Spotlight on diabetes, drugs, and dementia

Two recent studies looked at associations between medications prescribed to diabetes patients and development of dementia.

The first study, published by Diabetes Care on Dec. 4, was a follow-up to the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes trial, which included 2,536 patients with type 2 diabetes. From 2002 to 2017, they were randomly allocated to receive low-dose aspirin (81 mg or 100 mg/d) or no aspirin, and 84% retained their original allocation. During a median follow-up of 11.4 years, 128 patients developed dementia. Overall, low-dose aspirin use was not significantly associated with any change in dementia risk (hazard ratio [HR], 0.82; 95% CI, 0.58 to 1.16). However, in women, aspirin was associated with a significant reduction in dementia risk (HR, 0.58; 95% CI, 0.36 to 0.95); this was notably not true in men (HR 0.82; 95% CI, 0.75 to 2.13).

Previous observational research has found reduced risk of dementia with aspirin use, the study authors said. However, they believe this study to be the first to prospectively evaluate the question using real-world data, with the additional benefit of longer follow-up than other studies. They noted that the effects of aspirin on cardiovascular disease have been found to vary by sex, and although the causes of these sex differences are unknown, they might be related to genotypes or anti-inflammatory effects. Limitations of the study include that older men and women are cared for differently in Japan (e.g., home care is more common for men and women are more often admitted to nursing homes) and that dementia was not a prespecified outcome of the original trial, so the sample size was limited. “These findings should be further validated by studies with larger sample sizes and longer follow-up periods including genetic and sociocultural evaluation of the participants,” the authors concluded.

The other study, published by the Journal of Clinical Endocrinology & Metabolism on Nov. 28, looked for associations between metformin use and the development of Alzheimer's disease (AD). It included all community-dwelling Finnish people who were diagnosed with AD between 2005 and 2011 and had been diagnosed with diabetes at least three years earlier (n=9,862). They were matched with one or two controls without AD by age, sex, and diabetes duration (n=19,550). About three-quarters of both groups had received metformin at least once. Having ever used metformin was not associated with any change in risk for AD (adjusted odds ratio [aOR], 0.99; 95% CI, 0.94 to 1.05). However, risk of AD was lower among patients who had taken metformin for 10 years or more (aOR, 0.85; 95% CI, 0.76 to 0.95), taken at least 1,825 cumulative defined daily doses (aOR, 0.91 [95% CI, 0.84 to 0.98] for 1,825 to 3,650 doses and 0.77 [95% CI, 0.67 to 0.88] for >3,650 doses), or taken an average of at least 2 g/d (aOR, 0.89; 95% CI, 0.82 to 0.96).

The results should be reassuring to clinicians and patients, given that previous studies had found positive associations between metformin and AD, the study authors said. This study's requirement of a three-year lag between metformin initiation and AD diagnosis may explain the differing results, according to the authors. “Prodromal symptoms of AD lead to increased contact with healthcare personnel and screening for alternative causes of cognitive impairment such as changes in blood glucose levels, thus increasing the likelihood of metformin initiation,” they explained. The observed beneficial associations with long-term or high-dose metformin might be explained by reductions in macrovascular complications, reduced inflammation, or enhanced neuronal survival, the authors said. However, the findings should be interpreted cautiously and confirmed by population-based research with data on renal function and glycemic control, the authors recommended.