Impact of Long-Term Statin Therapy on Influenza Incidence and Overall Mortality: A Real-World Data Analysis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Toledo et al. studied the influence of chronic statin treatment on the incidence of influenza, the ICU admission rates, and overall mortality. They used electronic health data from around 6 million individuals, representing ~10% of the population of Spain. They found that while the unadjusted results showed the occurrence of the study outcomes more often among the statin users, the adjusted analysis did not show increased incidence or influenza-related ICU admissions, and there was a small but significant beneficial effect in terms of lesser overall mortality in the statin new users group compared with the non-users. Overall, the study confirms the lack of adverse influence of statin on influenza incidence and related ICU admission rates. The following few issues need to be addressed:

1. Those with 2 or more statin invoices within a 90-day period were included in the test group. However, how many of these were long-term statin users? Median follow-up was for 8.9 years. Did these individuals remain on statins over this duration? What was the interval between the filling up of statin prescription and the study outcome? These data would provide a more comprehensive picture of the events.
2. Figures 2, 3, and 4 show an increased cumulative outcome data for the statin group; is this the unadjusted value?
3. In Conclusion, the authors recommend the use of RCTs to confirm the study findings. However, would RCTs be practically feasible given the nature of the study?

 

Author Response

Reviewer 1

Toledo et al. studied the influence of chronic statin treatment on the incidence of influenza, the ICU admission rates, and overall mortality. They used electronic health data from around 6 million individuals, representing ~10% of the population of Spain. They found that while the unadjusted results showed the occurrence of the study outcomes more often among the statin users, the adjusted analysis did not show increased incidence or influenza-related ICU admissions, and there was a small but significant beneficial effect in terms of lesser overall mortality in the statin new users group compared with the non-users. Overall, the study confirms the lack of adverse influence of statin on influenza incidence and related ICU admission rates. The following few issues need to be addressed:

Those with 2 or more statin invoices within a 90-day period were included in the test group. However, how many of these were long-term statin users? Median follow-up was for 8.9 years. Did these individuals remain on statins over this duration? What was the interval between the filling up of statin prescription and the study outcome? These data would provide a more comprehensive picture of the events.

Reply: We appreciate this insightful comment. The criterion of having at least two statin invoices within a 90‑day period is a standard exposure definition widely used in pharmacoepidemiological studies assessing the effects of statins, and has been consistently applied in previous literature to identify statin users:

• Toledo D, Cartanyà-Hueso À, Morros R, Giner‑Soriano M, Domínguez À, Vilaplana‑Carnerero C, Grau M. Impact of Long-Term Statin Therapy on Incidence and Severity of Community-Acquired Pneumonia: A Real-World Data Analysis. Biomedicines. 2025;13(6):1438. doi:10.3390/biomedicines13061438.
• Garcia-Gil M, Comas-Cufí M, Ramos R, Martí R, Alves-Cabratosa L, Parramon D, Prieto-Alhambra D, Baena-Díez JM, Salvador-González B, Elosua R, Dégano IR, Marrugat J, Grau M. Effectiveness of Statins as Primary Prevention in People With Gout: A Population-Based Cohort Study. J Cardiovasc Pharmacol Ther. 2019;24(6):542‑550. doi:10.1177/1074248419857071.
• Ramos R, Comas-Cufí M, Martí‑Lluch R, Balló E, Ponjoan A, Alves‑Cabratosa L, Blanch J, Marrugat J, Elosua R, Grau M, Elosua‑Bayes M, García‑Ortiz L, Garcia‑Gil M. Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: retrospective cohort study. BMJ. 2018;362:k3359. doi:10.1136/bmj.k3359.
• Garcia-Gil M, Comas‑Cufí M, Blanch J, Martí R, Ponjoan A, Alves‑Cabratosa L, Petersen I, Marrugat J, Elosua R, Grau M, Ramos R. Effectiveness of Statins as Primary Prevention in People With Different Cardiovascular Risk: A Population-Based Cohort Study. Clin Pharmacol Ther. 2018;104(4):719‑732. doi:10.1002/cpt.954.
• Ramos R, García‑Gil M, Comas‑Cufí M, Quesada M, Marrugat J, Elosua R, Sala J, Grau M, Martí R, Ponjoan A, Alves‑Cabratosa L, Blanch J, Bolíbar B. Statins for Prevention of Cardiovascular Events in a Low-Risk Population With Low Ankle Brachial Index. J Am Coll Cardiol. 2016;67(6):630‑640. doi:10.1016/j.jacc.2015.11.052.Based on this convention, we classified participants meeting this requirement as statin users at baseline.

We fully understand the reviewer’s concern regarding the uncertainty about actual long‑term continuation of statin therapy during the almost nine years of median follow‑up. Unfortunately, our dataset does not allow us to confirm treatment persistence throughout the entire follow‑up period. For this reason, we will explicitly acknowledge this limitation in the revised manuscript, clarifying that changes in statin use beyond baseline cannot be fully ascertained with the available data (page 10; 4^th paragraph): “Another important limitation relates to the definition of statin exposure. Follow-ing the standard approach in pharmacoepidemiological research, individuals with at least two statin invoices within a 90‑day period were classified as statin users at base-line—an exposure definition consistently applied in previous real-world studies as-sessing statin effects [Toledo D. Biomedicines. 2025; Clin Pharmacol Ther. 2018; Ramos R. BMJ. 2018]. However, our data do not allow us to verify whether participants maintained long-term statin therapy throughout the nearly nine years of median follow-up. Consequently, changes in statin use over time cannot be fully as-certained, which introduces uncertainty in the interpretation of long-term exposure effects”.

 

Figures 2, 3, and 4 show an increased cumulative outcome data for the statin group; is this the unadjusted value?

Reply: Thank you for this helpful observation. Yes, Figures 2, 3, and 4 present unadjusted cumulative incidence curves based on Kaplan–Meier estimates. These figures are intended to provide a descriptive overview of the crude event patterns in both groups, prior to the application of propensity‑score matching and adjusted Cox models. To avoid any ambiguity, we have revised the figure titles and legends in the updated manuscript to explicitly indicate that these values are unadjusted.

New figure legends:

Figure 2. Unadjusted cumulative incidence curve of influenza over a ten-year period.

Figure 3. Unadjusted cumulative incidence curve of ICU admission over ten years among patients diagnosed with influenza.

Figure 4. Unadjusted cumulative incidence curve of all-cause mortality over a ten-year period.

In Conclusion, the authors recommend the use of RCTs to confirm the study findings. However, would RCTs be practically feasible given the nature of the study?

Reply: We thank the reviewer for this insightful observation. We agree that a randomized controlled trial assigning chronic statin therapy with the primary aim of evaluating influenza‑related outcomes would be challenging from both a practical and ethical perspective, as statins are not indicated for influenza prevention and such a design would require prolonged follow‑up to capture relatively infrequent events.

Our intention in the original conclusion was to acknowledge that, despite the strengths of our large and well‑adjusted real‑world analysis, residual confounding cannot be fully excluded in observational studies. Following the reviewer’s comment, we have revised the conclusion to avoid explicitly recommending RCTs and instead refer more broadly to the need for further research—whether through additional observational studies with enhanced exposure characterization, quasi‑experimental approaches, or other appropriate designs—to continue strengthening the evidence base on statins’ pleiotropic effects (page 11, 3^rd paragraph): “Prior statin therapy showed no association with the adjusted incidence of influenza and related ICU admissions, but was associated with a decreased risk of all‑cause mortality. These findings reaffirm the safety of statins in older adults and support existing evidence on their pleiotropic anti‑inflammatory effects, suggesting that the clinical implications of these properties extend beyond dyslipidemia management.

This study benefits from a very large sample and a high‑quality, population‑representative EHR database, enabling robust and consistent estimates. As with all observational designs, however, our results remain subject to residual confounding and other inherent limitations. For this reason, while our findings provide strong and methodologically sound real‑world evidence, further research—whether through additional observational studies with refined exposure measurements, qua-si‑experimental designs, or other appropriate methodological approaches—is war-ranted to clarify statins’ pleiotropic effects and their potential clinical and public health applications.”

Reviewer 2 Report

Comments and Suggestions for Authors

Congratulations for your work!

 

The manuscript "Impact of Long-Term Statin Therapy on Incidence of Influenza and Overall Mortality: A Real-World Data Analysis" is a retrospective observational study with propensity score adjustment that analyses the effects of chronic statin treatment on the incidence of influenza, the rate of intensive care unit admissions, and overall mortality.

The authors used an extensive, national longitudinal HER database to identify records of elderly patients statin-treated and untreated, enrolled over 9 years (from 2010 until 2019), and presented demographic and clinical data, as well as rates of influenza-related events, ICU admissions, and mortality per 1,000 person-years.

The obtained data were processed using statistical programs (R package) and methods (frequencies, percentages, means, standard deviation, medians with interquartile ranges, chi-square test, Student’s t-test, Wilcoxon rank-sum test).

The results reconfirm the safety profile of statins in older patients and strengthen the evidence for their pleiotropic anti-inflammatory effects (independent of cholesterol lowering), highlighting the opportunity to expand their clinical use beyond the management of dyslipidemia. The authors state that research on statins can continue through randomised controlled clinical trials to further understand their clinical and public health implications.

Moreover, the manuscript is structured into the mandatory parts according to the journal's instructions. The results are presented and discussed in two tables and four figures, and the references include recent articles in the field under review, with very few self-citations.
Consequently, the conclusions are clear and derive from the obtained results.

I suggest moving Table 1 (page 4) into the Results section, as it presents the first findings from the examined data.

Overall, this is a well-written manuscript; no ethical issues have been detected.
In conclusion, it is suitable for this journal and deserves publication.

Author Response

Reviewer 2

Congratulations for your work!

The manuscript "Impact of Long-Term Statin Therapy on Incidence of Influenza and Overall Mortality: A Real-World Data Analysis" is a retrospective observational study with propensity score adjustment that analyses the effects of chronic statin treatment on the incidence of influenza, the rate of intensive care unit admissions, and overall mortality.

The authors used an extensive, national longitudinal HER database to identify records of elderly patients statin-treated and untreated, enrolled over 9 years (from 2010 until 2019), and presented demographic and clinical data, as well as rates of influenza-related events, ICU admissions, and mortality per 1,000 person-years.

The obtained data were processed using statistical programs (R package) and methods (frequencies, percentages, means, standard deviation, medians with interquartile ranges, chi-square test, Student’s t-test, Wilcoxon rank-sum test).

The results reconfirm the safety profile of statins in older patients and strengthen the evidence for their pleiotropic anti-inflammatory effects (independent of cholesterol lowering), highlighting the opportunity to expand their clinical use beyond the management of dyslipidemia. The authors state that research on statins can continue through randomised controlled clinical trials to further understand their clinical and public health implications.

Moreover, the manuscript is structured into the mandatory parts according to the journal's instructions. The results are presented and discussed in two tables and four figures, and the references include recent articles in the field under review, with very few self-citations.

Consequently, the conclusions are clear and derive from the obtained results.

I suggest moving Table 1 (page 4) into the Results section, as it presents the first findings from the examined data.

Reply: We thank the reviewer for this thoughtful suggestion. We agree that Table 1 is conceptually part of the Results, as it presents the first descriptive findings of the cohort. In the revised manuscript, we have positioned Table 1 as close as possible to the beginning of the Results section. Due to space constraints and the size and complexity of Figure 1—which must necessarily precede Table 1 to present the cohort selection process—we were unable to place the table immediately at the start of the section. Nevertheless, we have moved it forward in the layout to better align with the reviewer’s recommendation.

Overall, this is a well-written manuscript; no ethical issues have been detected.

In conclusion, it is suitable for this journal and deserves publication.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for addressing the comments. I have no further concerns.

Author Response

Comments: Thank you for addressing the comments. I have no further concerns.

Reply: Thank you