Moderate Increase in Dementia Risk Linked to Tiotropium Use in Older COPD Patients: JAMA

A recent population-based study published in the Journal of American Medical Association identified a modest increase in dementia risk associated with the use of the inhaled bronchodilator tiotropium in older adults with chronic obstructive pulmonary disease (COPD). These findings raise questions about possible central nervous system effects of long-acting muscarinic antagonists (LAMAs), experts emphasize that the clinical impact remains minimal when balanced against the drug's respiratory benefits.

This study examined whether initiating tiotropium is associated with a higher risk of developing dementia when compared to initiating a combination therapy of long-acting β2-agonists and inhaled corticosteroids (LABA-ICS).

Using health records from Ontario, Canada, this research followed 50,490 patients aged 66 and older who began treatment between 2004 and 2012. All participants were newly prescribed either tiotropium monotherapy (30,960 patients) or LABA-ICS therapy (19,530 patients) and had no prior diagnosis of dementia. The patients were monitored for up to 10 years, with a median follow-up time of approximately 7.6 years.

The primary analysis used an “intention-to-treat” approach where the participants were analyzed based on their initial treatment group regardless of any later changes. During the study, 29.6 cases of dementia occurred per 1,000 person-years among tiotropium users, compared to 27.4 per 1,000 person-years among those using LABA-ICS. This resulted in a weighted incidence rate difference (IRD) of 2.3 additional cases per 1,000 person-years. The adjusted hazard ratio (HR) was 1.09, indicating a 9% relative increase in risk among tiotropium users, though still considered a small absolute difference.

A secondary “as-treated” analysis, which considered treatment changes over time, showed no statistically significant difference in dementia rates. In this analysis, the dementia incidence was 24.1 vs 21.4 cases per 1,000 person-years for tiotropium and LABA-ICS users, respectively, with an HR of 1.11. However, the confidence interval crossed unity (0.93–1.32), which suggested this result could be due to chance.

The strength of this study lies in its use of real-world data and a robust target trial emulation framework, which minimizes confounding by closely mimicking a randomized controlled trial. The research also applied a one-year lag in dementia diagnosis to reduce the potential for reverse causation and allow for disease latency.

Overall, the increase in dementia risk was small, and tiotropium remains a cornerstone in COPD management due to its well-documented benefits in reducing exacerbations and improving lung function. Further research is encouraged to explore whether cumulative anticholinergic burden plays a broader role in cognitive decline among older adults.

Source:

Wu, C.-Y., Kendzerska, T., Wang, C., Xiong, L. Y., Edwards, J. D., Liu, P. P., Saskin, R., & Swardfager, W. (2025). Tiotropium initiation and dementia risk in chronic obstructive pulmonary disease. JAMA Internal Medicine. https://doi.org/10.1001/jamainternmed.2025.1251