The association between statin use and skeletal muscle-related side effects is always controversial. This study aimed to comprehensively investigate the associations between statin use and muscle-related phenotypes ).This cross-sectional study included 22,549 patients aged ≥20 years with cardiovascular disease, diabetes, or hyperlipidemia. Weighted generalized linear regression analysis and propensity score matching methods were used to estimate the associations between the use of statins or other lipid-lowering agents and skeletal muscle-related phenotypes. Mendelian randomization (MR) analysis was additionally used to verify the causal relationship between statin use and skeletal muscle-related phenotypes.The weighted mean age was 59 years, 50.3% were male, and 37.6% (n=8,481) received statin treatment. In the unadjusted model, compared with adults without any lipid-lowering drugs, statin use was associated with a higher likelihood of sarcopenia (appendicular skeletal muscle mass [ASM]/Body mass index [BMI] OR 1.35 (95%CI 1.12 to 1.62, p < 0.001) ASM/weight [Wt] OR 1.86 (95%CI 1.62 to 2.13, p < 0.001), max HGS β -3.01 (95% CI -3.97 to -2.06, p < 0.001), relative HGS β -0.23 (95% CI -0.30 to -0.17, p < 0.001) and combined HGS β -5.90 (95% CI -7.86 to -3.93, p < 0.001)), sarcopenic obesity and body fat percentage definition [OR 1.36 (95% CI 1.13 to 1.63, p < 0.001]). After multivariable adjustment or propensity score match, the independent associations of statin use with sarcopenia, sarcopenic obesity, HGS, LDH, and musculoskeletal pain became nonsignificant. Stepwise regression suggested that age was the predominant confounding factor for the associations. MR analysis also revealed no significant causality between statin use and skeletal muscle-related phenotypes. Our epidemiological and MR analyses found no causality between statin use and skeletal muscle-related phenotypes, suggesting age as a potential contributor to higher risk in statin users.Future studies should delve deeper into the biological factors influencing statin-related muscle phenotypes.

The authors have declared no competing interest.

SW was funded by the National Natural Science Foundation of China (82200396), Natural Science Foundation of Heilongjiang Province of China (YQ2022H006), New era Longjiang outstanding doctoral key project (LJYXL2022-013), Cultivation Project of Second Affiliated Hospital of Harbin Medical University (PYMS2023-3); YZ was funded by the Gout Etiology and Functional Food Research Innovation Team, the North Medicine and Functional Food Characteristic Subject Project in Heilongjiang Province (HLJTSXK-2022-03), Postdoctoral Science Foundation of Heilongjiang Province of China (LBH-Q21047), National Fund Cultivation Program of Jiamusi University (JMSUGPZR2022-022), Scientific and Technological Innovation Team of Jiamusi University (cxtd202101).

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