Targeting the cholinergic anti‐inflammatory pathway for type 2 diabetes prevention: A retrospective cohort study

Abstract Background Chronic inflammation is a key factor in type 2 diabetes mellitus (T2DM) development. The cholinergic anti‐inflammatory pathway (CAP) reduces inflammation by activating α7 nicotinic acetylcholine receptors (α7nAChRs) on macrophages, suppressing proinflammatory cytokines. Acetylcholinesterase inhibitors (AChEis), primarily used for Alzheimer's disease (AD), may exert anti‐inflammatory effects through the CAP. One AChEi, galantamine, also directly agonizes α7nAChRs, potentially enhancing its anti‐inflammatory properties. Objective This study aimed to investigate the association between AChEi use, particularly galantamine, and T2DM risk in AD patients. Methods We conducted a retrospective analysis of Veterans Health Administration (VA) data, examining early‐ and late‐onset AD patients receiving galantamine or other AD medications. Propensity score matching was used to balance groups and minimize confounding. Cox proportional hazard models assessed T2DM risk for galantamine, other AChEis and memantine. Results A total of 40 065 AD patients were included in the study. Among early‐onset AD patients, galantamine use significantly reduced T2DM risk (hazard ratio [HR] = 0.80, 95% confidence interval [CI]: 0.66–0.98). Memantine also showed a protective effect (HR = 0.82, 95% CI: 0.69–1) in this group. Neither galantamine nor memantine influenced T2DM risk in late‐onset AD. Other AD medications showed no association with T2DM risk. Conclusion Galantamine use was associated with a lower risk of T2DM in early‐onset AD patients, potentially due to enhanced anti‐inflammatory effects through both AChE inhibition and direct α7nAChR agonism. Memantine also demonstrated a protective effect. These findings suggest potential new applications for existing AD medications in T2DM prevention, particularly in early‐onset AD patients. Further research, including randomized controlled trials with diverse populations, is needed to confirm these results and the underlying mechanisms.