 pandemic.”
→ The 300 mg dose group included 12 participants treated with LY3475766 due to the restart of the cohort during the COVID-19 pandemic.
Clarify that the restart was of the cohort.
MINORpunctuationMain text, paragraph 4
“In contrast, when ANGPTL8 associates with ANGPTL3, the resulting ANGPTL3/8 complex that is secreted by the liver acts in an endocrine manner as a potent inhibitor of LPL activity in oxidative tissues and has a greater effect on LPL than ANGPTL3 alone ,,”
→ Remove extra comma before the period.
Double comma at end of sentence.

Kaimen Rigor Action ItemsFinal pass before journal submission

This is a post-publication audit. The published work is methodologically sound for its phase 1 purpose, but the reporting gaps (randomization method, IRB name, code sharing, CIs for main outcomes) are deficiencies that a reader should weigh. These issues are not validity threats but merit a correction or clarification from the authors. No erratum is required for the core conclusions, but the transparency gaps could be addressed via a data note or supplementary update.

1.
HIGHethics
Name the specific institutional review board(s) that approved the study in the Methods section (Trial design and oversight), and include the protocol number (J1T-MC-GZEA) in the main text.
The current statement ‘approved by the institutional review board or ethics committee at each site’ lacks the named board, which is a standard requirement for adequate ethics reporting.
2.
HIGHreporting
Describe the randomization method (e.g., computer-generated random sequence, block size, stratification) in the Methods section (Trial design and oversight).
The paper states that participants were randomized but does not specify the method, which is a key design detail for assessing bias.
3.
HIGHreporting
Provide a sample size justification or explicitly note that the study is a phase 1 dose-escalation trial without formal power analysis in the Methods section.
The absence of any sample size rationale is a reporting gap, though common in early-phase trials; an explicit statement clarifies the design intent.
4.
HIGHstatistics
Report 95% confidence intervals for the main lipid efficacy outcomes (e.g., least-squares mean percent change) in the Results or Figure 2.
Reporting only standard errors without confidence intervals limits the interpretability of effect sizes and is a common expectation for transparent reporting.
5.
HIGHdata code
Share the custom SAS analysis code used for the mixed model and correlation analyses via a public repository (e.g., GitHub or Zenodo) and cite it in the Data availability section.
The absence of analysis code limits reproducibility, especially for model-derived estimates. The data are available via Vivli, but code is not shared.
6.
HIGHreporting
Report race/ethnicity of participants in the baseline characteristics table (Table 1).
Race/ethnicity is a standard demographic variable; its omission is a minor but notable reporting gap in a clinical trial.
7.
MEDIUMreporting
Clarify the blinding procedure: specify who was blinded (participants, investigators, outcome assessors) and how blinding was maintained in the Methods section.
The paper only states ‘double-blind’ without details; this is insufficient for reproducibility and bias assessment.
8.
MEDIUMcopyedit
Correct the typo ‘ANPTL3/8’ to ‘ANGPTL3/8’ in the Abstract and throughout the text where it appears.
The misspelling of the target protein name is a copyedit error that should be corrected for clarity.
9.
MEDIUMcopyedit
Change ‘area under the operating curve’ to ‘area under the concentration-time curve (AUC)’ in the Results section (Pharmacokinetics and target engagement).
The term ‘operating curve’ is a typo for the correct pharmacokinetic term ‘concentration-time curve’.
10.
MEDIUMcopyedit
Fix the misplaced percentage sign in ‘−52.1 (6.3%)’ to ‘−52.1% (6.3%)’ in the Results section (Effects on triglyceride-rich lipoproteins).
The percentage sign should be on the point estimate, not the standard error, to avoid confusion.
11.
MEDIUMcopyedit
Revise the Table 1 title from ‘Baseline characteristics of healthy participants with dyslipidemia’ to ‘Baseline characteristics of participants with mixed hyperlipidemia’ to accurately describe the study population.
Labeling participants as ‘healthy’ while they have dyslipidemia is inconsistent with the disease definition and the abstract’s terminology.
12.
LOWreporting
Consider showing individual data points in the figures for the main outcomes (e.g., scatter plots) to improve data transparency, given the small sample sizes.
Individual data points would allow readers to assess variability and potential outliers beyond the summary statistics.
13.
LOWreporting
Include a description of the handling of missing data (e.g., due to COVID-19 disruption) in the Statistical analysis section.
The restart of the 300 mg cohort is described, but missing data handling is not explicitly addressed, which is relevant for the mixed model analysis.

Full text (52,716 chars)Analyzed: Aug 10, 2026

RigorReviewer 1

RigorReviewer 2

RigorReviewer 3

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.

Targeting the angiopoietin-like protein 3/8 complex with a monoclonal antibody in patients with mixed hyperlipidemia: a phase 1 trial

Gaudet D, Gonciarz M, Shen X, Leohr JK, Beyer TP, Day JW, Mullins GR, Zhen EY, Hartley M, Larouche M, Konrad RJ, Benichou O, Ruotolo G.

DOI

10.1038/s41591-025-03830-4

Record issued

2026-08-10

Engine

7.29.0

Exported

2026-09-22