Reviewer ’s report  
 
Title: Comprehensive evaluation of effects and safety of statin on the progression of liver 
cirrhosis: a systematic review and meta -analysis  
 
Version: 1 Date: 27 Oct 2019  
 
Reviewer: Hla-Hla (Rosie) Thein  
 
Reviewer's report:  
 
Comments to the Authors  
The authors aimed to test the efficacy and safety of statin in liver cirrhosis treatment using a 
systematic review and meta -analysis. 17 clinical studies were finally included. The aut hors 
searched five databases, including PubMed, Ovid, EBSCO, Web of Science, and the Cochrane 
Library regarding statin, liver cirrhosis, hepatic portal hypertension, decompensation, and 
complication before June 2019. The results were presented as pooled ha zard ratio (HR) or pooled 
odds ratio (OR). All results of analysis were illustrated as forest plots. Publication bias was 
assessed using the Begg's adjusted rank correlation test. Standard mean difference (SMD) was 
calculated in continuous variables. Poole d HR or OR was  
calculated in catergorical variables. The following points should be addressed.  
 
Major comments  
1. Title: Better to add as "Comprehensive evaluation of effects and safety of statin on the 
progression of liver cirrhosis: a systematic review and meta -analysis".  
 
Abstract  
2. Background: According to the present study, may be better to add as "The present 
study aimed to comprehensively evaluate the efficacy and safety of statin on liver cirrhosis 
treatment and its development".  
 
3. Methods: Also be good to add according to these: A systematic review of published 
literature was undertaken. A meta -analysis wa s performed to obtain PubMed, MEDLINE on 
Ovid, Cumulative Index to Nursing and Allied Health Literature (CINAHL) on EBSCO, Web of 
Science, and Cochrane Library were searched for published human studies that examined statin, 
liver cirrhosis, hepatic portal hypertension, decompensation, and complication to retrieve related 
literature published before June 2019. Can also add EMBASE and Scopus if available?  
 
4. Line 32 -33 and 45 Results: Change "hepatic cell carcinoma" and add abbreviation: 
"hepatocellular carc inoma (HCC). Also change all below under Background, Results, 
Discussion, Conclusion and Figure Legends. Additionally, "decompensation" change to 
"decompensated cirrhosis".  
 
Background  
5. The major causes of liver cirrhosis are: alcoholic liver disease (AL D), chronic viral 
hepatitis (chronic hepatitis B, chronic hepatitis C), non -alcoholic fatty liver disease (NAFLD) or 
non-alcoholic steatohepatitis (NASH), and others such as primary biliary cholangitis (primary 
biliary cirrhosis, PBC), primary sclerosing c holangitis (PSC), autoimmune hepatitis, 
hemochromatosis, Wilson's disease, alpha -metabolic diseases such as: 1 -antitrypsin deficiency, 
galactosemia and glycogen storage disorders, and heart failure with liver congestion.  
This needs to change: "After liver  cirrhosis developed into decompensated its stage, the mortality 
rate would astoundingly increase[2]". E.g. "After liver cirrhosis developed into decompensated 
cirrhosis, mortality rate would astoundingly increase [2]".  
 
6. Page 4, line 30 -36: May be bette r to add according to this paper "Retrospective cohort 
studies in large populations of patients with cirrhosis and pre -cirrhotic conditions have shown 
that treatment with statins, with the purpose of decreasing high cholesterol levels, was associated 
with a reduced risk of disease progression, hepatic decompensation, hepatocellular carcinoma 
development, and death. Finally, a few randomised controlled trials (RCTs) have shown that 
treatment with simvastatin decreases portal pressure (two studies) and mortal ity (one study). 
Statin treatment was generally well tolerated but a few patients developed severe side effects, 
particularly rhabdomyolysis. Despite these promising beneficial effects, further RCTs are 
required, with larger patient series and hard clinica l endpoints should be performed before statins 
can be recommended for use in patients with chronic liver disease (Ref: Pose E, Trebicka J, 
Mookerjee RP, Angeli P, Gines P. Statins: Old drugs as new therapy for liver diseases? J 
Hepatol. 2019;70(1):194 -202)". 
Also check these and add references:  
* Kasia C, Scaglione SJ. Patients With Chronic Liver Disease/Cirrhosis Should Not Take 
Statin Medications. Clin Liver Dis (Hoboken). 2019;13(4):106 -10.  
* Unger LW, Forstner B, Schneglberger S, Muckenhuber M, Eigenb auer E, et al. 
Guideline -conform statin use reduces overall mortality in patients with compensated liver 
disease. Sci Rep. 2019;9(1):11674.  
* Patel SS, Guzman LA, Lin FP, Pence T, Reichman T, et al. Utilization of aspirin and 
statin in management of coron ary artery disease in patients with cirrhosis undergoing liver 
transplant evaluation. Liver Transpl. 2018;24(7):872 -80.  
* Sigler MA, Congdon L, Edwards KL. An Evidence -Based Review of Statin Use in 
Patients With Nonalcoholic Fatty Liver Disease. Clin Med Insights Gastroenterol. 
2018;111179552218787502.  
* Wright AP, Adusumalli S, Corey KE. Statin therapy in patients with cirrhosis. 
Frontline Gastroenterol. 2015;6(4):255 -61.  
 
Methods  
7. Page 5, Line 28: Regarding Ovid, it's MEDLINE on Ovid.  
 
8. Check thes e published papers methods and add references:  
* Efficacy and safety of statin therapy in older people: a meta -analysis of individual 
participant data from 28 randomised controlled trials. Lancet. 2019;393(10170):407 -15.  
* Wan S, Huang C, Zhu X. Systematic review with a meta -analysis: clinical effects of 
statins on the reduction of portal hypertension and variceal haemorrhage in cirrhotic patients. 
BMJ Open. 2019;9(7):e030038.  
* Choi HD, Chae SM. Comparison of efficacy and safety of combination therapy with 
statins and omega -3 fatty acids versus statin monotherapy in patients with dyslipidemia: A 
systematic review and meta -analysis. Medicine (Baltimore). 2018;97(50):e13593.  
* He Y, Li X, Gasevic D, Brunt E, McLachlan F, Mil lenson M, et al. Statins and 
Multiple Noncardiovascular Outcomes: Umbrella Review of Meta -analyses of Observational 
Studies and Randomized Controlled Trials. Ann Intern Med. 2018;169(8):543 -53.  
* Ma X, Sun D, Li C, Ying J, Yan Y. Statin use and virus -related cirrhosis: A systemic 
review and meta -analysis. Clinics and research in hepatology and gastroenterology. 
2017;41(5):533 -42. 
* Naci H, Brugts J, Ades T. Comparative tolerability and harms of individual statins: a 
study -level network meta -analysis of 246  955 participants from 135 randomized, controlled 
trials. Circ Cardiovasc Qual Outcomes. 2013;6(4):390 -9.  
 
9. Page 6, Regarding "Data synthesis and analysis" and "Statistics": add together as "Data 
synthesis and statistical analysis".  
 
10. Page 6, Line 40 : Add abbreviation - 95% confidential interval (CI) and add on List of 
abbreviations.  
 
Results  
11. Figure 1: Any reason to exclude of 1143 records?  
 
12. Table 1: Regarding Age (years), needs to add mean + SD and median (IQR).  
Variables expressed as e.g. Chang et al. 2017, Huang et al, 2016, added as mean + SD, Kaplan et 
al. 2019, added as median (IQR).  
Add abbreviations below the Table. SD, standard deviation; IQR, interquartile range; HBV, 
hepatitis B virus; HCV, hepatitis C virus; NAFLD, non -alcoholic fatty liver disease.  
Regarding Table 1 and Table 2, better to add first from 2019 followed by 2018, 2017, 2016, 
2015, 2014, 2009 studies and add references.  
 
13. Pages 7 -8: Prognosis of liver cirrhosis benefited from statin treatment in long term 
follow -up: "Statin treatment surprisingly improved survival rate in liver cirrhosis (HR = 0.782, 
95% CI: 0.718 - 0.846), and the decreased risk of mortality as a hard clinical end -point 
persuasively verified benefits brought by satin (Figure 3A)". What does "brough t by satin" 
means?  
 
14. Figure 2. Statin influenced parameters of hepatic portal vessel pressure in short -term 
treatment. A: hepatic venous pressure gradient (HVPG); B: wedged hepatic venous pressures 
(WHVP); C: free hepatic vein pressure (FHVP): 5 studies  (A) and 3 studies (B &amp;  C) - 
Abraldes et al, 2009; Bishnu et al, 2018; Elwan et al, 2018; Pollo -Flores et al, 2015; and Wani et 
al, 2017.  
In Figure 2, should change 'Elwan2019' to 'Elwan2018'.  
 
15. Figure 3. Prognosis of liver cirrhosis benefited fro m statin treatment in long term  
follow -up. A: mortality; B: decompensation events (8 studies - Bang et al, 2017; Chang et al, 
2017; Kaplan et al, 2019; Kumar et al, 2014; Mohanty et al, 2016; Abraldes et al, 2016; Bishnu 
et al, 2018; and Wong et al, 2017);  C: esophageal visceral bleeding (5 studies); D: spontaneous 
bacterial peritonitis (SBP) (4 studies); E: hepatic encephalopathy (HE) (3 studies); F: ascites (4 
studies); G:  
HCC (hepatocellular carcinoma) development (4 studies); H: liver transplantation ra te (2 
studies).  
 
16. Figure 4. Incidence of adverse events didn't increase in statin users. A: worsened 
ascites; B: myalgia; C: diarrhea: 2 studies only.  
 
17. Figure 5. Dose -dependent effects of statin on HCC development, decompensation 
events occurrence, and liver cirrhosis progression. A: HCC development; B: decompensation 
events occurrence; C: liver cirrhosis progression (L: low dose statin; M: medium dose st atin; H: 
high dose statin): There are A to H figures and 2 -3 studies. Please change as A -C: HCC 
development; D -F: decompensation events occurrence; and G -I: liver cirrhosis progression; L: 
low dose statin; M: medium dose statin; H: high dose statin.  
 
Discu ssion  
18.  Page 12, Line 11 -13: Regarding previous article "Kim RG, Loomba R, Prokop LJ, 
Singh S. Statin Use and Risk of Cirrhosis and Related Complications in Patients With Chronic 
Liver Diseases: A Systematic Review and Meta -analysis. Clin Gastroenterol Hepatol. 
2017;15(10):1521 -30.e8", they used 13 studies and reported "Based on a systematic review and 
meta -analysis, statin use is probably associated with lower risk of hepatic decompensation and 
mortality, and might reduce portal hypertension, in patient s with chronic liver diseases.  
See this information too related to liver disease: Newman CB, Preiss D, Tobert JA, Jacobson TA, 
Page RL, et al. Statin Safety and Associated Adverse Events: A Scientific Statement From the 
American Heart Association. Arterios cler Thromb Vasc Biol. 2019;39(2):e38 -e81. 
 
Minor comments  
1. Page 1: Authors should add as: Yue Gu1, Xueqin Yang2, Hang Liang3 and Deli Li3*  
1Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Jilin University,  
Changchun, Jilin, China  
2Department of Traditional Chinese Medicine, First Hospital of Jilin University,  
Changchun, Jilin, China  
3Department of Pediatric Respiratory II, First Hospital of Jilin University, Changchun, Jilin, 
China  
2. Page 4, Line 30 -33 Background: Add abbreviation related to this: 3 -hydroxy -3-
methylglutaryl co -enzyme A (HMG -CoA) as the authors added HMG -CoA under Discussion.  
3. Results: Page 7 -8 "Prognosis of liver cirrhosis benefited from statin treatment in long 
term follow -up": Please add SBP as spontaneous bacte rial peritonitis (SBP) and also add on List 
of abbreviations.  
4. Page 12, Line 47 -48 Limitation: change NALFD to "NAFLD".  
 
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an addition al statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
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 ga in 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 al l 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  
 
I agree to the open pee r review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the autho rs' 
responses. 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/ ). I understand that any comments  
which I do not wish to be included in my named report can be include d as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: Comprehensive evaluation of effects and safety of statin on the progression of liver 
cirrhosis: a systematic review and meta -analysis  
 
Version: 1 Date: 27 Oct 2019  
 
Reviewer: Hla-Hla (Rosie) Thein  
 
Reviewer's report:  
 
Comments to the Authors  
The authors aimed to test the efficacy and safety of statin in liver cirrhosis treatment using a 
systematic review and meta -analysis. 17 clinical studies were finally included. The aut hors 
searched five databases, including PubMed, Ovid, EBSCO, Web of Science, and the Cochrane 
Library regarding statin, liver cirrhosis, hepatic portal hypertension, decompensation, and 
complication before June 2019. The results were presented as pooled ha zard ratio (HR) or pooled 
odds ratio (OR). All results of analysis were illustrated as forest plots. Publication bias was 
assessed using the Begg's adjusted rank correlation test. Standard mean difference (SMD) was 
calculated in continuous variables. Poole d HR or OR was  
calculated in catergorical variables. The following points should be addressed.  
 
Major comments  
1. Title: Better to add as "Comprehensive evaluation of effects and safety of statin on the 
progression of liver cirrhosis: a systematic review and meta -analysis".  
 
Abstract  
2. Background: According to the present study, may be better to add as "The present 
study aimed to comprehensively evaluate the efficacy and safety of statin on liver cirrhosis 
treatment and its development".  
 
3. Methods: Also be good to add according to these: A systematic review of published 
literature was undertaken. A meta -analysis wa s performed to obtain PubMed, MEDLINE on 
Ovid, Cumulative Index to Nursing and Allied Health Literature (CINAHL) on EBSCO, Web of 
Science, and Cochrane Library were searched for published human studies that examined statin, 
liver cirrhosis, hepatic portal hypertension, decompensation, and complication to retrieve related 
literature published before June 2019. Can also add EMBASE and Scopus if available?  
 
4. Line 32 -33 and 45 Results: Change "hepatic cell carcinoma" and add abbreviation: 
"hepatocellular carc inoma (HCC). Also change all below under Background, Results, 
Discussion, Conclusion and Figure Legends. Additionally, "decompensation" change to 
"decompensated cirrhosis".  
 
Background  
5. The major causes of liver cirrhosis are: alcoholic liver disease (AL D), chronic viral 
hepatitis (chronic hepatitis B, chronic hepatitis C), non -alcoholic fatty liver disease (NAFLD) or 
non-alcoholic steatohepatitis (NASH), and others such as primary biliary cholangitis (primary 
biliary cirrhosis, PBC), primary sclerosing c holangitis (PSC), autoimmune hepatitis, 
hemochromatosis, Wilson's disease, alpha -metabolic diseases such as: 1 -antitrypsin deficiency, 
galactosemia and glycogen storage disorders, and heart failure with liver congestion.  
This needs to change: "After liver  cirrhosis developed into decompensated its stage, the mortality 
rate would astoundingly increase[2]". E.g. "After liver cirrhosis developed into decompensated 
cirrhosis, mortality rate would astoundingly increase [2]".  
 
6. Page 4, line 30 -36: May be bette r to add according to this paper "Retrospective cohort 
studies in large populations of patients with cirrhosis and pre -cirrhotic conditions have shown 
that treatment with statins, with the purpose of decreasing high cholesterol levels, was associated 
with a reduced risk of disease progression, hepatic decompensation, hepatocellular carcinoma 
development, and death. Finally, a few randomised controlled trials (RCTs) have shown that 
treatment with simvastatin decreases portal pressure (two studies) and mortal ity (one study). 
Statin treatment was generally well tolerated but a few patients developed severe side effects, 
particularly rhabdomyolysis. Despite these promising beneficial effects, further RCTs are 
required, with larger patient series and hard clinica l endpoints should be performed before statins 
can be recommended for use in patients with chronic liver disease (Ref: Pose E, Trebicka J, 
Mookerjee RP, Angeli P, Gines P. Statins: Old drugs as new therapy for liver diseases? J 
Hepatol. 2019;70(1):194 -202)". 
Also check these and add references:  
* Kasia C, Scaglione SJ. Patients With Chronic Liver Disease/Cirrhosis Should Not Take 
Statin Medications. Clin Liver Dis (Hoboken). 2019;13(4):106 -10.  
* Unger LW, Forstner B, Schneglberger S, Muckenhuber M, Eigenb auer E, et al. 
Guideline -conform statin use reduces overall mortality in patients with compensated liver 
disease. Sci Rep. 2019;9(1):11674.  
* Patel SS, Guzman LA, Lin FP, Pence T, Reichman T, et al. Utilization of aspirin and 
statin in management of coron ary artery disease in patients with cirrhosis undergoing liver 
transplant evaluation. Liver Transpl. 2018;24(7):872 -80.  
* Sigler MA, Congdon L, Edwards KL. An Evidence -Based Review of Statin Use in 
Patients With Nonalcoholic Fatty Liver Disease. Clin Med Insights Gastroenterol. 
2018;111179552218787502.  
* Wright AP, Adusumalli S, Corey KE. Statin therapy in patients with cirrhosis. 
Frontline Gastroenterol. 2015;6(4):255 -61.  
 
Methods  
7. Page 5, Line 28: Regarding Ovid, it's MEDLINE on Ovid.  
 
8. Check thes e published papers methods and add references:  
* Efficacy and safety of statin therapy in older people: a meta -analysis of individual 
participant data from 28 randomised controlled trials. Lancet. 2019;393(10170):407 -15.  
* Wan S, Huang C, Zhu X. Systematic review with a meta -analysis: clinical effects of 
statins on the reduction of portal hypertension and variceal haemorrhage in cirrhotic patients. 
BMJ Open. 2019;9(7):e030038.  
* Choi HD, Chae SM. Comparison of efficacy and safety of combination therapy with 
statins and omega -3 fatty acids versus statin monotherapy in patients with dyslipidemia: A 
systematic review and meta -analysis. Medicine (Baltimore). 2018;97(50):e13593.  
* He Y, Li X, Gasevic D, Brunt E, McLachlan F, Mil lenson M, et al. Statins and 
Multiple Noncardiovascular Outcomes: Umbrella Review of Meta -analyses of Observational 
Studies and Randomized Controlled Trials. Ann Intern Med. 2018;169(8):543 -53.  
* Ma X, Sun D, Li C, Ying J, Yan Y. Statin use and virus -related cirrhosis: A systemic 
review and meta -analysis. Clinics and research in hepatology and gastroenterology. 
2017;41(5):533 -42. 
* Naci H, Brugts J, Ades T. Comparative tolerability and harms of individual statins: a 
study -level network meta -analysis of 246  955 participants from 135 randomized, controlled 
trials. Circ Cardiovasc Qual Outcomes. 2013;6(4):390 -9.  
 
9. Page 6, Regarding "Data synthesis and analysis" and "Statistics": add together as "Data 
synthesis and statistical analysis".  
 
10. Page 6, Line 40 : Add abbreviation - 95% confidential interval (CI) and add on List of 
abbreviations.  
 
Results  
11. Figure 1: Any reason to exclude of 1143 records?  
 
12. Table 1: Regarding Age (years), needs to add mean + SD and median (IQR).  
Variables expressed as e.g. Chang et al. 2017, Huang et al, 2016, added as mean + SD, Kaplan et 
al. 2019, added as median (IQR).  
Add abbreviations below the Table. SD, standard deviation; IQR, interquartile range; HBV, 
hepatitis B virus; HCV, hepatitis C virus; NAFLD, non -alcoholic fatty liver disease.  
Regarding Table 1 and Table 2, better to add first from 2019 followed by 2018, 2017, 2016, 
2015, 2014, 2009 studies and add references.  
 
13. Pages 7 -8: Prognosis of liver cirrhosis benefited from statin treatment in long term 
follow -up: "Statin treatment surprisingly improved survival rate in liver cirrhosis (HR = 0.782, 
95% CI: 0.718 - 0.846), and the decreased risk of mortality as a hard clinical end -point 
persuasively verified benefits brought by satin (Figure 3A)". What does "brough t by satin" 
means?  
 
14. Figure 2. Statin influenced parameters of hepatic portal vessel pressure in short -term 
treatment. A: hepatic venous pressure gradient (HVPG); B: wedged hepatic venous pressures 
(WHVP); C: free hepatic vein pressure (FHVP): 5 studies  (A) and 3 studies (B &amp;  C) - 
Abraldes et al, 2009; Bishnu et al, 2018; Elwan et al, 2018; Pollo -Flores et al, 2015; and Wani et 
al, 2017.  
In Figure 2, should change 'Elwan2019' to 'Elwan2018'.  
 
15. Figure 3. Prognosis of liver cirrhosis benefited fro m statin treatment in long term  
follow -up. A: mortality; B: decompensation events (8 studies - Bang et al, 2017; Chang et al, 
2017; Kaplan et al, 2019; Kumar et al, 2014; Mohanty et al, 2016; Abraldes et al, 2016; Bishnu 
et al, 2018; and Wong et al, 2017);  C: esophageal visceral bleeding (5 studies); D: spontaneous 
bacterial peritonitis (SBP) (4 studies); E: hepatic encephalopathy (HE) (3 studies); F: ascites (4 
studies); G:  
HCC (hepatocellular carcinoma) development (4 studies); H: liver transplantation ra te (2 
studies).  
 
16. Figure 4. Incidence of adverse events didn't increase in statin users. A: worsened 
ascites; B: myalgia; C: diarrhea: 2 studies only.  
 
17. Figure 5. Dose -dependent effects of statin on HCC development, decompensation 
events occurrence, and liver cirrhosis progression. A: HCC development; B: decompensation 
events occurrence; C: liver cirrhosis progression (L: low dose statin; M: medium dose st atin; H: 
high dose statin): There are A to H figures and 2 -3 studies. Please change as A -C: HCC 
development; D -F: decompensation events occurrence; and G -I: liver cirrhosis progression; L: 
low dose statin; M: medium dose statin; H: high dose statin.  
 
Discu ssion  
18.  Page 12, Line 11 -13: Regarding previous article "Kim RG, Loomba R, Prokop LJ, 
Singh S. Statin Use and Risk of Cirrhosis and Related Complications in Patients With Chronic 
Liver Diseases: A Systematic Review and Meta -analysis. Clin Gastroenterol Hepatol. 
2017;15(10):1521 -30.e8", they used 13 studies and reported "Based on a systematic review and 
meta -analysis, statin use is probably associated with lower risk of hepatic decompensation and 
mortality, and might reduce portal hypertension, in patient s with chronic liver diseases.  
See this information too related to liver disease: Newman CB, Preiss D, Tobert JA, Jacobson TA, 
Page RL, et al. Statin Safety and Associated Adverse Events: A Scientific Statement From the 
American Heart Association. Arterios cler Thromb Vasc Biol. 2019;39(2):e38 -e81. 
 
Minor comments  
1. Page 1: Authors should add as: Yue Gu1, Xueqin Yang2, Hang Liang3 and Deli Li3*  
1Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Jilin University,  
Changchun, Jilin, China  
2Department of Traditional Chinese Medicine, First Hospital of Jilin University,  
Changchun, Jilin, China  
3Department of Pediatric Respiratory II, First Hospital of Jilin University, Changchun, Jilin, 
China  
2. Page 4, Line 30 -33 Background: Add abbreviation related to this: 3 -hydroxy -3-
methylglutaryl co -enzyme A (HMG -CoA) as the authors added HMG -CoA under Discussion.  
3. Results: Page 7 -8 "Prognosis of liver cirrhosis benefited from statin treatment in long 
term follow -up": Please add SBP as spontaneous bacte rial peritonitis (SBP) and also add on List 
of abbreviations.  
4. Page 12, Line 47 -48 Limitation: change NALFD to "NAFLD".  
 
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an addition al statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
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 ga in 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 al l 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  
 
I agree to the open pee r review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the autho rs' 
responses. 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/ ). I understand that any comments  
which I do not wish to be included in my named report can be include d as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Comprehensive evaluation of effects and safety of statin on the progression of liver 
cirrhosis: a systematic review and meta -analysis  
 
Version: 1 Date: 27 Oct 2019  
 
Reviewer: Hla-Hla (Rosie) Thein  
 
Reviewer's report:  
 
Comments to the Authors  
The authors aimed to test the efficacy and safety of statin in liver cirrhosis treatment using a 
systematic review and meta -analysis. 17 clinical studies were finally included. The aut hors 
searched five databases, including PubMed, Ovid, EBSCO, Web of Science, and the Cochrane 
Library regarding statin, liver cirrhosis, hepatic portal hypertension, decompensation, and 
complication before June 2019. The results were presented as pooled ha zard ratio (HR) or pooled 
odds ratio (OR). All results of analysis were illustrated as forest plots. Publication bias was 
assessed using the Begg's adjusted rank correlation test. Standard mean difference (SMD) was 
calculated in continuous variables. Poole d HR or OR was  
calculated in catergorical variables. The following points should be addressed.  
 
Major comments  
1. Title: Better to add as "Comprehensive evaluation of effects and safety of statin on the 
progression of liver cirrhosis: a systematic review and meta -analysis".  
 
Abstract  
2. Background: According to the present study, may be better to add as "The present 
study aimed to comprehensively evaluate the efficacy and safety of statin on liver cirrhosis 
treatment and its development".  
 
3. Methods: Also be good to add according to these: A systematic review of published 
literature was undertaken. A meta -analysis wa s performed to obtain PubMed, MEDLINE on 
Ovid, Cumulative Index to Nursing and Allied Health Literature (CINAHL) on EBSCO, Web of 
Science, and Cochrane Library were searched for published human studies that examined statin, 
liver cirrhosis, hepatic portal hypertension, decompensation, and complication to retrieve related 
literature published before June 2019. Can also add EMBASE and Scopus if available?  
 
4. Line 32 -33 and 45 Results: Change "hepatic cell carcinoma" and add abbreviation: 
"hepatocellular carc inoma (HCC). Also change all below under Background, Results, 
Discussion, Conclusion and Figure Legends. Additionally, "decompensation" change to 
"decompensated cirrhosis".  
 
Background  
5. The major causes of liver cirrhosis are: alcoholic liver disease (AL D), chronic viral 
hepatitis (chronic hepatitis B, chronic hepatitis C), non -alcoholic fatty liver disease (NAFLD) or 
non-alcoholic steatohepatitis (NASH), and others such as primary biliary cholangitis (primary 
biliary cirrhosis, PBC), primary sclerosing c holangitis (PSC), autoimmune hepatitis, 
hemochromatosis, Wilson's disease, alpha -metabolic diseases such as: 1 -antitrypsin deficiency, 
galactosemia and glycogen storage disorders, and heart failure with liver congestion.  
This needs to change: "After liver  cirrhosis developed into decompensated its stage, the mortality 
rate would astoundingly increase[2]". E.g. "After liver cirrhosis developed into decompensated 
cirrhosis, mortality rate would astoundingly increase [2]".  
 
6. Page 4, line 30 -36: May be bette r to add according to this paper "Retrospective cohort 
studies in large populations of patients with cirrhosis and pre -cirrhotic conditions have shown 
that treatment with statins, with the purpose of decreasing high cholesterol levels, was associated 
with a reduced risk of disease progression, hepatic decompensation, hepatocellular carcinoma 
development, and death. Finally, a few randomised controlled trials (RCTs) have shown that 
treatment with simvastatin decreases portal pressure (two studies) and mortal ity (one study). 
Statin treatment was generally well tolerated but a few patients developed severe side effects, 
particularly rhabdomyolysis. Despite these promising beneficial effects, further RCTs are 
required, with larger patient series and hard clinica l endpoints should be performed before statins 
can be recommended for use in patients with chronic liver disease (Ref: Pose E, Trebicka J, 
Mookerjee RP, Angeli P, Gines P. Statins: Old drugs as new therapy for liver diseases? J 
Hepatol. 2019;70(1):194 -202)". 
Also check these and add references:  
* Kasia C, Scaglione SJ. Patients With Chronic Liver Disease/Cirrhosis Should Not Take 
Statin Medications. Clin Liver Dis (Hoboken). 2019;13(4):106 -10.  
* Unger LW, Forstner B, Schneglberger S, Muckenhuber M, Eigenb auer E, et al. 
Guideline -conform statin use reduces overall mortality in patients with compensated liver 
disease. Sci Rep. 2019;9(1):11674.  
* Patel SS, Guzman LA, Lin FP, Pence T, Reichman T, et al. Utilization of aspirin and 
statin in management of coron ary artery disease in patients with cirrhosis undergoing liver 
transplant evaluation. Liver Transpl. 2018;24(7):872 -80.  
* Sigler MA, Congdon L, Edwards KL. An Evidence -Based Review of Statin Use in 
Patients With Nonalcoholic Fatty Liver Disease. Clin Med Insights Gastroenterol. 
2018;111179552218787502.  
* Wright AP, Adusumalli S, Corey KE. Statin therapy in patients with cirrhosis. 
Frontline Gastroenterol. 2015;6(4):255 -61.  
 
Methods  
7. Page 5, Line 28: Regarding Ovid, it's MEDLINE on Ovid.  
 
8. Check thes e published papers methods and add references:  
* Efficacy and safety of statin therapy in older people: a meta -analysis of individual 
participant data from 28 randomised controlled trials. Lancet. 2019;393(10170):407 -15.  
* Wan S, Huang C, Zhu X. Systematic review with a meta -analysis: clinical effects of 
statins on the reduction of portal hypertension and variceal haemorrhage in cirrhotic patients. 
BMJ Open. 2019;9(7):e030038.  
* Choi HD, Chae SM. Comparison of efficacy and safety of combination therapy with 
statins and omega -3 fatty acids versus statin monotherapy in patients with dyslipidemia: A 
systematic review and meta -analysis. Medicine (Baltimore). 2018;97(50):e13593.  
* He Y, Li X, Gasevic D, Brunt E, McLachlan F, Mil lenson M, et al. Statins and 
Multiple Noncardiovascular Outcomes: Umbrella Review of Meta -analyses of Observational 
Studies and Randomized Controlled Trials. Ann Intern Med. 2018;169(8):543 -53.  
* Ma X, Sun D, Li C, Ying J, Yan Y. Statin use and virus -related cirrhosis: A systemic 
review and meta -analysis. Clinics and research in hepatology and gastroenterology. 
2017;41(5):533 -42. 
* Naci H, Brugts J, Ades T. Comparative tolerability and harms of individual statins: a 
study -level network meta -analysis of 246  955 participants from 135 randomized, controlled 
trials. Circ Cardiovasc Qual Outcomes. 2013;6(4):390 -9.  
 
9. Page 6, Regarding "Data synthesis and analysis" and "Statistics": add together as "Data 
synthesis and statistical analysis".  
 
10. Page 6, Line 40 : Add abbreviation - 95% confidential interval (CI) and add on List of 
abbreviations.  
 
Results  
11. Figure 1: Any reason to exclude of 1143 records?  
 
12. Table 1: Regarding Age (years), needs to add mean + SD and median (IQR).  
Variables expressed as e.g. Chang et al. 2017, Huang et al, 2016, added as mean + SD, Kaplan et 
al. 2019, added as median (IQR).  
Add abbreviations below the Table. SD, standard deviation; IQR, interquartile range; HBV, 
hepatitis B virus; HCV, hepatitis C virus; NAFLD, non -alcoholic fatty liver disease.  
Regarding Table 1 and Table 2, better to add first from 2019 followed by 2018, 2017, 2016, 
2015, 2014, 2009 studies and add references.  
 
13. Pages 7 -8: Prognosis of liver cirrhosis benefited from statin treatment in long term 
follow -up: "Statin treatment surprisingly improved survival rate in liver cirrhosis (HR = 0.782, 
95% CI: 0.718 - 0.846), and the decreased risk of mortality as a hard clinical end -point 
persuasively verified benefits brought by satin (Figure 3A)". What does "brough t by satin" 
means?  
 
14. Figure 2. Statin influenced parameters of hepatic portal vessel pressure in short -term 
treatment. A: hepatic venous pressure gradient (HVPG); B: wedged hepatic venous pressures 
(WHVP); C: free hepatic vein pressure (FHVP): 5 studies  (A) and 3 studies (B &amp;  C) - 
Abraldes et al, 2009; Bishnu et al, 2018; Elwan et al, 2018; Pollo -Flores et al, 2015; and Wani et 
al, 2017.  
In Figure 2, should change 'Elwan2019' to 'Elwan2018'.  
 
15. Figure 3. Prognosis of liver cirrhosis benefited fro m statin treatment in long term  
follow -up. A: mortality; B: decompensation events (8 studies - Bang et al, 2017; Chang et al, 
2017; Kaplan et al, 2019; Kumar et al, 2014; Mohanty et al, 2016; Abraldes et al, 2016; Bishnu 
et al, 2018; and Wong et al, 2017);  C: esophageal visceral bleeding (5 studies); D: spontaneous 
bacterial peritonitis (SBP) (4 studies); E: hepatic encephalopathy (HE) (3 studies); F: ascites (4 
studies); G:  
HCC (hepatocellular carcinoma) development (4 studies); H: liver transplantation ra te (2 
studies).  
 
16. Figure 4. Incidence of adverse events didn't increase in statin users. A: worsened 
ascites; B: myalgia; C: diarrhea: 2 studies only.  
 
17. Figure 5. Dose -dependent effects of statin on HCC development, decompensation 
events occurrence, and liver cirrhosis progression. A: HCC development; B: decompensation 
events occurrence; C: liver cirrhosis progression (L: low dose statin; M: medium dose st atin; H: 
high dose statin): There are A to H figures and 2 -3 studies. Please change as A -C: HCC 
development; D -F: decompensation events occurrence; and G -I: liver cirrhosis progression; L: 
low dose statin; M: medium dose statin; H: high dose statin.  
 
Discu ssion  
18.  Page 12, Line 11 -13: Regarding previous article "Kim RG, Loomba R, Prokop LJ, 
Singh S. Statin Use and Risk of Cirrhosis and Related Complications in Patients With Chronic 
Liver Diseases: A Systematic Review and Meta -analysis. Clin Gastroenterol Hepatol. 
2017;15(10):1521 -30.e8", they used 13 studies and reported "Based on a systematic review and 
meta -analysis, statin use is probably associated with lower risk of hepatic decompensation and 
mortality, and might reduce portal hypertension, in patient s with chronic liver diseases.  
See this information too related to liver disease: Newman CB, Preiss D, Tobert JA, Jacobson TA, 
Page RL, et al. Statin Safety and Associated Adverse Events: A Scientific Statement From the 
American Heart Association. Arterios cler Thromb Vasc Biol. 2019;39(2):e38 -e81. 
 
Minor comments  
1. Page 1: Authors should add as: Yue Gu1, Xueqin Yang2, Hang Liang3 and Deli Li3*  
1Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Jilin University,  
Changchun, Jilin, China  
2Department of Traditional Chinese Medicine, First Hospital of Jilin University,  
Changchun, Jilin, China  
3Department of Pediatric Respiratory II, First Hospital of Jilin University, Changchun, Jilin, 
China  
2. Page 4, Line 30 -33 Background: Add abbreviation related to this: 3 -hydroxy -3-
methylglutaryl co -enzyme A (HMG -CoA) as the authors added HMG -CoA under Discussion.  
3. Results: Page 7 -8 "Prognosis of liver cirrhosis benefited from statin treatment in long 
term follow -up": Please add SBP as spontaneous bacte rial peritonitis (SBP) and also add on List 
of abbreviations.  
4. Page 12, Line 47 -48 Limitation: change NALFD to "NAFLD".  
 
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an addition al statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
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