Duration of Current Statin Use and Amyotrophic Lateral Sclerosis Risk: A Norwegian Population-Based Cohort Study

Although hypercholesterolemia may contribute to long-term amyotrophic lateral sclerosis (ALS) risk, it can also seem as a secondary effect during the early, prediagnostic phase of the disease. We aimed to investigate the relationship between short-term and long-term use of statins and subsequent ALS risk.

We designed a cohort study where information on cardiovascular risk factors among Norwegian participants in large population-based health surveys was linked to nationwide administrative data on subsequent statin use and ALS diagnosis. Duration of statin use was calculated based on cumulative defined daily doses and analyzed as time-varying exposure with 3 levels: 0-1 year (short-term), 1-5 years, and 5-17 years (long-term). In Cox regression models adjusted for sex, age, health survey participation, triglyceride and cholesterol levels, body mass index, smoking, diabetes, and hypertension, we calculated hazard ratios (HRs) for ALS according to time-varying statin exposure. In a negative control analysis, we examined whether exposure to renin-angiotensin system (RAS)-acting agents was associated with ALS risk.

A total of 425,564 participants (54% women), aged 40-65 years in January 2005, were followed for a mean period of 16 years (SD 2.3) during which 493 ALS cases (44% women) were identified. Compared with no current statin use, the HR for ALS was 3.56 (95% CI 2.58-4.90) for those with 0-1 year, 0.85 (95% CI 0.59-1.23) for those with 1-5 years, and 0.67 (95% CI 0.45-1.00) for those with 5-17 years of current use. The associations between both short-term and long-term statin use and ALS risk were most evident in men, with HRs for ALS of 4.03 (95% CI 2.72-5.95) and 0.47 (95% CI 0.26-0.86), respectively. There was no clear association between either short-term or long-term use of RAS-acting agents and ALS risk.

The strong association between short-term current statin use and increased ALS risk is consistent with reverse causality, where statin initiation in the prediagnostic phase may occur when lipid levels rise and individuals seek medical attention due to emerging ALS symptoms. Long-term statin use was associated with reduced risk of ALS in men.