Statin uses and skeletal muscle-related phenotypes: insights from epidemiological and Mendelian randomization analyses

BackgroundThe 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 including sarcopenia, sarcopenic obesity, serum lactate dehydrogenase (LDH), and musculoskeletal pain symptoms among adults with indications for statin use for secondary prevention (cardiovascular disease, diabetes, or hyperlipidemia). MethodsThis cross-sectional study included 22,549 patients aged [&ge;]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. ResultsThe 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 {beta} -3.01 (95% CI -3.97 to -2.06, p < 0.001), relative HGS {beta} -0.23 (95% CI -0.30 to -0.17, p < 0.001) and combined HGS {beta} -5.90 (95% CI -7.86 to -3.93, p < 0.001)), sarcopenic obesity (ASM/height squared [Ht2] 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. ConclusionsOur epidemiological and MR analyses did not support the causality between statin use and skeletal muscle-related phenotypes. A higher likelihood of skeletal muscle-related adverse phenotypes in statin users may be attributed to age. Future studies should further explore the biological factors that may affect statin-related muscle phenotypes to provide evidence for the safety of statins.