Statin Initiation and Risk of Amyotrophic Lateral Sclerosis

Abstract

Background:The evidence of an association between statins and amyotrophic lateral sclerosis (ALS) is heterogeneous and inconclusive. Methods: We performed a population-based cohort study consisting of 974,304 statin initiators ≥40 years of age and 1,948,606 matched general population comparators identified from Danish, nationwide registries . We computed incidence rates and hazard ratios (HRs) of a first-time hospital-based diagnosis of ALS. HRs were controlled for sex, birth year, calendar year, medically diagnosed comorbidities, and concomitant medications. Results: During a median follow-up of 7.7 years, 852 ALS events occurred among statin initiators (11.3 [95% confidence interval (CI) = 10.6, 12.1] events per 100,000 person-years) and 1,679 among noninitiators (11.4 [95% CI = 10.9, 12.0] events per 100,000 person years). The overall adjusted HR indicated a slight association between statin initiation and ALS (1.11 [95% CI = 1.00, 1.23]. In the first year after initiation, the HR was 1.40 (95% CI = 1.09, 1.79) for both sexes combined, 1.00 (95% CI = 0.70, 1.42) for men, and 1.92 (95% CI = 1.30, 2.82) for women. The associations diminished to approximately null after the first year of follow-up for both sexes combined and for men, but point estimates were above 1 for women until 10 years after initiation. Conclusions: Statin initiation was largely unassociated with ALS diagnosis but was associated with an elevated risk of ALS in women, especially in the first year after initiation. The association could be explained by reverse causation, detection bias, early neurotoxic effects of statins that affect women more than men, or a combination thereof.

Medication use and risk of amyotrophic lateral sclerosis—a systematic review

“…An inverse association of cholesterol lowering drugs with ALS risk was found in four studies [8][9][10][11], while a null or marginal association was observed in four [7,12,13,22]. The marginal association was likely due to the higher risk of ALS during the first year after statin use [13].…”

“…An inverse association of cholesterol lowering drugs with ALS risk was found in four studies [8][9][10][11], while a null or marginal association was observed in four [7,12,13,22]. The marginal association was likely due to the higher risk of ALS during the first year after statin use [13]. The differing results between studies might be attributable to diverse study designs, sample sizes, variable adjustments, or biological difference between populations.…”

“…Eight studies have explored the associations of cholesterol lowering drugs with the subsequent risk of ALS [7][8][9][10][11][12][13]22], among which seven studies focused on statins [7,[9][10][11][12][13]22] while one focused on a collection of cholesterol lowering drugs [8]. Four studies demonstrated a protective role of cholesterol lowering drugs in ALS development [8][9][10][11], while another four reported a lack of or near-null association between statins and risk of ALS [7,12,13,22].…”

“…In contrast, four studies showed a null or near-null association between statin use and risk of ALS, including a Danish population-based case-control study with 556 cases and 5560 controls [7], a Swedish nested casecontrol study with 2475 cases and 12,375 controls [12], and a German case-control study with 200 cases and 197 controls [22], demonstrating a null association; and a Danish population-based cohort study including 974,304 individuals with statin use and 1,948,606 individuals without statin use [13], showing a weak association between statin use and ALS risk.…”

Type 2 diabetes, obesity, and risk of amyotrophic lateral sclerosis: A population‐based cohort study

“…Smoking is associated with an increased risk of diabetes (Haire‐Joshu et al., 1999) and may also increase ALS risk (de Jong et al., 2012). We have previously shown that statins (primary and secondary therapeutic for patients with arterial cardiovascular disease) may increase ALS risk, especially in women (Skajaa et al., 2021). Thus, based on hospital‐based discharge diagnoses registered before the index date in the DNPR, we obtained information on chronic obstructive pulmonary disease (as an indicator of sustained smoking), myocardial infarction, stroke, hypercholesteremia, hypertension, atrial fibrillation, heart failure, cancer, and chronic kidney disease.…”