Statin use and risk of amyotrophic lateral sclerosis: An active-comparator, new-user cohort study

ImportanceElevated circulating low-density lipoprotein (LDL) cholesterol is associated with an increased risk of amyotrophic lateral sclerosis (ALS) onset. Previous studies have explored the relationship between statin use and ALS onset. However, findings have been inconsistent, potentially due to methodological limitations, such as confounding by indication, and failure to account for baseline differences in LDL cholesterol levels. ObjectiveTo compare the risk of ALS onset between new users of statins and ezetimibe among patients with hypercholesterolemia. DesignActive-comparator, new-user cohort study using inverse probability of treatment-weighted Cox proportional hazards models. The study period spanned April 2012 to February 2024. SettingTwo administrative claims databases in Japan. ParticipantsPatients with hypercholesterolemia who newly initiated statins or ezetimibe, and patients with dyslipidemia who newly initiated fibrates. All participants were required to have at least 365 days of baseline observation and no prior diagnosis of ALS. Exposure(s)Statin use compared with ezetimibe use. Fibrate use was assessed for benchmarking. Main Outcome(s) and Measure(s)The outcome was incident ALS, defined as a first definitive diagnosis of ALS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to compare ALS risk between statins and ezetimibe. ResultsThe study included 607,292 statin users (median [IQR] age, 61 [51-71] years; 51.4% male), 26,963 ezetimibe users (median [IQR] age, 59 [49-71] years; 50.1% male), and 114,871 fibrate users (median [IQR] age, 61 [51-71] years; 51.4% male). The incidence rate per 100,000 person-years of ALS was 6.8, 15.9, and 4.3, respectively. Statin use was associated with a lower hazard of ALS onset than ezetimibe use (adjusted HR [95% CI]: 0.42 [0.19-0.92]). The mean (SD) LDL cholesterol immediately prior to treatment initiation was 171.0 (28.6) mg/dL in the statin group and 162.8 (30.8) mg/dL in the ezetimibe group. After treatment, mean LDL cholesterol levels decreased to and stayed below 140 mg/dL in both groups. Conclusions and RelevanceThis study suggests that statins may lower the risk of ALS onset among patients with hypercholesterolemia. The mechanism underlying this association is not yet clear and may involve pathways beyond circulating LDL cholesterol reduction. Key pointsO_ST_ABSQuestionC_ST_ABSDoes statin use lower the risk of amyotrophic lateral sclerosis (ALS) onset among patients with hypercholesterolemia? FindingsIn this active-comparator, new-user cohort study of 607,292 statin users and 26,963 ezetimibe users with hypercholesterolemia, statin use was associated with a lower hazard of ALS onset compared with ezetimibe use. Prior to treatment initiation, mean LDL cholesterol levels were similar between statin and ezetimibe users. MeaningThese findings suggest that statins may lower the risk of ALS among patients with hypercholesterolemia.