Objectives: PPARγ activating drugs show various salutary effects in preclinical models of neurodegenerative disease. The decade-long clinical usage of these drugs as antidiabetics now allow for evaluation of patient-oriented data sources.

Methods: Using observational data from 2004-2010, we analyzed the association of pioglitazone and incidence of dementia in a prospective cohort study of 145,928 subjects aged 60 years or above who, at baseline, were free of dementia and insulin-dependent diabetes mellitus. We distinguished between non-diabetics, diabetics without pioglitazone, diabetics with prescriptions of less than eight calendar quarters of pioglitazone and diabetics with eight and more quarters. Cox proportional hazard models explored the relative risk of dementia incidence dependent on pioglitazone use adjusted for sex, age, use of rosiglitazone or metformin and cardiovascular comorbidities.

Results: Long-term use of pioglitazone was associated with a lower dementia incidence. Relative to non-diabetics, the cumulative long-term use of pioglitazone reduced the dementia risk by 47% (RR=0.53, p=0.029). If diabetes patients used pioglitazone less than eight quarters, the dementia risk was comparable to those of non-diabetics (RR=1.16, p=0.317), and diabetes patients without a pioglitazone treatment had a 23% increase in dementia risk (RR=1.23, p<0.001). We did not find evidence for age effects, nor for selection into pioglitazone treatment due to obesity.

Interpretation: These findings indicate that pioglitazone treatment is associated which a reduced dementia risk in initially non-insulin dependent diabetes mellitus patients. Prospective clinical trials are needed to evaluate a possible neuroprotective effect in these patients in an ageing population.

First published May, 2015