Alpha¹ by KaimenConfidential

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: 2026-08-15
Engine: 7.39.0
Exported: 2026-09-20

Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/8059716f-da6c-41df-a776-d0b42b31bb89 is authoritative.

Kaimen Rigor review

Kaimen Rigor reviewed

2.5 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated

Started at 5★ — deductions

IntegrityIntegrity concern ×3−1.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★

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

Not verified in this report

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.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The efficacy claim is based on changes in lipid biomarkers (triglycerides, remnant cholesterol, LDL-C, non-HDL-C, ApoB, HDL-C) as surrogates for cardiovascular risk reduction. Although target engagement is demonstrated by increased ANGPTL3/8 levels, the paper does not cite validated evidence linking these specific lipid changes to clinical outcomes in this context, and the authors explicitly state that effects on cardiovascular risk remain to be established.
“LY3475766 thus significantly reduced atherogenic lipoprotein levels while increasing HDL-C levels; however, the effects on cardiovascular risk remain to be established.”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported reductions in lipid biomarkers (e.g., triglycerides -70%, remnant cholesterol -86%, LDL-C -32%) are large relative to baseline, but the paper does not anchor these changes to established minimal clinically important differences or demonstrate that they translate to clinical benefit. The authors note that effects on cardiovascular risk remain to be established, indicating the effect size is not anchored to clinical meaningfulness.
“LY3475766 thus significantly reduced atherogenic lipoprotein levels while increasing HDL-C levels; however, the effects on cardiovascular risk remain to be established.”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 05AvailabilityNone found 06Copyedit15 minor suggestions

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

This is a well-conducted phase 1 clinical trial with strong scientific premise, rigorous design, and transparent reporting. The main weaknesses are minor reporting gaps: randomization method not specified, exact p-values not consistently reported, and a few internal inconsistencies in reported effect sizes between abstract and results.

Both reviewers agreed on study type (interventional) and all dimension statuses. Minor divergences on power analysis (not applicable vs not reported) and reporting guideline (not reported vs reported and adequate) were resolved in favor of the more contextually appropriate designation. The statistics verification component could only check a subset of tests (0 recomputed) due to limited reporting of test statistics with df; therefore, statistical correctness is not fully verified.

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 dose group is reported to have 12 participants treated with LY3475766, but the baseline table shows n=12 for that group. However, the text says the cohort was restarted with eight new participants, and each group included six treated with 300 mg, so total 12. This is consistent.
“Because each of these groups included six participants treated with 300 mg LY3475766 and two placebo-treated participants, a total of 12 participants were given 300 mg LY3475766.”
ResultsFind in source
lowinternal contradiction
The abstract reports maximum percent changes that differ slightly from the results section (e.g., triglycerides −70% vs −70.4%, remnant cholesterol −86% vs −85.7%). These are likely due to rounding, but could be clarified.
“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
lowinternal contradiction
The abstract reports different maximum percent changes for several lipid fractions compared to the Results section and Figure 2 legend.
Abstract: '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%)' vs. Results: '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%))'
Abstractreviewer’s wording

Overstated conclusions

2 findings · worst high

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

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed

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

supportedReviewers 1, 2
LY3475766 was well tolerated with no severe adverse events or adverse event-related discontinuations.
The safety results directly support this claim.
Evidence: Results section reports no deaths, serious AEs, severe TEAEs, or discontinuations due to TEAEs.
“No deaths, serious adverse events (AEs), severe treatment-emergent AEs (TEAEs) or discontinuations due to TEAEs were observed.”
ResultsFind in source
supportedReviewers 1, 2
LY3475766 dose-dependently reduced atherogenic lipoproteins and increased HDL-C.
The pharmacodynamic results show dose-dependent reductions in triglycerides, remnant cholesterol, LDL-C, non-HDL-C, and ApoB, and increases in HDL-C.
Evidence: Figure 2 and Results section report maximum percent changes for each lipid fraction.
“Figure 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%)).”
ResultsFind in source
supportedReviewer 1
LY3475766 specifically targets the ANGPTL3/8 complex and not ANGPTL3 alone.
The antibody development process and target engagement data support this claim.
Evidence: The antibody was selected to bind only the ANGPTL3/8 complex, and target engagement is demonstrated by increased ANGPTL3/8 levels.
we developed a fully human anti-ANGPTL3/8 antibody, LY3475766, that binds to the same ANGPTL3/8 active site epitope that is recognized by LPL and ApoA-V.
Introduction ¶4reviewer’s wording
supportedReviewers 1, 2
The effects on cardiovascular risk remain to be established.
The paper appropriately notes that this is a phase 1 trial and longer-term outcomes are needed.
Evidence: The abstract and discussion state that effects on cardiovascular risk are not yet established.
“however, the effects on cardiovascular risk remain to be established.”
AbstractFind in source
supportedReviewer 2
LY3475766 specifically blocks ANGPTL3/8-mediated inhibition of LPL activity.
The paper describes the antibody development and in vitro assays showing it binds the ANGPTL3/8 active site and inhibits its LPL-inhibitory activity.
Evidence: Introduction, paragraph 5
“LY3475766, a human monoclonal antibody that specifically blocks ANGPTL3/8-mediated inhibition of LPL activity.”
AbstractFind in source
supportedReviewer 2
LY3475766 is a more potent inhibitor of ANGPTL3/8 than evinacumab.
The paper states this based on in vitro assays, which is appropriate evidence for this claim.
Evidence: Introduction, paragraph 5
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.
Introductionreviewer’s wording

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

INADEQUATESurrogate endpoint
The efficacy claim is based on changes in lipid biomarkers (triglycerides, remnant cholesterol, LDL-C, non-HDL-C, ApoB, HDL-C) as surrogates for cardiovascular risk reduction. Although target engagement is demonstrated by increased ANGPTL3/8 levels, the paper does not cite validated evidence linking these specific lipid changes to clinical outcomes in this context, and the authors explicitly state that effects on cardiovascular risk remain to be established.
“LY3475766 thus significantly reduced atherogenic lipoprotein levels while increasing HDL-C levels; however, the effects on cardiovascular risk remain to be established.”
Find in source
INADEQUATEEffect size
The reported reductions in lipid biomarkers (e.g., triglycerides -70%, remnant cholesterol -86%, LDL-C -32%) are large relative to baseline, but the paper does not anchor these changes to established minimal clinically important differences or demonstrate that they translate to clinical benefit. The authors note that effects on cardiovascular risk remain to be established, indicating the effect size is not anchored to clinical meaningfulness.
“LY3475766 thus significantly reduced atherogenic lipoprotein levels while increasing HDL-C levels; however, the effects on cardiovascular risk remain to be established.”
Find in source

Data authenticity concerns

None found

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

Checked — nothing surfaced.

Reporting gaps

None found

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

Checked — nothing surfaced.

Eight Dimensions8 pass

The introduction thoroughly reviews the ANGPTL protein family, the role of ANGPTL3/8 in inhibiting LPL, and genetic evidence supporting ANGPTL3/8 as a therapeutic target. The rationale for developing LY3475766 is logically derived from this evidence, and the study objectives follow directly. Limitations of prior research are implicitly addressed by the design of the antibody to specifically target the ANGPTL3/8 complex, but the paper does not explicitly discuss limitations of prior studies in a dedicated section.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a strong scientific premise by citing extensive prior work on ANGPTL3/8 biology and lipid metabolism, and clearly links this to the study rationale.

Evidence

paraphrase[Introduction, paragraphs 1-4]

“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.”

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

Introduction ¶4Find in source

absence[Introduction]

The paper does not explicitly discuss limitations of prior research.

PASSReviewer 2· 90% conf

The paper establishes a strong scientific premise by citing extensive prior work on ANGPTL3/8 biology and lipid metabolism, and clearly links this to the study rationale.

Evidence

paraphrase[Introduction, paragraphs 1-4]

“In recent years, agents inhibiting angiopoietin-like protein 3 (ANGPTL3) have been developed and have been shown to be effective in a wide spectrum of lipid disorders...”

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

Introduction ¶4Find in source

paraphrase[Introduction, paragraph 5]

“In the current study, we describe a single ascending dose trial conducted with LY3475766 to assess its safety, tolerability, pharmacokinetics and pharmacodynamics in participants with mixed hyperlipidemia.”

The trial is described as randomized, double-blind, and placebo-controlled with a 6:2 allocation. Randomization method is not explicitly detailed but is standard for such trials. Blinding is stated. Power analysis is not reported, which is typical for phase 1 dose-escalation studies. Inclusion/exclusion criteria are clearly defined. Outlier handling is described in the statistical analysis. Controls are the placebo group. Independent replication is not applicable for a single trial.

Sub-criteria

controlsADEQUATE

power analysisNOT REPORTED

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodINADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The study design is rigorous for a phase 1 trial, with clear randomization, blinding, and a pre-specified analysis population, though some elements like power analysis are not applicable for a first-in-human dose-escalation study.

Evidence

paraphrase[Methods, Trial design and oversight]

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

“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· 90% conf

The study design is rigorous for a phase 1 trial, with clear randomization, blinding, and pre-specified endpoints, though some details like power analysis are not applicable for a first-in-human dose-escalation study.

Evidence

“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.”

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

Statistical analysisFind in source

Sex is reported for the overall population and per group in Table 1. Age, BMI, and health status (mixed hyperlipidemia) are reported. Since both sexes are enrolled, sex justification is not applicable. Demographics are adequately reported in Table 1, including age, sex, and BMI. Species/strain and housing conditions are not applicable for a human trial.

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

Biological variables are well reported for a human trial, including sex, age, BMI, and baseline lipid levels, with demographics in Table 1.

Evidence

“Male sex (%) | 75 | 100 | 100 | 50 | 67 | 67”

Table 1Find in source

“Age (years) | 52 (20, 65) | 44 (25, 61) | 50 (31, 62) | 56 (30, 60) | 52 (33, 65) | 51 (31, 58)”

Table 1Find in source

paraphrase[Methods, Study participants]

PASSReviewer 2· 90% conf

Biological variables are well reported for a human trial, including sex, age, BMI, and baseline lipid levels.

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, triglycerides 194 mg dl−1 and LDL-C 143 mg dl−1.”

“Table 1 Baseline characteristics of healthy participants with dyslipidemia”

Table 1Find in source

The paper states that the trial was approved by the institutional review board or ethics committee at each site, and that participants provided written informed consent. It also states compliance with the Declaration of Helsinki and ICH-GCP. Although the specific IRB names are not given, the statement is adequate for a clinical trial report.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals are adequately reported: the trial was approved by an IRB/ethics committee, participants gave written informed consent, and compliance with the Declaration of Helsinki and ICH-GCP is 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

PASSReviewer 2· 95% conf

Ethical approvals and consent 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

LY3475766 is described as a fully human monoclonal antibody, and its development is detailed. The placebo is identified as 0.9% sodium chloride. Statistical software (SAS 9.4) and PK software (Phoenix WinNonlin 8.1) are named. Other reagents are not applicable as this is a clinical trial without wet-lab assays.

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 investigational product LY3475766 is adequately identified as a human monoclonal antibody, and the statistical software is identified; other bench resources are not applicable.

Evidence

paraphrase[Introduction, paragraph 4]

“we developed a fully human anti-ANGPTL3/8 antibody, LY3475766, that binds to the same ANGPTL3/8 active site epitope that is recognized by LPL and ApoA-V.”

“Data analysis was performed using SAS version 9.4.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

The investigational product (LY3475766) is adequately identified, and software tools are named.

Evidence

“LY3475766, a human monoclonal antibody that specifically blocks ANGPTL3/8-mediated inhibition of LPL activity.”

AbstractFind in source

“Data analysis was performed using SAS version 9.4.”

Statistical analysisFind in source

“Pharmacokinetics were determined using noncompartmental methods (Phoenix WinNonlin version 8.1)”

MethodsFind in source

The paper names the statistical tests used (mixed model for repeated measures, Pearson correlation, power model for dose proportionality). Assumptions are handled by log-transformation and outlier exclusion. Exact p-values are not always given, but effect sizes with confidence intervals are reported, which is acceptable for a clinical trial. Software is identified. Data presentation includes per-group n and standard errors. Mathematical plausibility checks were not possible for most outcomes due to continuous data and small n, but no obvious errors were found.

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 80% conf

Statistical methods are appropriate and adequately described, with named tests, effect sizes with CIs, and software identified; exact p-values are not always reported but this is acceptable for a phase 1 trial.

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

paraphrase[Results, Pharmacokinetics and target engagement]

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

paraphrase[Results, Lipid profile correlation analysis]

“Extended Data Tables – list Pearson correlation coefficients (r) and P values for correlations among changes of key measures”

PASSReviewer 2· 85% conf

Statistical methods are appropriate and adequately described, with effect sizes and confidence intervals reported.

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

paraphrase[Results, Pharmacokinetics and target engagement]

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

“Due to computational limitations in SAS, P values are presented in the table to only four decimal places.”

Statistical analysisFind in source

The data availability statement is detailed, specifying that individual participant data are available after anonymization through a managed access process via Vivli, with conditions and timeframe. This is adequate for a clinical trial. Source data for figures are provided as supplementary material. Code sharing is not applicable as no custom code is mentioned.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data availability is adequately described with a concrete mechanism for accessing individual participant data via Vivli, and the paper provides source data for figures.

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 are available by request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later.”

Data availabilityFind in source

“Source Data Figs. 1–5 and Extended Data Figs. 2–5”

Supplementary materialFind in source

PASSReviewer 2· 95% conf

Data availability is well described with a concrete access route via Vivli, and source data are provided.

Evidence

Data availabilityFind in source

“Source Data Figs. 1–5 and Extended Data Figs. 2–5”

Supplementary materialFind in source

The trial is registered (NCT04052594). Methods are detailed enough for replication. A reporting summary is mentioned. All outcomes appear to be reported, including negative findings. Limitations are discussed in the Discussion. Conclusions are proportional to the evidence. Funding and competing interests are disclosed.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The paper is transparent: methods are detailed, the trial is registered, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov registration: NCT04052594”

AbstractFind in source

“Further studies are needed to confirm these findings, with the next steps likely to include a multiple ascending dose study to determine the optimal dosing of LY3475766”

Discussion ¶8Find in source

“These results warrant further human trials to assess the safety and efficacy of LY3475766 for the treatment of lipid disorders and for the prevention and/or treatment of atherosclerotic CVD, acute pancreatitis, or other morbidities.”

DiscussionFind in source

PASSReviewer 2· 90% conf

Reporting is transparent with trial registration, detailed methods, and discussion of limitations.

Evidence

“ClinicalTrials.gov registration: NCT04052594”

AbstractFind in source

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

AbstractFind in source

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

AcknowledgementsFind 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: 1 verified — 47 no DOI (shown, not verified).

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

15 minor

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

No major wording or formatting errors. 15 minor suggestions below.

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

MINORtypoAbstract
“ANPTL3/8”
→ ANGPTL3/8
Typo in the abstract: 'ANPTL3/8' should be 'ANGPTL3/8'.
MINORconsistencyResults, Maximum percent change in lipid fractions
“triglycerides (−69.9% (4.7%))”
→ triglycerides (−70.4% (5.8%))
The abstract and text report different maximum triglyceride reductions; ensure consistency.
MINORconsistencyResults, Maximum percent change in lipid fractions
“remnant cholesterol (−84.4% (10.2%))”
→ remnant cholesterol (−85.7% (13.1%))
The abstract and text report different maximum remnant cholesterol reductions; ensure consistency.
MINORconsistencyResults, Maximum percent change in lipid fractions
“LDL-C (−36.5% (4.6%))”
→ LDL-C (−31.9% (6.3%))
The abstract and text report different maximum LDL-C reductions; ensure consistency.
MINORconsistencyResults, Maximum percent change in lipid fractions
“non-HDL-C (−37.2% (4.1%))”
→ non-HDL-C (−34.9% (5.4%))
The abstract and text report different maximum non-HDL-C reductions; ensure consistency.
MINORconsistencyResults, Maximum percent change in lipid fractions
“ApoB (−31.4% (3.2%))”
→ ApoB (−29.3% (4.3%))
The abstract and text report different maximum ApoB reductions; ensure consistency.
MINORconsistencyResults, Maximum percent change in lipid fractions
“HDL-C (+21.2% (6.5%))”
→ HDL-C (+26.7% (8.6%))
The abstract and text report different maximum HDL-C increases; ensure consistency.
MINORclarityMethods, Statistical analysis
“Due to computational limitations in SAS, P values are presented in the table to only four decimal places.”
→ Consider reporting p-values to three decimal places as is standard, or clarify the limitation.
The statement about SAS limitations is unusual; consider rephrasing.
MINORconsistencyResults, Maximum percent change in lipid fractions
“−69.9% (4.7%)”
→ −70.4% (5.8%)
The abstract reports −70% while the results section reports −70.4% for triglycerides; ensure consistency.
MINORconsistencyResults, Maximum percent change in lipid fractions
“−84.4% (10.2%)”
→ −85.7% (13.1%)
The abstract reports −86% while the results section reports −85.7% for remnant cholesterol; ensure consistency.
MINORconsistencyResults, Maximum percent change in lipid fractions
“−36.5% (4.6%)”
→ −31.9% (6.3%)
The abstract reports −32% while the results section reports −31.9% for LDL-C; ensure consistency.
MINORconsistencyResults, Maximum percent change in lipid fractions
“−37.2% (4.1%)”
→ −34.9% (5.4%)
The abstract reports −35% while the results section reports −34.9% for non-HDL-C; ensure consistency.
MINORconsistencyResults, Maximum percent change in lipid fractions
“−31.4% (3.2%)”
→ −29.3% (4.3%)
The abstract reports −29% while the results section reports −29.3% for ApoB; ensure consistency.
MINORconsistencyResults, Maximum percent change in lipid fractions
“+21.2% (6.5%)”
→ +26.7% (8.6%)
The abstract reports +27% while the results section reports +26.7% for HDL-C; ensure consistency.
MINORclarityMethods, Statistical analysis
“Log-transformed Cmax estimates were evaluated using a power model (in which the log dose acted as an explanatory variable) to estimate ratios of dose-normalized geometric means and corresponding 90% confidence intervals.”
→ Consider clarifying that the power model is a linear regression of log(Cmax) on log(dose).
The description could be clearer.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and well-reported, with no major integrity concerns. An informed reader should weigh the minor internal inconsistencies in reported effect sizes (abstract vs results) and the lack of explicit randomization method details, which are typical for phase 1 trials but could warrant clarification. No erratum is required, but the authors may consider issuing a correction for the inconsistent numbers.

1.
HIGHcopyedit
Reconcile the maximum percent change values reported in the Abstract with those in the Results section and Figure 2 legend (e.g., triglycerides −69.9% vs −70.4%, remnant cholesterol −84.4% vs −85.7%, LDL-C −36.5% vs −31.9%, non-HDL-C −37.2% vs −34.9%, ApoB −31.4% vs −29.3%, HDL-C +21.2% vs +26.7%).
Internal inconsistencies in reported effect sizes undermine data integrity and could confuse readers; a correction is warranted.
2.
HIGHreporting
In the Methods, specify the randomization method (e.g., computer-generated random sequence, block size) and whether allocation was concealed.
Transparency of randomization is a key methodological detail expected in clinical trial reports.
3.
MEDIUMstatistics
In the Results, report exact p-values for all primary and secondary comparisons, or explicitly state that effect sizes with confidence intervals are the primary reporting method.
Exact p-values facilitate interpretation and meta-analysis; the current reporting is incomplete.
4.
MEDIUMreporting
In the Methods, mention adherence to a reporting guideline such as CONSORT and consider submitting a CONSORT checklist as supplementary material.
Explicit adherence to reporting guidelines improves transparency and reproducibility.
5.
MEDIUMreporting
In the Methods, clarify the blinding process (who was blinded, how allocation was concealed).
Detailed blinding procedures strengthen confidence in the trial's internal validity.
6.
MEDIUMstatistics
In the Methods, provide more detail on the outlier exclusion criteria and report how many participants were excluded.
Transparent outlier handling is essential for reproducibility and assessing robustness.
7.
MEDIUMreporting
In the Methods, clarify the power model description for dose proportionality (e.g., linear regression of log(Cmax) on log(dose)).
Clearer statistical descriptions aid reader understanding and replication.
8.
LOWcopyedit
Fix the typo 'ANPTL3/8' to 'ANGPTL3/8' in the Abstract.
Correcting typos improves professionalism and clarity.
9.
LOWreporting
In the Introduction, add a brief paragraph explicitly discussing limitations of prior ANGPTL3/8 studies and how the current study addresses them.
Explicitly addressing prior limitations strengthens the scientific premise.
10.
LOWdata code
In the Data Availability section, clarify that the source data for figures are available as supplementary files and provide a direct link or accession number if applicable.
Clearer data access instructions improve usability and transparency.

Full text (52,716 chars)Analyzed: Aug 15, 2026

RigorReviewer 1

RigorReviewer 2

RigorPre-Submission Reviewer

CopyeditAgent Scribe

CitationsCitation Integrity

StatisticsStatistics Consistency

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

PreregistrationDeterministic check· no model (rule-based)

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

How stars are deducted

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

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

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

The eight reporting dimensions

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

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

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

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

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

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

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

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

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

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

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

2026-08-15

Engine

7.39.0

Exported

2026-09-20