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Does Metformin Increase Dementia Risk?

Does Metformin Increase Dementia Risk?

  • Here is evidence that metformin, especially at high doses and for long periods, is associated with increased risk for neurodegenerative diseases and dementia.
  • Metformin and Neurodegenerative Disease: An Unknown Link?
    O Epidemiological studies link T2D with increased risk for neurodegenerative diseases, like Alzheimer Disease (AD) and Parkinson Disease (PD)
    O 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]

  • Taiwanese Study Evaluated Risk for Dementia, PD with Metformin[3]
    O 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
    O Minimized bias with propensity score matching; adjusted for age, sex, comorbidities, diabetes complications, medications
    O 12-year followup

  • PD and Dementia Risk Increased with Metformin
    0 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)
    0  All-cause dementia: Significantly increased risk with metformin
    . 66% increased risk (HR 1.66, 95% CI 1.35–2.04, p<0.001)
    0 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)
    0 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
    0 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)
    0 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
    0 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)
    0 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
    . No data on lifestyle, dietary habits, family history, vitamin B12 levels, HbA1c, smoking, alcohol
    . Only included Taiwanese patients, results may not generalize to more diverse populations

  • Monitor for Vitamin B12 in Metformin Users?
    0 Metformin exposure may increase risk for neurodegenerative disorders, including PD and dementia
    0 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]
    0 Patients on metformin may need regular monitoring of vitamin B12 levels, especially those on long-term or high-dose metformin
    0 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

Comments

This is great to know. My mom was recently dx with moderate dementia and she is on (in my opinion) a high dose of metformin. I know that she takes B12 but now I will do a better job of making sure she is taking it.

Alva @

This is great to know. My mom was recently dx with moderate dementia and she is on (in my opinion) a high dose of metformin. I know that she takes B12 but now I will do a better job of making sure she is taking it.

Alva @

I am signed into the site which welcomes me by name, but unable to get the slides to change either by arrow or double clicking on the slides below. Most frustrating.
John Kelly, MD, MPH

John @

Interesting doubt.
The remark that patients on Metformin should have Vit BV12 checked is very positive, again differentiating a cause-effect connection and an 'innocent watcher' is difficult.

I'd point Thyroid function, Folates and B12 should be checked whenever a high MCHC is seen.

When Folate supplements are given, for example, as enhancers of anti-cancer drugs, B12 is to be added, better parenteral, also in any patient with gastric surgery.

Did you know that in Europe, even if registered in France, Italy, Germany, Sustained Release or Modified Release Metformin, being more efficacious and having less side effects, is available only in the UK?
Why?

Jose @

Kudos for the above.

Assuming you suggest B12 "parenteral", meaning IV?

Would consider B12 sublingual instead? With same results?

Thank you for your answer.

Sandy @

Since Type 2 Diabetes poses an even larger and proven risk and causal relationship with neurodegenerative diseases and dementia, then the risks of Metformin are mitigated by the enormous benefit to treatment. Further, Metformin may also reduce the damage that occurs from a stroke.

In any case, the risk for Metformin for dementia is greatly reduced or eliminated completely if it is coupled with other treatments for Type 2 Diabetes. This includes:
1) improving nutrition - suboptimal nutrition increases the risk of diabetes 600%.
2) exercise
3) Pioglitazone
4) supplements including Vitamin D, Cinnamon, etc.
5) optimizing thyroid hormone
6) testosterone supplementation in men - reduces insulin resistance

I would also avoid the use of Statins since they reduce cholesterol production in the brain. Cholesterol is the primary signal for memory. Cholesterol is half of the dry weight of the brain. Cholesterol is the primary component of myelin. Statins increase insulin resistance and contribute to diabetes.

Romeo @

7/16/2017 - The slideshow does not seem to advance....even when I click on the 4 frames below the title slide and intro paragraph. No captions show. Thanks for checking.

Joni @

I have the same problem.

herbert @

Lack of B12 is the real issue

Marye @

This appears to be a 2012 study

Norine @

To Norine

The main citation for this piece is from 2017: Kuan YC, Huang KW, Lin CL, et al. Effects of metformin exposure on neurodegenerative diseases in elderly patients with type 2 diabetes mellitus. Prog Neuropsychopharmacol Biol Psych. 2017; Jun 2. pii: S0278-5846(17)30287-7. doi: 10.1016/j.pnpbp.2017.06.002. https://www.ncbi.nlm.nih.gov/pubmed/28583443

Thank you,
The Editors

PsychTimes @

where is the article. was it pulled out????

Mel @

The article is a slideshow with captions.
Thank you,
The Editors

PsychTimes @

Hi, this article has disappeared.

Megan @

The article is a slideshow with captions.
Thank you,
The Editors

PsychTimes @

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