Effectiveness of Aspirin as Dementia Prophylaxis in Patients with Type 2 Diabetes 

Multiple risk factors put patients with T2DM at a high risk of developing dementia; is there evidence for effectiveness of aspirin as dementia prophylaxis?

Rates of dementia are steadily climbing, with estimates as high as 152 million by the year 2050. As a result, the total international cost for managing patients with dementia is also rising. With type 2 diabetes being a risk factor for dementia, especially vascular dementia, researchers have begun to work with diabetes patients to discover a means of preventing debilitating disease. This follow-up cohort study serves to compare and evaluate the efficacy of low-dose aspirin when used long-term as the prevention of dementia for both females and males.  

Over a series of years from 2002 to 2017, the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial was ongoing. The long-term randomized control trial enrolled 2,536 Japanese patients, all of whom were diagnosed with type 2 diabetes mellitus. The occurrence of dementia was the primary outcome of this retrospective analysis which was established as admission or prescription for dementia. The patients of the trial were monitored for fatal cardiovascular events until July 2017. To be included in the original trial, patients must have been between 30 to 85 years of age, capable of giving informed consent and diagnosed with type-2 diabetes. Any history of prior cardiovascular disease including antiplatelet or antithrombotic treatment or cerebrovascular disease were excluded from the follow-up study. During the open-label, controlled standard care study, patients were evenly divided to randomly receive either 81 mg to 100 mg of aspirin daily or none at all. Concurrent therapies were allowed in all subjects. 

Statistical analysis was presented as standard deviation and means for continuous variables and categorical variables. Wilcoxon rank–sum test or T-test was used for continuous variables while x2 tests were utilized for numeric and percentage categorical variables. This allowed for the characteristic comparisons amongst the two groups at baseline. The differences in the incidence of dementia were assessed by employing long-rank tests. Hazard ratio calculations involved Cox proportional models with a 95% confidence interval for low-dose aspirin efficaciously decreasing dementia incidence. The JPAD2 study observed body mass index, dyslipidemia, hemoglobin A1C, hypertension, and smoking status. To be considered statistically significant, two-tailed p-values must have been less than 0.05. 

With adjustments for age, sex, and other risk factors, the association between the risk of dementia and low dose aspirin was insignificant (HR 0.82, 95% CI 0.58-1.16). Among the variables, age showed a significant association with an increased risk of developing dementia. Within 11 years, dementia developed in 128 patients; however, there was no statistical difference in those who received low-dose aspirin and for those who did not according to the JPAD2 study. In comparison to men, women were more likely to develop dementia (P<0.001). However, the incidence was decreased in women who received aspirin as opposed to those who did not within the other group.  This effect was not found to be statistically significant in the men receiving low-dose aspirin (HR 1.12, 95% CI 0.62-2.02). 

Cardiovascular disease and dementia share multiple pathophysiological risk factors. Variations of trials implicating aspirin as a preventive measure for these complications have been evaluated. Upon review, the findings are inconsistent, and the reason is unclear. The efficacy of aspirin can be influenced by several factors such as age, kidney function, and obesity. Previous studies reported improved cognitive function in women using aspirin, but a mechanism explaining the different responses amongst males and females had yet to be established. Studies have shown NSAID users, especially women, with the ApoE E4 allele have a significantly lower risk of developing Alzheimer’s disease than nonusers.  

Further studies comprising of genetic testing and evaluation of variations in inflammation cytokines between the sexes may assist in supporting the findings of this study. Considering dementia can be influenced by sociocultural and socioeconomic factors, future studies could account for education level, occupation as well as the setting in which the subject is cared for. This study did not utilize diagnostic imaging or a test for cognitive function when defining dementia which may limit the results to those with moderate to severe dementia.  

Practice Pearls: 

• Type 2 diabetes is a worldwide burden and risk factor for declining cognitive function, making the need for dementia prevention pertinent. 
• Socioeconomic and sociocultural factors need to be taking into consideration when evaluating the efficacy of preventing dementia and treating type 2 diabetes. 
• Women with T2DM may benefit from long-term use of low-dose aspirin as a means to decrease the incidence of dementia. 

Reference for “Effectiveness of Aspirin as Dementia Prophylaxis in Patients with Type 2 Diabetes”:
Matsumoto, Chisa, et al. “Sex Difference in Effects of Low-Dose Aspirin on Prevention of Dementia in Patients With Type 2 Diabetes: A Long-Term Follow-up Study of a Randomized Clinical Trial.” Diabetes Care, vol. 43, no. 2, Feb. 2020, pp. 314 LP – 320, doi:10.2337/dc19-1188. 

Mia Flowers, PharmD. Candidate of Florida Agricultural & Mechanical University School of Pharmacy

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