Atorvastatin Reduces the Severity of COVID-19: A Nationwide, Total Population-Based, Case-Control Study

Round 1

Reviewer 1 Report

This research addresses the important question of the effects of statins on the outcome of COVID-19. This is especially important due to the high number of at risk people who take statins regularly. However, a large number of studies focusing on the effect of statins on SARS-CoV-2 infections, both using retrospective data and wet-lab data, have been published. Therefore, the uniqueness of this research is confined to Korea.

The analysis was performed using appropriate age and co-morbidity matched patients and is well presented.

I have the following suggestions and questions:

The data used in this analysis is, in the rapidly evolving pandemic, very outdated. There are a large number of differences between the early stages of the pandemic and where we are now, in terms of testing capabilities and diagnosis of symptoms, to varying variants circulating. This analysis would be much more relevant if a more complete dataset was used.

Numerous studies in different countries have shown a negative association with statin treatment and outcome of a COVID-19 infection (e.g. Bergqvist et al., 2021, 10.1371/journal.pmed.1003820). Please speculate why you do not see this in your dataset.

Please include data for all the statins included in the study. Do any of the statins result in increased COVID-19 severity and/or mortality?

Lines 137-138. The data presented here do not support the claim that patients taking statins had lower COVID-19 mortality and severity. Please correct and include the total effect of statin treatment in Fig 2 and 3.

Author Response

This research addresses the important question of the effects of statins on the outcome of COVID-19. This is especially important due to the high number of at risk people who take statins regularly. However, a large number of studies focusing on the effect of statins on SARS-CoV-2 infections, both using retrospective data and wet-lab data, have been published. Therefore, the uniqueness of this research is confined to Korea. The analysis was performed using appropriate age and co-morbidity matched patients and is well presented.

I have the following suggestions and questions:

The data used in this analysis is, in the rapidly evolving pandemic, very outdated. There are a large number of differences between the early stages of the pandemic and where we are now, in terms of testing capabilities and diagnosis of symptoms, to varying variants circulating. This analysis would be much more relevant if a more complete dataset was used.

• I totally agree with the reviewer's comments. It is unfortunate that the results of this study do not reflect the reality in a situation where various mutations continue to occur. The reason for this limitation is that it takes a lot of time for the government to collect and disclose national data. In fact, these results were obtained by collecting data from the first few months of a covid-19 outbreak. Please consider this limitation.

Numerous studies in different countries have shown a negative association with statin treatment and outcome of a COVID-19 infection (e.g. Bergqvist et al., 2021, 10.1371/journal.pmed.1003820). Please speculate why you do not see this in your dataset.

• (Bergqvist et al., 2021, 10.1371/journal.pmed.1003820) The results of this study also showed a negative association for mortality, which is consistent with the results of our study.

Please include data for all the statins included in the study. Do any of the statins result in increased COVID-19 severity and/or mortality?

• That's a very good idea. In fact, like your opinion, we initially wanted to display results for all statins. However, except for atorvastatin and rosuvastatin, the remaining statins were classified as “other” and analyzed (Table 1). Because, the use of pitavastatin, lovastatin, and simvastatin included in Others was very small (less than 100 people), so it was not statistically meaningful to include them in the analysis.

Lines 137-138. The data presented here do not support the claim that patients taking statins had lower COVID-19 mortality and severity. Please correct and include the total effect of statin treatment in Fig 2 and 3.

• I agree with your concerns. However, since Figures 2 and 3, which draw the forest plot, show the correction variables of the multivariate model, it is logically unreasonable to draw the total effect of statin together. Instead, the contents of Tables 3 and 4 support the contents of Lines 137-138.

"Please see the attachment."

Reviewer 2 Report

The current article "Atorvastatin Reduces the Severity of COVID-19: A Nationwide, 2 Total Population-Based, Case-Control Study” by Dong-Hyuk Cho and al. is a retrospective observational studies that have investigated the relationship between statins and COVID-19. The study is well structured, the topic is of enormous importance in this period of pandemic COVID-19, and the data and graphs are well represented. The title of the article is coherent with the body of the manuscript. The authors have written a clear and very detailed methodology. The images are clear and the captions complete. The material is well presented without excessive jargon. The references used are adequate and it is new and updated material, I believe the article can be accepted. I only have a few observations that I would suggest be included:

• The authors show that the effects of atorvastatin was associated with decreased COVID-19 severity and mortality, what do they think of other hypolipidemic drugs such as PCSK-9 inhibitors? Include the hypothesis in the discussions, in the future it would be important an observational study with PCSK-9i.

• In the discussions section, include the effects of atorvastatin on other inflammatory biomarkers as well, not just IL-6.

• I suggest including the following references:

Vitiello A, Ferrara F. Plausible Positive Effects of Statins in COVID-19 Patient. Cardiovasc Toxicol. 2021;21(10):781-789. doi:10.1007/s12012-021-09674-x

Ferrara F, Vitiello A. The advantages of drug treatment with statins in patients with SARS-CoV-2 infection. Wien Klin Wochenschr. 2021;133(17-18):958-965. doi:10.1007/s00508-021-01845-8

Author Response

The current article "Atorvastatin Reduces the Severity of COVID-19: A Nationwide, 2 Total Population-Based, Case-Control Study” by Dong-Hyuk Cho and al. is a retrospective observational studies that have investigated the relationship between statins and COVID-19. The study is well structured, the topic is of enormous importance in this period of pandemic COVID-19, and the data and graphs are well represented. The title of the article is coherent with the body of the manuscript. The authors have written a clear and very detailed methodology. The images are clear and the captions complete. The material is well presented without excessive jargon. The references used are adequate and it is new and updated material, I believe the article can be accepted. I only have a few observations that I would suggest be included:

The authors show that the effects of atorvastatin was associated with decreased COVID-19 severity and mortality, what do they think of other hypolipidemic drugs such as PCSK-9 inhibitors? Include the hypothesis in the discussions, in the future it would be important an observational study with PCSK-9i.

• Since PCSK-9 inhibitor data were not included in this study, we thought it is a good suggestion. We have added about the PCSK-9 inhibitor to the discussion by referring to the studies you recommended.

In the discussions section, include the effects of atorvastatin on other inflammatory biomarkers as well, not just IL-6.

• We have added the content of other inflammatory biomarkers to the discussion by referring to the studies you recommended.

I suggest including the following references:

• I appreciate your recommendation for good studies. I added all of suggested studies to the References section.

"Please see the attachment."

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.