Diclofenac reduces the risk of Alzheimer's disease: a pilot analysis of NSAIDs in two US veteran populations

Background: Our aim was to determine whether specific nonsteroidal anti-inflammatory (NSAID) agents are associated with a decreased frequency of Alzheimer's disease (AD). Materials and methods: Days of drug exposure were determined for diclofenac, etodolac, and naproxen using US Department of Veterans Affairs (VA) pharmacy transaction records, combined from two separate VA sites. AD diagnosis was established by the International Classification of Diseases, ninth revision (ICD-9)/ICD-10 diagnostic codes and the use of AD medications. Cox regression survival analysis was used to evaluate the association between AD frequency and NSAID exposure over time. Age at the end of the study and the medication-based disease burden index (a comorbidity index) were used as covariates. Results: Frequency of AD was significantly lower in the diclofenac group (4/1431, 0.28%) compared with etodolac (328/14,646, 2.24%), and naproxen (202/12,203, 1.66%). For regression analyses, naproxen was chosen as the comparator drug, since it has been shown to have no effect on the development of AD. Compared with naproxen, etodolac had no effect on the development of AD, hazard ratio (HR) 1.00 [95% confidence interval (CI): 0.84-1.20,p = 0.95]. In contrast, diclofenac had a significantly lower HR of AD compared with naproxen, HR 0.25 (95% CI: 0.09-0.68,p <0.01). After site effects were controlled for, age at end of the study (HR = 1.08, 95% CI: 1.07-1.09,p <0.001) was also found to influence the development of AD, and the medication-based disease burden index was a strong predictor for AD, HR 5.17 (95% CI: 4.60-5.81) indicating that as comorbidities increase, the risk for AD increases very significantly. Conclusion: Diclofenac, which has been shown to have active transport into the central nervous system, and which has been shown to lower amyloid beta and interleukin 1 beta, is associated with a significantly lower frequency of AD compared with etodolac and naproxen. These results are compelling, and parallel animal studies of the closely related fenamate NSAID drug class.