Does Metformin Increase Dementia Risk?

Metformin and Neurodegenerative Disease: An Unknown Link?
Epidemiological studies link T2D with increased risk for neurodegenerative diseases, like Alzheimer Disease (AD) and Parkinson Disease (PD). Research is conflicting about whether metformin contributes to the increased risk for neurodegenerative diseases in T2D. Some studies have linked metformin to decreased risk of dementia.¹ Others suggest increased risk of AD with long-term metformin.²

A Taiwanese Study Evaluated Risk for Dementia, PD with Metformin.³
A Retrospective cohort study used insurance claims data from Taiwan’s National Health Insurance Research Database.
. Included patients ≥50 years, recently diagnosed with T2D
. 4651 on metformin for at least 90 days
. 4651 never on metformin
Minimized bias with propensity score matching; adjusted for age, sex, comorbidities, diabetes complications, medications
12-year followup

PD and Dementia Risk Increased with Metformin
Parkinson disease: Significantly increased risk with metformin vs without
. Risk over twice as high (HR 2.27, 95% CI 1.68–3.07, p<0.001)
All-cause dementia: Significantly increased risk with metformin
. 66% increased risk (HR 1.66, 95% CI 1.35–2.04, p<0.001)
Alzheimer’s disease: Significantly increased risk with metformin
. Risk over twice as high (HR 2.13, 95% CI 1.20–3.79, p<0.01)
Vascular dementia: Significantly increased risk with metformin
. Risk over twice as high (HR 2.30, 95% CI 1.25–4.22, p<0.01)

Longer Duration, Higher Dose Linked to Higher PD Risk
Longer Metformin Duration: Significantly increased risk for PD with metformin vs without
. 180-299 days: 46% increased risk (HR 1.46, 95%CI 0.90–2.37, results NS)
. ≥400 days: 4.5 times increased risk (HR 4.49, 95%CI 3.06–6.58, p<0.001)
Higher Dose: Significantly increased risk for PD with metformin
. Average ≤ 130 g/yr: 58% increased risk (HR 1.58, 95%CI 1.02–2.44, p<0.05)
. Average >385 g/yr: 3.5 times increased risk (HR 3.54, 95% CI 2.41–5.20, p<0.001)

Longer Duration, Higher Dose Linked to Higher All-Cause Dementia Risk
Longer Metformin Duration: Significantly increased risk for all-cause dementia with metformin
. 180–299 days: 79% increased risk (HR 1.79, 95%CI 1.32–2.43, p<0.001)
. 400 days: Almost 3 times increased risk (HR 2.84, 95% CI 2.12–3.82, p<0.001)
Higher Dose: Significantly increased risk for all-cause dementia with metformin vs without
. Average ≤ 130 g/yr: 22% increased risk (HR 1.22, 95% CI = 0.90–1.67, results not significant)
. Average ≥ 385 g/yr: 97% increased risk (HR 1.97, 95% CI = 1.45–2.68, p<0.001)

Limitations
Retrospective cohort design may introduce bias. Claims data subject to coding errors, misdiagnosis. There was no data on lifestyle, dietary habits, family history, vitamin B12 levels, HbA1c, smoking, or alcohol. The study only included Taiwanese patients, so results may not generalize to more diverse populations.

Monitor for Vitamin B12 in Metformin Users?
Metformin exposure may increase risk for neurodegenerative disorders, including PD and dementia
Possible mechanism:
. Experimental evidence suggests metformin may increase beta amyloid^4,5
. Metformin has been linked to low vitamin B12 levels, which have been linked to neurodegenerative diseases and cognitive impairment^6,7
Patients on metformin may need regular monitoring of vitamin B12 levels, especially those on long-term or high-dose metformin
Prospective controlled studies are needed to confirm the results

Take Home Points
. Retrospective cohort study in Taiwan suggests metformin is associated with increased risk for PD, AD, dementia, and vascular dementia
. Longer term use and higher doses of metformin were associated with increased risk for PD and all-cause dementia
. Possible mechanisms include increased beta amyloid and decreased vitamin B12 levels with metformin; metformin users may need monitoring of vitamin B12 levels
. Prospective controlled studies are needed to confirm the results