DIABETES MEDICATIONS AND RISK OF DEMENTIA AND ALZHEIMER’S DISEASE: POOLED ANALYSIS FROM 5 COHORTS

Abstract

Type-2 diabetes drugs mechanisms of action may involve multiple pathologies common to diabetes and AD. Hence, specific drugs may reduce the risk or slow the progression of dementia through direct effects in the brain that are independent of their approved indications for treating hyperglycemia. Diabetes medications can also increase dementia risk through their tendency to cause hypoglycemic episodes. We combined data from 4 large population-based cohort studies to assess the relationships between diabetes medication classes and risk of dementia and AD. The study is based on data from the following cohorts: The Framingham Heart Study, the Rotterdam Study, the Atherosclerosis Risk in Communities Study, the Sacramento Area Latino Study on Aging and Age (SALSA), Gene/Environment Susceptibility (AGES)-Reykjavik Study. Diabetes drug classes included Metformin, Sulfonylurea, Insulin or other medications. Participants with dementia at baseline were excluded, and cox regression models were used to compare risk of dementia and AD between users of a specific class (single or in combination with drugs from other classes) vs. other classes. The reference groups firstly consisted of individuals with diabetes and subsequently was restricted to those who are taking diabetes medications. We adjusted for multiple potential confounders, including markers of disease severity (e.g. HbA1C, fasting blood glucose) to control for potential indication bias. Heterogeneity was assessed and HRs from each cohort were meta-analyzed. A total of 2,982 non-demented diabetic participants (ages at baseline range between 64±8y and 76±5y) were followed-up for 5.2–12.3 years. Tests for heterogeneity were non-significant therefore fixed effect models were primarily used. After adjustment for multiple covariates, Insulin was associated with an increased HR(95%CI)=1.55(1.12,2.15); p=0.009) and Sulfonylurea with decreased (HR(95%CI)=0.67(0.50,0.91); p=0.010) risk of dementia but not AD. The associations with Insulin remained significant after excluding participants with diabetes who do not take diabetes medications and when random effect models were used. Despite its advantages in controlling glycemic dysregulation and preventing complications, Insulin treatment may be associated with increased adverse cognitive outcomes possibly due to a greater risk of hypoglycemia. A protective effect of Sulfonylurea on the brain of individuals with diabetes may also have large public health consequences.