Association Between Atorvastatin and Sarcopenia: A Study Based on NHANES and FAERS Databases

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However, further large-scale observational studies are needed to confirm this preliminary finding. Objective This study aims to comprehensively investigate the relationship between atorvastatin exposure and sarcopenia, with the goal of providing more accurate safety and efficacy profiles to guide its clinical use. Methds We utilized two primary datasets: the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018 and the Food and Drug Administration Adverse Event Reporting System (FAERS) from 2004 to 2018. Using a multi-step analytical approach that included descriptive statistical analysis, multivariable logistic regression, and Receiver Operating Characteristic (ROC) curve analysis, we systematically assessed the relationship between atorvastatin exposure and the incidence of sarcopenia. Results In the NHANES cohort analysis, after adjusting for demographic variables, lifestyle factors, and other confounders in the multivariable logistic regression model, atorvastatin use was significantly associated with an increased risk of sarcopenia (OR = 2.21; 95% CI: 1.07–4.55; p = 0.032). An analysis of the FAERS database identified 13,625 adverse event reports related to atorvastatin, of which 5,370 specifically documented myasthenia-related events. Conclusion Independent analyses from both population-based epidemiological surveys and pharmacovigilance systems consistently indicate that atorvastatin use may increase the risk of sarcopenia. Based on these findings, we recommend that healthcare providers implement comprehensive risk communication strategies before prescribing atorvastatin, with particular emphasis on the need for regular musculoskeletal assessments in patients undergoing long-term statin therapy. Atorvastatin Sarcopenia NHANES FAERS Adverse Reaction Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Sarcopenia, a geriatric syndrome marked by the progressive decline in skeletal muscle mass, strength, and function, is strongly associated with increased fall risk, functional impairments, and higher mortality rates [ 1 ] . In the context of global population aging, this condition has become a significant public health concern, with epidemiological studies reporting prevalence rates between 10% and 27% among community-dwelling older adults, while severe sarcopenia affects approximately 2–9% of this population [ 2 ] . The multifactorial etiology of sarcopenia includes genetic factors, modifiable lifestyle choices, obesity-related metabolic disturbances, and iatrogenic drug-induced complications. Atorvastatin, a statin approved for clinical use in 2003, is primarily indicated for the management of hypercholesterolemia and the prevention of cardiovascular events [ 3 ] . In addition to its established lipid-lowering efficacy, emerging evidence suggests potential pleiotropic effects across a range of pathologies. Pharmacological studies have demonstrated that atorvastatin’s anti-inflammatory and antioxidant properties may reduce the risk of acute exacerbations in COPD patients [ 4 ] , while its nephroprotective effects contribute to cardiovascular risk reduction in individuals with chronic kidney disease [ 5 ] . Hepatoprotective benefits have also been identified in patients with NAFLD, where atorvastatin has been shown to improve liver function and slow disease progression [ 6 ] . Oncological studies further suggest a potential reduction in mortality for breast [ 7 ] and colorectal cancers [ 8 ] , though musculoskeletal safety profiles remain a critical concern. Myopathic symptoms, particularly proximal muscle weakness that interferes with activities such as opening jars or snapping fingers, often overlap with conditions like rhabdomyolysis or autoimmune myopathy. Pharmacovigilance data support these concerns: Kim et al. identified musculoskeletal disorders (14.4%) as the second most common statin-related adverse event in Korean databases [ 9 ] , while Montastruc’s VigiBase analysis reported a Relative Odds Ratio (ROR) of 33.93 (95% CI: 32.70–35.20) for atorvastatin-associated rhabdomyolysis [ 10 ] . FAERS data mining by Zhang et al. ranked atorvastatin third among drugs linked to sarcopenia-related reports [ 11 ] , and Suliman et al. documented 51 cases of myasthenia (16.3% prevalence) in their cohort of 313 atorvastatin users [ 12 ] . In a randomized controlled trial, Parker et al. observed a significant CK elevation of 20.8 ± 141.1 U/L (p < 0.0001) and an increased incidence of myalgia [ 13 ] . Additionally, Yan et al.'s disproportionality analysis confirmed higher reporting rates of statin-related myasthenia gravis compared to other lipid-lowering agents [ 14 ] . Collectively, these findings underscore the importance of a thorough risk-benefit assessment and vigilant patient monitoring during atorvastatin therapy. This study aimed to systematically assess the association between atorvastatin use and sarcopenia through dual analyses of the NHANES (National Health and Nutrition Examination Survey) and FAERS (FDA Adverse Event Reporting System) databases. By stratifying population subgroups, we aimed to explore the differential effects of atorvastatin on sarcopenia risk across various demographic and clinical profiles. The findings are expected to provide evidence-based insights that can inform clinical decision-making and guide the development of personalized pharmacotherapy strategies, ultimately improving drug safety monitoring in high-risk populations. 1 Materials and Methods 1.1 Data Sources The NHANES (National Health and Nutrition Examination Survey), conducted by the National Center for Health Statistics (NCHS), is a nationally representative survey that utilizes multi-stage stratified probability sampling. Participant selection involved comprehensive household interviews to collect demographic and medical history data, alongside standardized physical examinations and biospecimen collection conducted through Mobile Examination Centers (MECs). The study protocol was approved by the NCHS Institutional Review Board. To ensure covariate consistency, we used NHANES datasets from 2011 to 2018, with full documentation available through the official repository [15] . OpenVigil 2.1 (http://openvigil.sourceforge.net/) is an open-source pharmacovigilance platform that facilitates automated detection of adverse drug events (ADEs) via disproportionality analysis of FAERS data [16] . We queried this database from January 1, 2004, to December 31, 2018, using "atorvastatin" as the primary suspect drug (PS) and extracted ADE records where atorvastatin was identified as the primary suspect agent. 1.2 Exposure Factors Atorvastatin exposure was determined based on participants' responses regarding prescription medication use in the preceding month. Specifically, individuals who answered "No" to the question, "Have you taken or used any prescription medications in the past month?" were categorized as the control group, while those who confirmed atorvastatin use were classified as the exposed cohort. Additionally, the prescription drug questionnaire gathered data on treatment duration through the question, "How long have you been using/taking [product name]?" 1.3 Sarcopenia Status In NHANES, sarcopenia was defined using dual-energy X-ray absorptiometry (DXA) measurements of appendicular skeletal muscle mass (ASMM), which quantifies lean tissue while excluding adipose and osseous components. The sarcopenia index was calculated as ASMM (kg) divided by body mass index (BMI, kg/m²), with BMI measured by trained personnel at Mobile Examination Centers. Established diagnostic thresholds defined sarcopenia as a sarcopenia index of <0.789 for males and <0.512 for females, respectively [17] . 1.4 Covariates This study assessed several potential covariates, including age (treated as a continuous variable), sex, race (self-reported and categorized as Mexican American, Other Hispanic, Non-Hispanic White, Non-Hispanic Black, or Other Race), education level (classified as ≤high school, some college, or ≥college graduate), smoking status (never smoker [<100 cigarettes lifetime] vs. ever smoker [≥100 cigarettes]), and dietary factors, including caffeine, sugar, and alcohol intake. Physical activity was defined based on the question: "During a typical week, do you engage in any moderate-intensity sports/fitness/recreational activities that cause slight increases in breathing/heart rate (e.g., brisk walking, cycling, swimming, volleyball) lasting ≥10 minutes per session?" Body mass index (BMI) was calculated as weight (kg) divided by height (m)². Diabetes and hypertension were defined by physician-diagnosed status as reported in the survey [15] . 1.5 Statistical analysis Given the complex, multi-stage stratified probability sampling design of NHANES, all analyses incorporated sampling weights, clustering, and stratification. Continuous variables were expressed as mean ± standard deviation (SD), and categorical variables as n (%). Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association between atorvastatin use and sarcopenia. Three nested models were constructed: Model 1 (unadjusted), Model 2 (adjusted for age, sex, race, and education), and Model 3 (fully adjusted, adding physical activity, diabetes, hypertension, caffeine, alcohol, and sugar intake to Model 2). Effect modification was evaluated using interaction terms and stratified analyses across age groups, sex, BMI categories, smoking status, hypertension status, physical activity levels, and diabetes status. Sensitivity analyses included: (1) calculating the E-value for Model 3 to assess the robustness of results against unmeasured confounding, and (2) evaluating diagnostic performance using receiver operating characteristic (ROC) curves with area under the curve (AUC) calculation to quantify predictive accuracy [18] . To assess clinical relevance, we conducted disproportionality analyses of FAERS data using both the Reporting Odds Ratio (ROR) and Bayesian Confidence Propagation Neural Network (BCPNN) algorithms [19] . Adverse drug event (ADE) signals were generated only when both methods exceeded pre-specified thresholds (detailed in Tables 1-2), indicating statistically significant drug-event associations. All analyses were performed in R v4.4.0 and Excel, with statistical significance defined as p < 0.05. 2 Results 2.1 Characteristics of participants From the 2011-2018 NHANES cycles, we applied stringent exclusion criteria—age <20 years, missing appendicular lean mass data, incomplete medication records, missing dietary intake data, undocumented hypertension or diabetes status, unknown smoking history, and incomplete physical activity data—resulting in a final analytic cohort of 5,997 participants. This cohort was stratified into atorvastatin users (n=278) and non-users (n=5,719), with 474 cases meeting the definition of sarcopenia and 5,523 non-cases. Demographic analysis revealed a mean age of 37 years, a male predominance of 56.5%, and a diverse racial composition (29.7% Non-Hispanic White). Nearly half of the participants had an education level above high school. Notably, sarcopenia cases had significantly higher body mass index (BMI) compared to non-cases (34 vs. 28, p<0.001), despite having similar sugar intake. Paradoxically, sarcopenia cases reported lower alcohol and caffeine consumption. Comorbidities, such as smoking, hypertension, and diabetes, were more prevalent in the non-sarcopenia group. Physical inactivity (≥65% in the sarcopenia group) emerged as a key factor. Further stratification details are provided in Figure 1 and Table 3. 2.2 Logistic regression results To examine the association between atorvastatin use and sarcopenia, we constructed three hierarchical logistic regression models, progressively adjusting for potential confounders:Model 1 (Crude Analysis): In the unadjusted analysis, atorvastatin users exhibited 177% higher odds of sarcopenia compared to non-users (OR=2.77, 95% CI 1.70-4.53, p<0.001). However, this estimate may be influenced by unmeasured confounding factors.Model 2 (Demographic Adjustment): After adjusting for age, sex, race, and education, the association remained significant (OR=2.78, 95% CI 1.65-4.70, p<0.001), suggesting that demographic variables did not fully account for the observed relationship.Model 3 (Full Multivariate Adjustment): With further inclusion of lifestyle factors and comorbidities, the association showed moderate attenuation but retained statistical significance (OR=2.21, 95% CI 1.07-4.55, p=0.032), indicating a persistent, independent link between atorvastatin use and increased sarcopenia risk after comprehensive adjustment for confounders.These results, summarized in Table 4, demonstrate a consistent positive relationship across all models. The findings underscore the need for additional research to explore the underlying mechanisms and clinical implications of this association. 2.3 Interaction and Subgroup Analyses Stratified analyses, incorporating covariates such as gender, age, BMI, smoking status, hypertension, physical activity, and diabetes mellitus, revealed that the interaction terms between these variables and atorvastatin use all yielded p-values greater than 0.05 (Figure 2). This suggests that these potential effect modifiers did not significantly influence the primary association between atorvastatin exposure and sarcopenia risk, indicating that the observed relationship is consistent across various demographic and clinical subgroups. The uniformity of findings across stratification layers further strengthens the validity of the primary conclusion. 2.4 Sensitivity analyses To assess the robustness of our findings, we calculated the E-value, a metric that quantifies the minimum strength of association required for an unmeasured confounder to fully account for the observed association. The fully adjusted E-value was 1.814, which exceeds conventional thresholds, suggesting that residual confounding is unlikely to explain away the atorvastatin-sarcopenia relationship. Additionally, we evaluated the predictive performance of our model using the area under the receiver operating characteristic curve (AUC-ROC). Our model demonstrated excellent discriminatory power, with an AUC-ROC of 0.835 (95% CI: 0.818-0.852), indicating strong predictive accuracy for sarcopenia risk stratification. These validation results are presented in Figure 3. 2.5 FAERS database results Through data mining of the FDA Adverse Event Reporting System (FAERS), we systematically identified and quantified post-marketing adverse event reports in which atorvastatin was listed as the primary suspect drug. For sarcopenia-related outcomes, we identified a total of 5,370 qualifying cases, with event distributions depicted in Figure 4. This substantial case series suggests a potential clinical association between atorvastatin exposure and muscle-related adverse outcomes. To quantitatively assess this signal, we calculated the reporting odds ratio (ROR) with 95% confidence intervals (CI) for the top-ranked adverse events. As shown in Figure 5, the five most frequently reported muscle-related events—ophthalmoplegia, myopathy, muscle atrophy, muscular dystrophy, and neuropathic muscular atrophy—all demonstrated statistically significant RORs with non-overlapping 95% CIs. These findings further support the pharmacovigilance signal indicating disproportionate reporting of myopathic events among atorvastatin users. 3 Discussion In this study, we leveraged the extensive data resources of the National Health and Nutrition Examination Survey (NHANES) database spanning from 2011 to 2018 to examine the potential association between atorvastatin exposure and sarcopenia risk. After performing statistical analyses and adjusting for a range of potential confounders—including demographic characteristics, dietary habits, smoking and alcohol consumption, hypertension, diabetes prevalence, and physical activity—we found that atorvastatin use was associated with a significantly increased risk of sarcopenia compared to non-users, a finding that remained statistically significant even after adjusting for these confounders. However, although the interaction terms between covariates did not reach statistical significance (p > 0.05), indicating limited direct moderating effects of these variables on atorvastatin’s impact on muscle mass, the robustness of our results was further supported by the E-value in sensitivity analyses. The E-value suggested that unmeasured confounders would need to have a very strong association with both atorvastatin use and sarcopenia to fully explain the observed relationship. Additionally, the receiver operating characteristic (ROC) curve analysis demonstrated excellent predictive accuracy, further validating the reliability of our analytical framework. To complement these findings, we also explored real-world data from the FDA Adverse Event Reporting System (FAERS), identifying several reports of skeletal muscle-related adverse events, such as myasthenia gravis, which highlight the potential risks associated with atorvastatin use in certain patient populations. These findings underscore the importance of individualized medication decisions and patient education in clinical practice. In conclusion, this study not only enhances our understanding of the complex relationship between atorvastatin and sarcopenia, but also emphasizes the critical need for continuous drug safety monitoring based on large-scale data analysis. Hassani conducted an experiment using 12 healthy adult male rats, which were randomly divided into two groups. The control group was administered distilled water as a placebo via gavage, while the treatment group received 80 mg/kg atorvastatin (dissolved in distilled water) daily through a gastric tube for 8 weeks. The results revealed significant morphological changes in skeletal muscle fibers and nerve fibers induced by atorvastatin. These changes included muscle fiber atrophy, infarct formation, disordered arrangement of myonuclei, displacement of nuclei from their normal peripheral position, acute skeletal muscle infarction, and inflammatory cell infiltration [ 20 ] . Research has shown that atorvastatin-induced muscle cell damage is closely associated with an imbalance in the oxidative stress regulatory network. Specifically, intracellular levels of reduced glutathione (GSH) were significantly decreased, resulting in an oxidative stress microenvironment. Concurrently, the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant response pathway was suppressed, and the expression of its downstream target genes, including glutathione peroxidase 4 (GPx4) and the cystine/glutamate antiporter (SLC7A11), were significantly downregulated. This multi-target dysregulation, particularly the functional inhibition of mitochondrial GPx4, may be a central pathological mechanism underlying atorvastatin-induced muscle cell ferroptosis. This study proposes a novel potential link between abnormal iron metabolism regulation and drug-induced myopathy, offering a new molecular biological perspective on the muscle-related adverse effects of statin drugs [ 21 ] . Additionally, studies have shown that statin treatment activates marker proteins of the unfolded protein response (UPR), including ATF6, CHOP, and spliced XBP1, with these responses being inhibited by the endoplasmic reticulum stress inhibitor TUDCA [ 22 ] . Atorvastatin's inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase alters the gene expression levels of muscle atrophy markers (atrogen-1, murf) and mitochondrial biogenesis markers (pgc-1α), leading to abnormal motor behavior and reduced systemic tissue metabolism in zebrafish larvae. These effects can be reversed by coenzyme Q10 supplementation [ 23 ] . Research also indicates that atorvastatin significantly inhibits L-lactate efflux transport in human skeletal muscle cells (SkMC), potentially leading to intracellular lactate accumulation and subsequently triggering drug-induced muscle toxicity, as reported in the literature [ 24 ] . These findings underscore the potential side effects of atorvastatin on sarcopenia. Therefore, in clinical practice, medical professionals should consider the patient's overall health, individual differences, and the potential risks and benefits of atorvastatin, aiming to develop personalized treatment plans that balance its cardiovascular protective effects with the risk of sarcopenia. This approach would provide a more solid scientific basis for clinical decision-making. 4 Limitations The NHANES database is a cross-sectional study primarily based on questionnaires, providing observational data. However, the absence of certain covariates and the reduction in the sample size may introduce bias into the study. The FAERS database, a spontaneous reporting system, is subject to limitations such as underreporting, misreporting, and incomplete data. As the data is collected from a variety of sources, including pharmaceutical companies, patients, and physicians, it is prone to certain reporting biases [ 25 ] . Although this study utilized both the ROR and BCPNN methods to strengthen the threshold for adverse drug event (ADE) signal detection, the possibility of false-positive signals cannot be entirely ruled out. Consequently, this study demonstrates an association rather than establishing a causal relationship. 5 Conclusion In summary, considering the potential for atorvastatin to induce sarcopenia during treatment, it is crucial to closely monitor patients' skeletal muscle health in clinical practice. Patients should be encouraged to adopt lifestyle interventions, including a balanced diet, regular exercise, sufficient sleep, and stress management, as these measures may help mitigate risks and potentially enhance the therapeutic effects of atorvastatin. By taking into account individual patient characteristics, drug responses, and lifestyle factors, personalized treatment and care plans should be developed and implemented to maximize the cardiovascular benefits of atorvastatin while minimizing its potential risks, ultimately optimizing patients' overall health outcomes. Abbreviations NHANES National Health and Nutrition Examination Survey FAERS Food and Drug Administration Adverse Event Reporting System ROC Receiver Operating Characteristic OR Odds ratio CI Confidence Interval COPD chronic obstructive pulmonary disease NAFLD nonalcoholic fatty liver disease ROR reporting odds ratio MECs Mobile Examination Centers ADEs adverse drug event PS Primary suspect DXA dual-energy X-ray absorptiometry ASMM appendicular skeletal muscle mass BMI body mass index SD standard deviation AUC-ROC area under the receiver operating characteristic curve Nrf2 nuclear factor erythroid 2-related factor 2 GPx4 glutathione peroxidase 4 UPR unfolded protein response SkMC skeletal muscle cells BCPNN Bayesian confidence propagation neural network Declarations Acknowledge We are grateful to the staff and participants of the National Health and Nutrition Examination Survey. Author contributions HZ performed the study and wrote the manuscript. PZ,XL, PLZ and HH designed the study and performed the main data analyses. HQO revised the manuscript. All authors contributed to the manuscript and approved the submitted version. Funding None Ethics approval and consent to participate The protocols of NHANES were approved by the institutional review board of the National Center for Health Statistics, CDC(https://www.cdc.gov/nchs/nhanes/irba98.htm). All participants provided written consent after being fully informed. Competing interests The authors declare that they have no competing interests. Data availability The data included in the study are available from the corresponding author upon reasonable request. References Campo-Rivera N, Ocampo-Chaparro JM, Carvajal-Ortiz R, Reyes-Ortiz CA. Sarcopenic Dysphagia Is Associated With Mortality in Institutionalized Older Adults. J Am Med Dir Assoc. Oct 2022;23(10):1720.e11-1720.e17. doi:10.1016/j.jamda.2022.06.016 Petermann-Rocha F, Balntzi V, Gray SR, et al. Global prevalence of sarcopenia and severe sarcopenia: a systematic review and meta-analysis. J Cachexia Sarcopenia Muscle. Feb 2022;13(1):86-99. doi:10.1002/jcsm.12783 Wierzbicki AS, Mikhailidis DP, Wray R, et al. Statin-fibrate combination: therapy for hyperlipidemia: a review. Curr Med Res Opin. 2003;19(3):155-68. doi:10.1185/030079903125001668 Tulbah AS. The potential of Atorvastatin for chronic lung diseases therapy. Saudi Pharm J. Nov 2020;28(11):1353-1363. doi:10.1016/j.jsps.2020.08.025 Villegas-Quintero VE, Rivas-Ruíz R, García-Rivero AA, Rivera-Lara P, González-Tovar NB. [Efficacy and safety of atorvastatin in major cardiovascular events: Meta-analysis]. Rev Med Inst Mex Seguro Soc. Oct 2 2023;61(Suppl 3):S407-s415. Eficacia y seguridad de la atorvastatina en eventos cardiovasculares mayores: metaanálisis.doi:10.5281/zenodo.8319748 Doumas M, Imprialos K, Dimakopoulou A, Stavropoulos K, Binas A, Athyros VG. The Role of Statins in the Management of Nonalcoholic Fatty Liver Disease. Curr Pharm Des. 2018;24(38):4587-4592. doi:10.2174/1381612825666190117114305 Abolghasemi R, Ebrahimi-Barough S, Bahrami N, Ai J. Atorvastatin Inhibits Viability and Migration of MCF7 Breast Cancer Cells. Asian Pac J Cancer Prev. Mar 1 2022;23(3):867-875. doi:10.31557/apjcp.2022.23.3.867 Cai S, Gao Z. Atorvastatin inhibits proliferation and promotes apoptosis of colon cancer cells via COX-2/PGE2/β-Catenin Pathway. J buon. Jul-Aug 2021;26(4):1219-1225. Kim H, Kim N, Lee DH, Kim HS. Analysis of National Pharmacovigilance Data Associated with Statin Use in Korea. Basic Clin Pharmacol Toxicol. Nov 2017;121(5):409-413. doi:10.1111/bcpt.12808 Montastruc JL. Rhabdomyolysis and statins: A pharmacovigilance comparative study between statins. Br J Clin Pharmacol. Aug 2023;89(8):2636-2638. doi:10.1111/bcp.15757 Zhang Z, Yao L. Drug risks associated with sarcopenia: a real-world and GWAS study. BMC Pharmacol Toxicol. Nov 7 2024;25(1):84. doi:10.1186/s40360-024-00813-y Suliman I, Batarfi A, Almohammadi H, Aljeraisi H, Alnaserallah H, Alghamdi A. Prevalence of Self-Reported Muscle Pain Among Statin Users From National Guard Hospital, Riyadh. Cureus. Mar 2022;14(3):e23463. doi:10.7759/cureus.23463 Tomaszewski M, Stępień KM, Tomaszewska J, Czuczwar SJ. Statin-induced myopathies. Pharmacol Rep. 2011;63(4):859-66. doi:10.1016/s1734-1140(11)70601-6 Yan L, Huang D, Shen J, Yang M, Wang S. Statin‑associated myasthenia gravis: a real-world retrospective and pharmacovigilance study. Expert Opin Drug Saf. Feb 17 2025:1-8. doi:10.1080/14740338.2025.2467183 Zhang H, Huang H, Zhao P. Correlation of atorvastatin with subjective memory deficits: a study from the NHANES and FAERS databases. Front Neurol. 2025;16:1526959. doi:10.3389/fneur.2025.1526959 Böhm R, Höcker J, Cascorbi I, Herdegen T. OpenVigil--free eyeballs on AERS pharmacovigilance data. Nat Biotechnol. Feb 8 2012;30(2):137-8. doi:10.1038/nbt.2113 She Y, Zhu L, Guo X, et al. Association between the composite dietary antioxidant index and sarcopenia risk in American adults: a cross-sectional NHANES study. BMJ Public Health. Jan 2025;3(1):e001447. doi:10.1136/bmjph-2024-001447 Nahm FS. Receiver operating characteristic curve: overview and practical use for clinicians. Korean J Anesthesiol. Feb 2022;75(1):25-36. doi:10.4097/kja.21209 Zhang H, Zhao P, Huang H. Adverse events of Capmatinib: A real-world drug safety surveillance study based on the FDA adverse event reporting system (FAERS) database. Medicine (Baltimore). Jan 31 2025;104(5):e41460. doi:10.1097/md.0000000000041460 Hassani KM. Investigation of the Effect of Atorvastatin on Skeletal Muscles in Male Rats and the Involved Mechanisms. Arch Razi Inst. Feb 2022;77(1):285-291. doi:10.22092/ari.2021.356683.1895 https://doi.org/10.1038/sj.bjp.0704070 Zhang Q, Qu H, Chen Y, et al. Atorvastatin Induces Mitochondria-Dependent Ferroptosis via the Modulation of Nrf2-xCT/GPx4 Axis. Front Cell Dev Biol. 2022;10:806081. doi:10.3389/fcell.2022.806081 Kim WH, Lee CH, Han JH, et al. C/EBP homologous protein deficiency inhibits statin-induced myotoxicity. Biochem Biophys Res Commun. Jan 15 2019;508(3):857-863. doi:10.1016/j.bbrc.2018.11.166 Pasha R, Moon TW. Coenzyme Q10 protects against statin-induced myotoxicity in zebrafish larvae (Danio rerio). Environ Toxicol Pharmacol. Jun 2017;52:150-160. doi:10.1016/j.etap.2017.03.021 Leung YH, Turgeon J, Michaud V. Study of Statin- and Loratadine-Induced Muscle Pain Mechanisms Using Human Skeletal Muscle Cells. Pharmaceutics. Oct 10 2017;9(4)doi:10.3390/pharmaceutics9040042 Sakaeda T, Tamon A, Kadoyama K, Okuno Y. Data mining of the public version of the FDA Adverse Event Reporting System. Int J Med Sci. 2013;10(7):796-803. doi:10.7150/ijms.6048 Tables Tables 1-4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Table2.docx Table3.docx Table4.docx Cite Share Download PDF Status: Published Journal Publication published 08 Oct, 2025 Read the published version in Naunyn-Schmiedeberg's Archives of Pharmacology → Version 1 posted Editorial decision: Revision requested 07 Jul, 2025 Reviews received at journal 04 Jul, 2025 Reviewers agreed at journal 28 Jun, 2025 Reviewers agreed at journal 27 Jun, 2025 Reviewers invited by journal 25 Jun, 2025 Editor assigned by journal 24 Jun, 2025 Submission checks completed at journal 24 Jun, 2025 First submitted to journal 23 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6960351","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":477815331,"identity":"de65806b-20ca-4ccc-836d-522e5291e53c","order_by":0,"name":"Hao Zhang","email":"","orcid":"","institution":"Chengdu Seventh People's Hospital (Affiliated Cancer Hospital of Chengdu Medical College)","correspondingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Zhang","suffix":""},{"id":477815332,"identity":"7157ff67-6b2f-41f0-8261-37b864de93d8","order_by":1,"name":"Ping Zhang","email":"","orcid":"","institution":"Chengdu Seventh People's Hospital (Affiliated Cancer Hospital of Chengdu Medical College)","correspondingAuthor":false,"prefix":"","firstName":"Ping","middleName":"","lastName":"Zhang","suffix":""},{"id":477815333,"identity":"e3abce9e-e233-4a0d-9ea5-50cae46c6cec","order_by":2,"name":"Xi Luo","email":"","orcid":"","institution":"Chengdu Seventh People's Hospital (Affiliated Cancer Hospital of Chengdu Medical College)","correspondingAuthor":false,"prefix":"","firstName":"Xi","middleName":"","lastName":"Luo","suffix":""},{"id":477815334,"identity":"a08c1fdb-dff6-4ec5-a944-4140914d7c58","order_by":3,"name":"Panli Zhao","email":"","orcid":"","institution":"Chengdu Seventh People's Hospital (Affiliated Cancer Hospital of Chengdu Medical College)","correspondingAuthor":false,"prefix":"","firstName":"Panli","middleName":"","lastName":"Zhao","suffix":""},{"id":477815335,"identity":"e7d0e499-f752-4210-9c8f-0f2f38921eb1","order_by":4,"name":"Hua Huang","email":"","orcid":"","institution":"Chengdu Seventh People's Hospital (Affiliated Cancer Hospital of Chengdu Medical College)","correspondingAuthor":false,"prefix":"","firstName":"Hua","middleName":"","lastName":"Huang","suffix":""},{"id":477815336,"identity":"e9c56a56-bea4-4aec-b21b-a94d3d728dbc","order_by":5,"name":"Hongqi Ou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIie3RsQrCMBCA4RMhOBwUF4kI9hUiBXUQfJUcQqYKjo6K4uQDVPQhHB0rAV3qLrhUXB06dtO4iti4OeQjY36SXAAc5w/1I5qmctxDz9dxnOUWSSkaaJEmqlmPGO1XS6tEqep1rgNxxkBXmEVS5mEbaFKmyWWZaUDwvVr8PWH+vZ3SjtF0c9rqURdaq7X8niAPO4ISpBkMtzpCkOJSkHBzMU4LsyBMNTKLRHClzH4RmOPANjFDlolscjwIM2Re/JbXV17z8QP7x9kty/Ke7zUKknf8t+2O4zjOZ09VtUx2aXC55gAAAABJRU5ErkJggg==","orcid":"","institution":"Chengdu Seventh People's Hospital (Affiliated Cancer Hospital of Chengdu Medical College)","correspondingAuthor":true,"prefix":"","firstName":"Hongqi","middleName":"","lastName":"Ou","suffix":""}],"badges":[],"createdAt":"2025-06-24 01:08:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6960351/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6960351/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00210-025-04559-0","type":"published","date":"2025-10-08T15:57:17+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85847061,"identity":"909b2d41-2d10-4d3b-9e0d-7a2053944e7d","added_by":"auto","created_at":"2025-07-02 09:50:44","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":327866,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the sample selection from NHANES\u003c/p\u003e","description":"","filename":"Fig.1FlowchartofthesampleselectionfromNHANES.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6960351/v1/03076f98f798adc6ad9afdbb.jpg"},{"id":85847066,"identity":"a90e45cd-242c-4216-b065-9590575dd0eb","added_by":"auto","created_at":"2025-07-02 09:50:44","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":220886,"visible":true,"origin":"","legend":"\u003cp\u003eThe subgrous analysis of taking atorvastatin\u003c/p\u003e","description":"","filename":"Fig.2Thesubgrousanalysisoftakingatorvastatin.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6960351/v1/9e1c099278f45c61f6603519.jpg"},{"id":85846489,"identity":"b3479b4f-b906-4180-88a2-afa5bab24431","added_by":"auto","created_at":"2025-07-02 09:42:44","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":23377,"visible":true,"origin":"","legend":"\u003cp\u003eThe result of Receiver operator curve (ROC)\u003c/p\u003e","description":"","filename":"Fig.3TheresultofReceiveroperatorcurveROC.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6960351/v1/08d925758c35992b9cb31022.jpg"},{"id":85846496,"identity":"4b1fef1d-10e6-43f9-8abf-f5fc6d66d738","added_by":"auto","created_at":"2025-07-02 09:42:44","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":226162,"visible":true,"origin":"","legend":"\u003cp\u003eAdverse Events Count and Composition Ratio\u003c/p\u003e","description":"","filename":"Fig.4AdverseEventsCountandCompositionRatio.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6960351/v1/e6e8494cd3fe9c783701f240.jpg"},{"id":85847064,"identity":"6dba13e2-8929-421b-b7af-3c9689cbefd4","added_by":"auto","created_at":"2025-07-02 09:50:44","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":232191,"visible":true,"origin":"","legend":"\u003cp\u003ePT of signal intensity\u003c/p\u003e","description":"","filename":"Fig.5PTofsignalintensity.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6960351/v1/7d2b6b3e569a90752832a3e5.jpg"},{"id":93419656,"identity":"759a6275-257f-47dc-b99f-42372065c8b1","added_by":"auto","created_at":"2025-10-13 16:05:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1504458,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6960351/v1/f3755672-04eb-4936-9d09-c7ba40cf7a5d.pdf"},{"id":85846485,"identity":"642d70c1-ab12-4730-b226-33ca9c231492","added_by":"auto","created_at":"2025-07-02 09:42:44","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":16102,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6960351/v1/99eb68efd0e451c8cdcb8368.docx"},{"id":85846486,"identity":"5c270481-170c-4825-a565-f06918fc9710","added_by":"auto","created_at":"2025-07-02 09:42:44","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":17317,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-6960351/v1/a26af6df0cd5a75230cab05a.docx"},{"id":85848558,"identity":"44eb1b43-a2eb-42e8-ad95-8f0b157fddbd","added_by":"auto","created_at":"2025-07-02 09:58:44","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":21637,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-6960351/v1/04dca4f18a191ff176782be3.docx"},{"id":85847056,"identity":"7f60fb72-1bf8-4e42-9b39-60fd0f5503c9","added_by":"auto","created_at":"2025-07-02 09:50:44","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":17107,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.docx","url":"https://assets-eu.researchsquare.com/files/rs-6960351/v1/b7250fa7fa6681e5f50371a7.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association Between Atorvastatin and Sarcopenia: A Study Based on NHANES and FAERS Databases","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSarcopenia, a geriatric syndrome marked by the progressive decline in skeletal muscle mass, strength, and function, is strongly associated with increased fall risk, functional impairments, and higher mortality rates \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. In the context of global population aging, this condition has become a significant public health concern, with epidemiological studies reporting prevalence rates between 10% and 27% among community-dwelling older adults, while severe sarcopenia affects approximately 2\u0026ndash;9% of this population \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. The multifactorial etiology of sarcopenia includes genetic factors, modifiable lifestyle choices, obesity-related metabolic disturbances, and iatrogenic drug-induced complications.\u003c/p\u003e \u003cp\u003eAtorvastatin, a statin approved for clinical use in 2003, is primarily indicated for the management of hypercholesterolemia and the prevention of cardiovascular events \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. In addition to its established lipid-lowering efficacy, emerging evidence suggests potential pleiotropic effects across a range of pathologies. Pharmacological studies have demonstrated that atorvastatin\u0026rsquo;s anti-inflammatory and antioxidant properties may reduce the risk of acute exacerbations in COPD patients \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e, while its nephroprotective effects contribute to cardiovascular risk reduction in individuals with chronic kidney disease \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Hepatoprotective benefits have also been identified in patients with NAFLD, where atorvastatin has been shown to improve liver function and slow disease progression \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Oncological studies further suggest a potential reduction in mortality for breast \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e and colorectal cancers \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, though musculoskeletal safety profiles remain a critical concern. Myopathic symptoms, particularly proximal muscle weakness that interferes with activities such as opening jars or snapping fingers, often overlap with conditions like rhabdomyolysis or autoimmune myopathy. Pharmacovigilance data support these concerns: Kim et al. identified musculoskeletal disorders (14.4%) as the second most common statin-related adverse event in Korean databases \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e, while Montastruc\u0026rsquo;s VigiBase analysis reported a Relative Odds Ratio (ROR) of 33.93 (95% CI: 32.70\u0026ndash;35.20) for atorvastatin-associated rhabdomyolysis \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. FAERS data mining by Zhang et al. ranked atorvastatin third among drugs linked to sarcopenia-related reports \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e, and Suliman et al. documented 51 cases of myasthenia (16.3% prevalence) in their cohort of 313 atorvastatin users \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. In a randomized controlled trial, Parker et al. observed a significant CK elevation of 20.8\u0026thinsp;\u0026plusmn;\u0026thinsp;141.1 U/L (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and an increased incidence of myalgia \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Additionally, Yan et al.'s disproportionality analysis confirmed higher reporting rates of statin-related myasthenia gravis compared to other lipid-lowering agents \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Collectively, these findings underscore the importance of a thorough risk-benefit assessment and vigilant patient monitoring during atorvastatin therapy.\u003c/p\u003e \u003cp\u003eThis study aimed to systematically assess the association between atorvastatin use and sarcopenia through dual analyses of the NHANES (National Health and Nutrition Examination Survey) and FAERS (FDA Adverse Event Reporting System) databases. By stratifying population subgroups, we aimed to explore the differential effects of atorvastatin on sarcopenia risk across various demographic and clinical profiles. The findings are expected to provide evidence-based insights that can inform clinical decision-making and guide the development of personalized pharmacotherapy strategies, ultimately improving drug safety monitoring in high-risk populations.\u003c/p\u003e"},{"header":"1 Materials and Methods","content":"\u003cp\u003e1.1\u0026nbsp;\u0026nbsp;Data Sources The NHANES (National Health and Nutrition Examination Survey), conducted by the National Center for Health Statistics (NCHS), is a nationally representative survey that utilizes multi-stage stratified probability sampling. Participant selection involved comprehensive household interviews to collect demographic and medical history data, alongside standardized physical examinations and biospecimen collection conducted through Mobile Examination Centers (MECs). The study protocol was approved by the NCHS Institutional Review Board. To ensure covariate consistency, we used NHANES datasets from 2011 to 2018, with full documentation available through the official repository \u003csup\u003e[15]\u003c/sup\u003e. OpenVigil 2.1 (http://openvigil.sourceforge.net/) is an open-source pharmacovigilance platform that facilitates automated detection of adverse drug events (ADEs) via disproportionality analysis of FAERS data \u003csup\u003e[16]\u003c/sup\u003e. We queried this database from January 1, 2004, to December 31, 2018, using \u0026quot;atorvastatin\u0026quot; as the primary suspect drug (PS) and extracted ADE records where atorvastatin was identified as the primary suspect agent.\u003c/p\u003e\n\u003cp\u003e1.2\u0026nbsp;\u0026nbsp;Exposure Factors Atorvastatin exposure was determined based on participants\u0026apos; responses regarding prescription medication use in the preceding month. Specifically, individuals who answered \u0026quot;No\u0026quot; to the question, \u0026quot;Have you taken or used any prescription medications in the past month?\u0026quot; were categorized as the control group, while those who confirmed atorvastatin use were classified as the exposed cohort. Additionally, the prescription drug questionnaire gathered data on treatment duration through the question, \u0026quot;How long have you been using/taking [product name]?\u0026quot;\u003c/p\u003e\n\u003cp\u003e1.3 Sarcopenia Status In NHANES, sarcopenia was defined using dual-energy X-ray absorptiometry (DXA) measurements of appendicular skeletal muscle mass (ASMM), which quantifies lean tissue while excluding adipose and osseous components. The sarcopenia index was calculated as ASMM (kg) divided by body mass index (BMI, kg/m\u0026sup2;), with BMI measured by trained personnel at Mobile Examination Centers. Established diagnostic thresholds defined sarcopenia as a sarcopenia index of \u0026lt;0.789 for males and \u0026lt;0.512 for females, respectively \u003csup\u003e[17]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e1.4 Covariates This study assessed several potential covariates, including age (treated as a continuous variable), sex, race (self-reported and categorized as Mexican American, Other Hispanic, Non-Hispanic White, Non-Hispanic Black, or Other Race), education level (classified as\u0026nbsp;\u0026le;high school, some college, or\u0026nbsp;\u0026ge;college graduate), smoking status (never smoker [\u0026lt;100 cigarettes lifetime] vs. ever smoker [\u0026ge;100 cigarettes]), and dietary factors, including caffeine, sugar, and alcohol intake. Physical activity was defined based on the question: \u0026quot;During a typical week, do you engage in any moderate-intensity sports/fitness/recreational activities that cause slight increases in breathing/heart rate (e.g., brisk walking, cycling, swimming, volleyball) lasting\u0026nbsp;\u0026ge;10 minutes per session?\u0026quot; Body mass index (BMI) was calculated as weight (kg) divided by height (m)\u0026sup2;. Diabetes and hypertension were defined by physician-diagnosed status as reported in the survey \u003csup\u003e[15]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e1.5 Statistical analysis Given the complex, multi-stage stratified probability sampling design of NHANES, all analyses incorporated sampling weights, clustering, and stratification. Continuous variables were expressed as mean\u0026nbsp;\u0026plusmn;\u0026nbsp;standard deviation (SD), and categorical variables as n (%). Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association between atorvastatin use and sarcopenia. Three nested models were constructed: Model 1 (unadjusted), Model 2 (adjusted for age, sex, race, and education), and Model 3 (fully adjusted, adding physical activity, diabetes, hypertension, caffeine, alcohol, and sugar intake to Model 2). Effect modification was evaluated using interaction terms and stratified analyses across age groups, sex, BMI categories, smoking status, hypertension status, physical activity levels, and diabetes status. Sensitivity analyses included: (1) calculating the E-value for Model 3 to assess the robustness of results against unmeasured confounding, and (2) evaluating diagnostic performance using receiver operating characteristic (ROC) curves with area under the curve (AUC) calculation to quantify predictive accuracy \u003csup\u003e[18]\u003c/sup\u003e. To assess clinical relevance, we conducted disproportionality analyses of FAERS data using both the Reporting Odds Ratio (ROR) and Bayesian Confidence Propagation Neural Network (BCPNN) algorithms\u003csup\u003e\u0026nbsp;[19]\u003c/sup\u003e. Adverse drug event (ADE) signals were generated only when both methods exceeded pre-specified thresholds (detailed in Tables 1-2), indicating statistically significant drug-event associations. All analyses were performed in R v4.4.0 and Excel, with statistical significance defined as p \u0026lt; 0.05.\u003c/p\u003e"},{"header":"2 Results","content":"\u003cp\u003e2.1 Characteristics of participants From the 2011-2018 NHANES cycles, we applied stringent exclusion criteria\u0026mdash;age \u0026lt;20 years, missing appendicular lean mass data, incomplete medication records, missing dietary intake data, undocumented hypertension or diabetes status, unknown smoking history, and incomplete physical activity data\u0026mdash;resulting in a final analytic cohort of 5,997 participants. This cohort was stratified into atorvastatin users (n=278) and non-users (n=5,719), with 474 cases meeting the definition of sarcopenia and 5,523 non-cases. Demographic analysis revealed a mean age of 37 years, a male predominance of 56.5%, and a diverse racial composition (29.7% Non-Hispanic White). Nearly half of the participants had an education level above high school. Notably, sarcopenia cases had significantly higher body mass index (BMI) compared to non-cases (34 vs. 28, p\u0026lt;0.001), despite having similar sugar intake. Paradoxically, sarcopenia cases reported lower alcohol and caffeine consumption. Comorbidities, such as smoking, hypertension, and diabetes, were more prevalent in the non-sarcopenia group. Physical inactivity (\u0026ge;65% in the sarcopenia group) emerged as a key factor. Further stratification details are provided in Figure 1 and Table 3.\u003c/p\u003e\n\u003cp\u003e2.2\u0026nbsp;Logistic regression results To examine the association between atorvastatin use and sarcopenia, we constructed three hierarchical logistic regression models, progressively adjusting for potential confounders:Model 1 (Crude Analysis): In the unadjusted analysis, atorvastatin users exhibited 177% higher odds of sarcopenia compared to non-users (OR=2.77, 95% CI 1.70-4.53, p\u0026lt;0.001). However, this estimate may be influenced by unmeasured confounding factors.Model 2 (Demographic Adjustment): After adjusting for age, sex, race, and education, the association remained significant (OR=2.78, 95% CI 1.65-4.70, p\u0026lt;0.001), suggesting that demographic variables did not fully account for the observed relationship.Model 3 (Full Multivariate Adjustment): With further inclusion of lifestyle factors and comorbidities, the association showed moderate attenuation but retained statistical significance (OR=2.21, 95% CI 1.07-4.55, p=0.032), indicating a persistent, independent link between atorvastatin use and increased sarcopenia risk after comprehensive adjustment for confounders.These results, summarized in Table 4, demonstrate a consistent positive relationship across all models. The findings underscore the need for additional research to explore the underlying mechanisms and clinical implications of this association.\u003c/p\u003e\n\u003cp\u003e2.3 Interaction and Subgroup Analyses Stratified analyses, incorporating covariates such as gender, age, BMI, smoking status, hypertension, physical activity, and diabetes mellitus, revealed that the interaction terms between these variables and atorvastatin use all yielded p-values greater than 0.05 (Figure 2). This suggests that these potential effect modifiers did not significantly influence the primary association between atorvastatin exposure and sarcopenia risk, indicating that the observed relationship is consistent across various demographic and clinical subgroups. The uniformity of findings across stratification layers further strengthens the validity of the primary conclusion.\u003c/p\u003e\n\u003cp\u003e2.4 Sensitivity analyses To assess the robustness of our findings, we calculated the E-value, a metric that quantifies the minimum strength of association required for an unmeasured confounder to fully account for the observed association. The fully adjusted E-value was 1.814, which exceeds conventional thresholds, suggesting that residual confounding is unlikely to explain away the atorvastatin-sarcopenia relationship. Additionally, we evaluated the predictive performance of our model using the area under the receiver operating characteristic curve (AUC-ROC). Our model demonstrated excellent discriminatory power, with an AUC-ROC of 0.835 (95% CI: 0.818-0.852), indicating strong predictive accuracy for sarcopenia risk stratification. These validation results are presented in Figure 3.\u003c/p\u003e\n\u003cp\u003e2.5 FAERS database results Through data mining of the FDA Adverse Event Reporting System (FAERS), we systematically identified and quantified post-marketing adverse event reports in which atorvastatin was listed as the primary suspect drug. For sarcopenia-related outcomes, we identified a total of 5,370 qualifying cases, with event distributions depicted in Figure 4. This substantial case series suggests a potential clinical association between atorvastatin exposure and muscle-related adverse outcomes. To quantitatively assess this signal, we calculated the reporting odds ratio (ROR) with 95% confidence intervals (CI) for the top-ranked adverse events. As shown in Figure 5, the five most frequently reported muscle-related events\u0026mdash;ophthalmoplegia, myopathy, muscle atrophy, muscular dystrophy, and neuropathic muscular atrophy\u0026mdash;all demonstrated statistically significant RORs with non-overlapping 95% CIs. These findings further support the pharmacovigilance signal indicating disproportionate reporting of myopathic events among atorvastatin users.\u003c/p\u003e"},{"header":"3 Discussion","content":"\u003cp\u003eIn this study, we leveraged the extensive data resources of the National Health and Nutrition Examination Survey (NHANES) database spanning from 2011 to 2018 to examine the potential association between atorvastatin exposure and sarcopenia risk. After performing statistical analyses and adjusting for a range of potential confounders\u0026mdash;including demographic characteristics, dietary habits, smoking and alcohol consumption, hypertension, diabetes prevalence, and physical activity\u0026mdash;we found that atorvastatin use was associated with a significantly increased risk of sarcopenia compared to non-users, a finding that remained statistically significant even after adjusting for these confounders. However, although the interaction terms between covariates did not reach statistical significance (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05), indicating limited direct moderating effects of these variables on atorvastatin\u0026rsquo;s impact on muscle mass, the robustness of our results was further supported by the E-value in sensitivity analyses. The E-value suggested that unmeasured confounders would need to have a very strong association with both atorvastatin use and sarcopenia to fully explain the observed relationship. Additionally, the receiver operating characteristic (ROC) curve analysis demonstrated excellent predictive accuracy, further validating the reliability of our analytical framework. To complement these findings, we also explored real-world data from the FDA Adverse Event Reporting System (FAERS), identifying several reports of skeletal muscle-related adverse events, such as myasthenia gravis, which highlight the potential risks associated with atorvastatin use in certain patient populations. These findings underscore the importance of individualized medication decisions and patient education in clinical practice. In conclusion, this study not only enhances our understanding of the complex relationship between atorvastatin and sarcopenia, but also emphasizes the critical need for continuous drug safety monitoring based on large-scale data analysis.\u003c/p\u003e \u003cp\u003eHassani conducted an experiment using 12 healthy adult male rats, which were randomly divided into two groups. The control group was administered distilled water as a placebo via gavage, while the treatment group received 80 mg/kg atorvastatin (dissolved in distilled water) daily through a gastric tube for 8 weeks. The results revealed significant morphological changes in skeletal muscle fibers and nerve fibers induced by atorvastatin. These changes included muscle fiber atrophy, infarct formation, disordered arrangement of myonuclei, displacement of nuclei from their normal peripheral position, acute skeletal muscle infarction, and inflammatory cell infiltration \u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. Research has shown that atorvastatin-induced muscle cell damage is closely associated with an imbalance in the oxidative stress regulatory network. Specifically, intracellular levels of reduced glutathione (GSH) were significantly decreased, resulting in an oxidative stress microenvironment. Concurrently, the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant response pathway was suppressed, and the expression of its downstream target genes, including glutathione peroxidase 4 (GPx4) and the cystine/glutamate antiporter (SLC7A11), were significantly downregulated. This multi-target dysregulation, particularly the functional inhibition of mitochondrial GPx4, may be a central pathological mechanism underlying atorvastatin-induced muscle cell ferroptosis. This study proposes a novel potential link between abnormal iron metabolism regulation and drug-induced myopathy, offering a new molecular biological perspective on the muscle-related adverse effects of statin drugs \u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Additionally, studies have shown that statin treatment activates marker proteins of the unfolded protein response (UPR), including ATF6, CHOP, and spliced XBP1, with these responses being inhibited by the endoplasmic reticulum stress inhibitor TUDCA \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Atorvastatin's inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase alters the gene expression levels of muscle atrophy markers (atrogen-1, murf) and mitochondrial biogenesis markers (pgc-1α), leading to abnormal motor behavior and reduced systemic tissue metabolism in zebrafish larvae. These effects can be reversed by coenzyme Q10 supplementation \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. Research also indicates that atorvastatin significantly inhibits L-lactate efflux transport in human skeletal muscle cells (SkMC), potentially leading to intracellular lactate accumulation and subsequently triggering drug-induced muscle toxicity, as reported in the literature \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. These findings underscore the potential side effects of atorvastatin on sarcopenia. Therefore, in clinical practice, medical professionals should consider the patient's overall health, individual differences, and the potential risks and benefits of atorvastatin, aiming to develop personalized treatment plans that balance its cardiovascular protective effects with the risk of sarcopenia. This approach would provide a more solid scientific basis for clinical decision-making.\u003c/p\u003e"},{"header":"4 Limitations","content":"\u003cp\u003eThe NHANES database is a cross-sectional study primarily based on questionnaires, providing observational data. However, the absence of certain covariates and the reduction in the sample size may introduce bias into the study. The FAERS database, a spontaneous reporting system, is subject to limitations such as underreporting, misreporting, and incomplete data. As the data is collected from a variety of sources, including pharmaceutical companies, patients, and physicians, it is prone to certain reporting biases \u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. Although this study utilized both the ROR and BCPNN methods to strengthen the threshold for adverse drug event (ADE) signal detection, the possibility of false-positive signals cannot be entirely ruled out. Consequently, this study demonstrates an association rather than establishing a causal relationship.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eIn summary, considering the potential for atorvastatin to induce sarcopenia during treatment, it is crucial to closely monitor patients' skeletal muscle health in clinical practice. Patients should be encouraged to adopt lifestyle interventions, including a balanced diet, regular exercise, sufficient sleep, and stress management, as these measures may help mitigate risks and potentially enhance the therapeutic effects of atorvastatin. By taking into account individual patient characteristics, drug responses, and lifestyle factors, personalized treatment and care plans should be developed and implemented to maximize the cardiovascular benefits of atorvastatin while minimizing its potential risks, ultimately optimizing patients' overall health outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eNHANES\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNational Health and Nutrition Examination Survey\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFAERS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFood and Drug Administration Adverse Event Reporting System\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eROC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eReceiver Operating Characteristic\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOdds ratio\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCI\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConfidence Interval\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOPD\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003echronic obstructive pulmonary disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNAFLD\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003enonalcoholic fatty liver disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eROR\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ereporting odds ratio\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMECs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMobile Examination Centers\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eADEs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eadverse drug event\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrimary suspect\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDXA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003edual-energy X-ray absorptiometry\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eASMM\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eappendicular skeletal muscle mass\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBMI\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ebody mass index\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSD\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003estandard deviation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUC-ROC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003earea under the receiver operating characteristic curve\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNrf2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003enuclear factor erythroid 2-related factor 2\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGPx4\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eglutathione peroxidase 4\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUPR\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eunfolded protein response\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSkMC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eskeletal muscle cells\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBCPNN\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBayesian confidence propagation neural network\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledge\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to the staff and participants of the National Health and Nutrition Examination Survey.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHZ performed the study and wrote the manuscript. PZ,XL, PLZ and HH designed the study and performed the main data analyses. HQO revised the manuscript. All authors contributed to the manuscript and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThe protocols of NHANES were approved by the institutional review board of the National Center for Health Statistics, CDC(https://www.cdc.gov/nchs/nhanes/irba98.htm). All participants provided written consent after being fully informed.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data included in the study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCampo-Rivera N, Ocampo-Chaparro JM, Carvajal-Ortiz R, Reyes-Ortiz CA. Sarcopenic Dysphagia Is Associated With Mortality in Institutionalized Older Adults. J Am Med Dir Assoc. Oct 2022;23(10):1720.e11-1720.e17. doi:10.1016/j.jamda.2022.06.016\u003c/li\u003e\n\u003cli\u003ePetermann-Rocha F, Balntzi V, Gray SR, et al. Global prevalence of sarcopenia and severe sarcopenia: a systematic review and meta-analysis. J Cachexia Sarcopenia Muscle. Feb 2022;13(1):86-99. doi:10.1002/jcsm.12783\u003c/li\u003e\n\u003cli\u003eWierzbicki AS, Mikhailidis DP, Wray R, et al. Statin-fibrate combination: therapy for hyperlipidemia: a review. Curr Med Res Opin. 2003;19(3):155-68. doi:10.1185/030079903125001668 \u003c/li\u003e\n\u003cli\u003eTulbah AS. The potential of Atorvastatin for chronic lung diseases therapy. Saudi Pharm J. Nov 2020;28(11):1353-1363. doi:10.1016/j.jsps.2020.08.025\u003c/li\u003e\n\u003cli\u003eVillegas-Quintero VE, Rivas-Ru\u0026iacute;z R, Garc\u0026iacute;a-Rivero AA, Rivera-Lara P, Gonz\u0026aacute;lez-Tovar NB. [Efficacy and safety of atorvastatin in major cardiovascular events: Meta-analysis]. Rev Med Inst Mex Seguro Soc. Oct 2 2023;61(Suppl 3):S407-s415. Eficacia y seguridad de la atorvastatina en eventos cardiovasculares mayores: metaan\u0026aacute;lisis.doi:10.5281/zenodo.8319748\u003c/li\u003e\n\u003cli\u003eDoumas M, Imprialos K, Dimakopoulou A, Stavropoulos K, Binas A, Athyros VG. The Role of Statins in the Management of Nonalcoholic Fatty Liver Disease. Curr Pharm Des. 2018;24(38):4587-4592. doi:10.2174/1381612825666190117114305\u003c/li\u003e\n\u003cli\u003eAbolghasemi R, Ebrahimi-Barough S, Bahrami N, Ai J. Atorvastatin Inhibits Viability and Migration of MCF7 Breast Cancer Cells. Asian Pac J Cancer Prev. Mar 1 2022;23(3):867-875. doi:10.31557/apjcp.2022.23.3.867\u003c/li\u003e\n\u003cli\u003eCai S, Gao Z. Atorvastatin inhibits proliferation and promotes apoptosis of colon cancer cells via COX-2/PGE2/\u0026beta;-Catenin Pathway. J buon. Jul-Aug 2021;26(4):1219-1225.\u003c/li\u003e\n\u003cli\u003eKim H, Kim N, Lee DH, Kim HS. Analysis of National Pharmacovigilance Data Associated with Statin Use in Korea. Basic Clin Pharmacol Toxicol. Nov 2017;121(5):409-413. doi:10.1111/bcpt.12808\u003c/li\u003e\n\u003cli\u003eMontastruc JL. Rhabdomyolysis and statins: A pharmacovigilance comparative study between statins. Br J Clin Pharmacol. Aug 2023;89(8):2636-2638. doi:10.1111/bcp.15757\u003c/li\u003e\n\u003cli\u003eZhang Z, Yao L. Drug risks associated with sarcopenia: a real-world and GWAS study. BMC Pharmacol Toxicol. Nov 7 2024;25(1):84. doi:10.1186/s40360-024-00813-y\u003c/li\u003e\n\u003cli\u003eSuliman I, Batarfi A, Almohammadi H, Aljeraisi H, Alnaserallah H, Alghamdi A. Prevalence of Self-Reported Muscle Pain Among Statin Users From National Guard Hospital, Riyadh. Cureus. Mar 2022;14(3):e23463. doi:10.7759/cureus.23463 \u003c/li\u003e\n\u003cli\u003eTomaszewski M, Stępień KM, Tomaszewska J, Czuczwar SJ. Statin-induced myopathies. Pharmacol Rep. 2011;63(4):859-66. doi:10.1016/s1734-1140(11)70601-6\u003c/li\u003e\n\u003cli\u003eYan L, Huang D, Shen J, Yang M, Wang S. Statin‑associated myasthenia gravis: a real-world retrospective and pharmacovigilance study. Expert Opin Drug Saf. Feb 17 2025:1-8. doi:10.1080/14740338.2025.2467183\u003c/li\u003e\n\u003cli\u003eZhang H, Huang H, Zhao P. Correlation of atorvastatin with subjective memory deficits: a study from the NHANES and FAERS databases. Front Neurol. 2025;16:1526959. doi:10.3389/fneur.2025.1526959\u003c/li\u003e\n\u003cli\u003eB\u0026ouml;hm R, H\u0026ouml;cker J, Cascorbi I, Herdegen T. OpenVigil--free eyeballs on AERS pharmacovigilance data. Nat Biotechnol. Feb 8 2012;30(2):137-8. doi:10.1038/nbt.2113 \u003c/li\u003e\n\u003cli\u003eShe Y, Zhu L, Guo X, et al. Association between the composite dietary antioxidant index and sarcopenia risk in American adults: a cross-sectional NHANES study. BMJ Public Health. Jan 2025;3(1):e001447. doi:10.1136/bmjph-2024-001447\u003c/li\u003e\n\u003cli\u003eNahm FS. Receiver operating characteristic curve: overview and practical use for clinicians. Korean J Anesthesiol. Feb 2022;75(1):25-36. doi:10.4097/kja.21209\u003c/li\u003e\n\u003cli\u003eZhang H, Zhao P, Huang H. Adverse events of Capmatinib: A real-world drug safety surveillance study based on the FDA adverse event reporting system (FAERS) database. Medicine (Baltimore). Jan 31 2025;104(5):e41460. doi:10.1097/md.0000000000041460\u003c/li\u003e\n\u003cli\u003eHassani KM. Investigation of the Effect of Atorvastatin on Skeletal Muscles in Male Rats and the Involved Mechanisms. Arch Razi Inst. Feb 2022;77(1):285-291. doi:10.22092/ari.2021.356683.1895 https://doi.org/10.1038/sj.bjp.0704070\u003c/li\u003e\n\u003cli\u003eZhang Q, Qu H, Chen Y, et al. Atorvastatin Induces Mitochondria-Dependent Ferroptosis via the Modulation of Nrf2-xCT/GPx4 Axis. Front Cell Dev Biol. 2022;10:806081. doi:10.3389/fcell.2022.806081\u003c/li\u003e\n\u003cli\u003eKim WH, Lee CH, Han JH, et al. C/EBP homologous protein deficiency inhibits statin-induced myotoxicity. Biochem Biophys Res Commun. Jan 15 2019;508(3):857-863. doi:10.1016/j.bbrc.2018.11.166\u003c/li\u003e\n\u003cli\u003ePasha R, Moon TW. Coenzyme Q10 protects against statin-induced myotoxicity in zebrafish larvae (Danio rerio). Environ Toxicol Pharmacol. Jun 2017;52:150-160. doi:10.1016/j.etap.2017.03.021\u003c/li\u003e\n\u003cli\u003eLeung YH, Turgeon J, Michaud V. Study of Statin- and Loratadine-Induced Muscle Pain Mechanisms Using Human Skeletal Muscle Cells. Pharmaceutics. Oct 10 2017;9(4)doi:10.3390/pharmaceutics9040042 \u003c/li\u003e\n\u003cli\u003eSakaeda T, Tamon A, Kadoyama K, Okuno Y. Data mining of the public version of the FDA Adverse Event Reporting System. Int J Med Sci. 2013;10(7):796-803. doi:10.7150/ijms.6048\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1-4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"naunyn-schmiedebergs-archives-of-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nsap","sideBox":"Learn more about [Naunyn-Schmiedeberg's Archives of Pharmacology](https://www.springer.com/journal/210)","snPcode":"210","submissionUrl":"https://submission.nature.com/new-submission/210/3","title":"Naunyn-Schmiedeberg's Archives of Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Atorvastatin, Sarcopenia, NHANES, FAERS, Adverse Reaction","lastPublishedDoi":"10.21203/rs.3.rs-6960351/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6960351/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePost-marketing surveillance data suggest a potential link between atorvastatin use and sarcopenia. However, further large-scale observational studies are needed to confirm this preliminary finding.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThis study aims to comprehensively investigate the relationship between atorvastatin exposure and sarcopenia, with the goal of providing more accurate safety and efficacy profiles to guide its clinical use.\u003c/p\u003e\u003ch2\u003eMethds\u003c/h2\u003e \u003cp\u003eWe utilized two primary datasets: the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018 and the Food and Drug Administration Adverse Event Reporting System (FAERS) from 2004 to 2018. Using a multi-step analytical approach that included descriptive statistical analysis, multivariable logistic regression, and Receiver Operating Characteristic (ROC) curve analysis, we systematically assessed the relationship between atorvastatin exposure and the incidence of sarcopenia.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn the NHANES cohort analysis, after adjusting for demographic variables, lifestyle factors, and other confounders in the multivariable logistic regression model, atorvastatin use was significantly associated with an increased risk of sarcopenia (OR\u0026thinsp;=\u0026thinsp;2.21; 95% CI: 1.07\u0026ndash;4.55; p\u0026thinsp;=\u0026thinsp;0.032). An analysis of the FAERS database identified 13,625 adverse event reports related to atorvastatin, of which 5,370 specifically documented myasthenia-related events.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIndependent analyses from both population-based epidemiological surveys and pharmacovigilance systems consistently indicate that atorvastatin use may increase the risk of sarcopenia. Based on these findings, we recommend that healthcare providers implement comprehensive risk communication strategies before prescribing atorvastatin, with particular emphasis on the need for regular musculoskeletal assessments in patients undergoing long-term statin therapy.\u003c/p\u003e","manuscriptTitle":"Association Between Atorvastatin and Sarcopenia: A Study Based on NHANES and FAERS Databases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-02 09:42:39","doi":"10.21203/rs.3.rs-6960351/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-07-07T10:29:45+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-04T15:30:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"110619037454311174634913855637215351250","date":"2025-06-28T19:53:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"63322586430993794972807106215306352131","date":"2025-06-27T12:39:36+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-25T11:50:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-25T02:18:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-25T02:17:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"Naunyn-Schmiedeberg's Archives of Pharmacology","date":"2025-06-24T01:01:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"naunyn-schmiedebergs-archives-of-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nsap","sideBox":"Learn more about [Naunyn-Schmiedeberg's Archives of Pharmacology](https://www.springer.com/journal/210)","snPcode":"210","submissionUrl":"https://submission.nature.com/new-submission/210/3","title":"Naunyn-Schmiedeberg's Archives of Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"69e94b8f-a388-49f5-be15-e61f3a9647b8","owner":[],"postedDate":"July 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-13T15:59:53+00:00","versionOfRecord":{"articleIdentity":"rs-6960351","link":"https://doi.org/10.1007/s00210-025-04559-0","journal":{"identity":"naunyn-schmiedebergs-archives-of-pharmacology","isVorOnly":false,"title":"Naunyn-Schmiedeberg's Archives of Pharmacology"},"publishedOn":"2025-10-08 15:57:17","publishedOnDateReadable":"October 8th, 2025"},"versionCreatedAt":"2025-07-02 09:42:39","video":"","vorDoi":"10.1007/s00210-025-04559-0","vorDoiUrl":"https://doi.org/10.1007/s00210-025-04559-0","workflowStages":[]},"version":"v1","identity":"rs-6960351","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6960351","identity":"rs-6960351","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}