Reviewer’s report
Title: 
A Systematic Review on Pharmacokinetics, Cardiovascular Outcomes and
Safety Profiles of Statins in Cirrhosis
Version: 
0 
Date: 
22 Jan 2021
Reviewer's report:
General
This manuscript is a systemic review that seeks to find answers to the three
critical questions facing the field *around* the use of statins in patients with
chronic liver disease: (1) How do the pharmacokinetics of statins change in
cirrhosis, (2) how to statins affect major adverse cardiovascular events in
patients with cirrhosis, and (3) do any of the currently used prognostic scores
predict when it is time to dose adjust or stop statin usage?
Data Source & Methods 
This systematic review searched multiple well-established databases
(MEDLINE, EMBASE, Cochrane, etc) with consultation from a University of
Alberta librarian. Articles were screened independently by two of the authors,
with the senior author serving to judge discrepancies, and rated based on quality,
bias, and heterogeneity using accepted tools such as Cochrane Risk of Bias and
Newcastle-Ottawa Assessment scale. Data were supplemented by searching the
Health Canada and FDA Drug Databases and product monographs. 
Strengths
As discussed in the background, there is now a breadth of retrospective data and
ongoing prospective trials evaluating the role of statins for chronic liver disease,
especially cirrhosis. However, there are many questions that remain before these
observations can be operationalized into clinical practice. This systematic review
identifies critical questions and seeks to answer them. The authors have
performed a high quality search and have been thorough and exhaustive in their
presentation of the data available to us. 
Weaknesses
The main weakness of this paper are limitations of the field itself. There is a lack
of high quality information on pharmacokinetics of statins, and most hepatically
cleared therapies, in the setting of cirrhosis and decompensated cirrhosis. The
authors did an admirable job summarizing the available data in tables and charts,
but the dearth of data makes extrapolation to clinical care difficult. 
A separate weakness of this paper involves its description of the biochemical
processing and degradation of the statins in the liver. In the introduction,
CYP450 is the main catabolic enzyme mentioned, whereas later mention of
organic anion transporters (OATPs) is only framed in the context of rosuvastatin
use. However, uptake of all statins is affected by OATPs, though there are
differences between statins due in part to interactions with different OATPs. For
example, the SLCO1B1 polymorphism of OATP1B1 has a large effect on
simvastatin, resulting in a 221% increase in AUC. (Niemi, M. Clin Pharm &
Ther. (2010); 87 1:130-133.) 
While the literature is not robust enough to formulate guidelines on weaning
protocols in the setting of advancing liver disease, there is enough data to urge
caution with statin use in decompensated cirrhosis. Consider additionally
mentioning the role of drug-drug interactions, especially for drugs that are
known to interact with CYP450, OATP and p-glycoprotein. (Francis P, Forman
L. Clin Liver Dis. 2020 Feb 25; 15(1):40-45).
Finally, as a minor point, the formatting of the tables is currently difficult to
read. Where possible, please try to standardize outputs of trials so as to paint a
clearer picture of the data.
Conclusions
In conclusion, the authors have identified three fundamental and pressing
questions regarding statin use and performed a thorough systematic review to try
to identify answers from the literature. While the literature lacks robust data, the
absence of high quality data is a useful piece of information. With improvements
to organization, corrections to statin metabolism mentioned above, and
consideration of offering more caution of use of statins in decompensated/Childs
Pugh C, this should be a worth contribution to the literature.
Publons Reviewer Recognition
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find the details of processing in Publons’ privacy policy
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Yes
Declaration of competing interests
Please complete a declaration of competing interests, considering the following
questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this
paper?
If you can answer no to all of the above, write 'I declare that I have no competing
interests' below. If your reply is yes to any, please give details below.
I declare that I have no competing interests.
Reviewer Publication Consent.
 I agree for my report to be made available
under an Open Access Creative Commons CC-BY License (
http://creativecommons.org/licenses/by/4.0
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the editorial
office before completing the review.
If you wish, you can include your name in your published report. Please note
you must decide whether to include your name at the start of the process and
confirm this decision whenever prompted. If you change your decision later, we
will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name
with my report. (default)
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
Yes
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Reviewer’s report
Title: 
A Systematic Review on Pharmacokinetics, Cardiovascular Outcomes and
Safety Profiles of Statins in Cirrhosis
Version: 
0 
Date: 
22 Jan 2021
Reviewer's report:
General
This manuscript is a systemic review that seeks to find answers to the three
critical questions facing the field *around* the use of statins in patients with
chronic liver disease: (1) How do the pharmacokinetics of statins change in
cirrhosis, (2) how to statins affect major adverse cardiovascular events in
patients with cirrhosis, and (3) do any of the currently used prognostic scores
predict when it is time to dose adjust or stop statin usage?
Data Source & Methods 
This systematic review searched multiple well-established databases
(MEDLINE, EMBASE, Cochrane, etc) with consultation from a University of
Alberta librarian. Articles were screened independently by two of the authors,
with the senior author serving to judge discrepancies, and rated based on quality,
bias, and heterogeneity using accepted tools such as Cochrane Risk of Bias and
Newcastle-Ottawa Assessment scale. Data were supplemented by searching the
Health Canada and FDA Drug Databases and product monographs. 
Strengths
As discussed in the background, there is now a breadth of retrospective data and
ongoing prospective trials evaluating the role of statins for chronic liver disease,
especially cirrhosis. However, there are many questions that remain before these
observations can be operationalized into clinical practice. This systematic review
identifies critical questions and seeks to answer them. The authors have
performed a high quality search and have been thorough and exhaustive in their
presentation of the data available to us. 
Weaknesses
The main weakness of this paper are limitations of the field itself. There is a lack
of high quality information on pharmacokinetics of statins, and most hepatically
cleared therapies, in the setting of cirrhosis and decompensated cirrhosis. The
authors did an admirable job summarizing the available data in tables and charts,
but the dearth of data makes extrapolation to clinical care difficult. 
A separate weakness of this paper involves its description of the biochemical
processing and degradation of the statins in the liver. In the introduction,
CYP450 is the main catabolic enzyme mentioned, whereas later mention of
organic anion transporters (OATPs) is only framed in the context of rosuvastatin
use. However, uptake of all statins is affected by OATPs, though there are
differences between statins due in part to interactions with different OATPs. For
example, the SLCO1B1 polymorphism of OATP1B1 has a large effect on
simvastatin, resulting in a 221% increase in AUC. (Niemi, M. Clin Pharm &
Ther. (2010); 87 1:130-133.) 
While the literature is not robust enough to formulate guidelines on weaning
protocols in the setting of advancing liver disease, there is enough data to urge
caution with statin use in decompensated cirrhosis. Consider additionally
mentioning the role of drug-drug interactions, especially for drugs that are
known to interact with CYP450, OATP and p-glycoprotein. (Francis P, Forman
L. Clin Liver Dis. 2020 Feb 25; 15(1):40-45).
Finally, as a minor point, the formatting of the tables is currently difficult to
read. Where possible, please try to standardize outputs of trials so as to paint a
clearer picture of the data.
Conclusions
In conclusion, the authors have identified three fundamental and pressing
questions regarding statin use and performed a thorough systematic review to try
to identify answers from the literature. While the literature lacks robust data, the
absence of high quality data is a useful piece of information. With improvements
to organization, corrections to statin metabolism mentioned above, and
consideration of offering more caution of use of statins in decompensated/Childs
Pugh C, this should be a worth contribution to the literature.
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons after the final decision on the manuscript has been made. If you have
already registered at Publons, they will notify you of the receipt of this review
and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to
register in order for them to be able to recognize your review on your new
profile page. Publons may use the Review Data to generate derivative metadata
for the benefit of Publons and you as a reviewer, carefully considering the
sensitivity of such information. For example, Publons may verify your record as
a reviewer by updating your profile published on its webservice if you have
registered for such service or help editors to identify candidate reviewers. Please
find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
Yes
Declaration of competing interests
Please complete a declaration of competing interests, considering the following
questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this
paper?
If you can answer no to all of the above, write 'I declare that I have no competing
interests' below. If your reply is yes to any, please give details below.
I declare that I have no competing interests.
Reviewer Publication Consent.
 I agree for my report to be made available
under an Open Access Creative Commons CC-BY License (
http://creativecommons.org/licenses/by/4.0
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the editorial
office before completing the review.
If you wish, you can include your name in your published report. Please note
you must decide whether to include your name at the start of the process and
confirm this decision whenever prompted. If you change your decision later, we
will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name
with my report. (default)
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
Yes
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Please review this paper.
user
Reviewer’s report
Title: 
A Systematic Review on Pharmacokinetics, Cardiovascular Outcomes and
Safety Profiles of Statins in Cirrhosis
Version: 
0 
Date: 
22 Jan 2021
Reviewer's report:
General
This manuscript is a systemic review that seeks to find answers to the three
critical questions facing the field *around* the use of statins in patients with
chronic liver disease: (1) How do the pharmacokinetics of statins change in
cirrhosis, (2) how to statins affect major adverse cardiovascular events in
patients with cirrhosis, and (3) do any of the currently used prognostic scores
predict when it is time to dose adjust or stop statin usage?
Data Source & Methods 
This systematic review searched multiple well-established databases
(MEDLINE, EMBASE, Cochrane, etc) with consultation from a University of
Alberta librarian. Articles were screened independently by two of the authors,
with the senior author serving to judge discrepancies, and rated based on quality,
bias, and heterogeneity using accepted tools such as Cochrane Risk of Bias and
Newcastle-Ottawa Assessment scale. Data were supplemented by searching the
Health Canada and FDA Drug Databases and product monographs. 
Strengths
As discussed in the background, there is now a breadth of retrospective data and
ongoing prospective trials evaluating the role of statins for chronic liver disease,
especially cirrhosis. However, there are many questions that remain before these
observations can be operationalized into clinical practice. This systematic review
identifies critical questions and seeks to answer them. The authors have
performed a high quality search and have been thorough and exhaustive in their
presentation of the data available to us. 
Weaknesses
The main weakness of this paper are limitations of the field itself. There is a lack
of high quality information on pharmacokinetics of statins, and most hepatically
cleared therapies, in the setting of cirrhosis and decompensated cirrhosis. The
authors did an admirable job summarizing the available data in tables and charts,
but the dearth of data makes extrapolation to clinical care difficult. 
A separate weakness of this paper involves its description of the biochemical
processing and degradation of the statins in the liver. In the introduction,
CYP450 is the main catabolic enzyme mentioned, whereas later mention of
organic anion transporters (OATPs) is only framed in the context of rosuvastatin
use. However, uptake of all statins is affected by OATPs, though there are
differences between statins due in part to interactions with different OATPs. For
example, the SLCO1B1 polymorphism of OATP1B1 has a large effect on
simvastatin, resulting in a 221% increase in AUC. (Niemi, M. Clin Pharm &
Ther. (2010); 87 1:130-133.) 
While the literature is not robust enough to formulate guidelines on weaning
protocols in the setting of advancing liver disease, there is enough data to urge
caution with statin use in decompensated cirrhosis. Consider additionally
mentioning the role of drug-drug interactions, especially for drugs that are
known to interact with CYP450, OATP and p-glycoprotein. (Francis P, Forman
L. Clin Liver Dis. 2020 Feb 25; 15(1):40-45).
Finally, as a minor point, the formatting of the tables is currently difficult to
read. Where possible, please try to standardize outputs of trials so as to paint a
clearer picture of the data.
Conclusions
In conclusion, the authors have identified three fundamental and pressing
questions regarding statin use and performed a thorough systematic review to try
to identify answers from the literature. While the literature lacks robust data, the
absence of high quality data is a useful piece of information. With improvements
to organization, corrections to statin metabolism mentioned above, and
consideration of offering more caution of use of statins in decompensated/Childs
Pugh C, this should be a worth contribution to the literature.
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons after the final decision on the manuscript has been made. If you have
already registered at Publons, they will notify you of the receipt of this review
and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to
register in order for them to be able to recognize your review on your new
profile page. Publons may use the Review Data to generate derivative metadata
for the benefit of Publons and you as a reviewer, carefully considering the
sensitivity of such information. For example, Publons may verify your record as
a reviewer by updating your profile published on its webservice if you have
registered for such service or help editors to identify candidate reviewers. Please
find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
Yes
Declaration of competing interests
Please complete a declaration of competing interests, considering the following
questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this
paper?
If you can answer no to all of the above, write 'I declare that I have no competing
interests' below. If your reply is yes to any, please give details below.
I declare that I have no competing interests.
Reviewer Publication Consent.
 I agree for my report to be made available
under an Open Access Creative Commons CC-BY License (
http://creativecommons.org/licenses/by/4.0
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the editorial
office before completing the review.
If you wish, you can include your name in your published report. Please note
you must decide whether to include your name at the start of the process and
confirm this decision whenever prompted. If you change your decision later, we
will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name
with my report. (default)
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
Yes
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
assistant