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Metformin

  • Drugs
  • Updated April 28, 2022

Metformin is a prescription drug used to treat type 2 diabetes, alone, or in combination with other drugs. In diabetics, it can help to control blood sugar and insulin sensitivity. Type 2 diabetes is a risk factor for Alzheimer’s disease, and insulin sensitivity may be altered in Alzheimer’s patients. Some studies suggest metformin treatment is associated with decreased risk of Alzheimer’s disease in people with type 2 diabetes, but results are mixed and inconsistent. No clinical trials have confirmed whether metformin is beneficial for cognitive health in people without diabetes. And long-term metformin use may decrease blood levels of vitamin B12, so levels should be monitored by a physician.

Evidence

In people with type 2 diabetes, metformin treatment has been associated with decreased dementia risk, but results have been inconsistent and depended on many factors. Our search identified:

  • 5 meta-analyses of observational studies examining the associations between metformin treatment and risk of dementia or cognitive impairment
  • 2 small clinical studies in patients with mild cognitive impairment or mild Alzheimer’s diseas
  • 1 clinical trial in patients with abnormal glucose metabolism and vascular cognitive impairment
  • 1 clinical trial in people with depression and type 2 diabete
  • 6 observational studies for future Alzheimer’s risk in patients with type 2 diabetes
  • Numerous review articles
  • Numerous preclinical studies

Potential Benefit

There have been numerous observational studies on metformin treatment in people with type 2 diabetes, but results have been inconsistent. In several recent meta-analyses of numerous studies enrolling people with type 2 diabetes, metformin treatment was associated with reduced risks of neurodegenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease, and others) [1] and cognitive dysfunction [2] compared to those not taking metformin, and risk reduction was more prominent in people taking metformin long-term (over 4 years) [1]. A different meta-analysis enrolling people with or without diabetes reported that there was no relationship between metformin treatment and cognitive performance, or protection against Alzheimer’s disease, vascular dementia, or cognitive impairment [3]. Three individual studies, however, reported an increased risk for impaired cognitive performance, dementia, or Alzheimer’s disease with metformin treatment compared to those taking other medications [4; 5; 6].

In a small randomized controlled trial of patients with depression and type 2 diabetes, metformin treatment for 24 weeks improved cognitive performance and symptoms of depression [7].

Several factors could account for the varying results, such as duration and severity of diabetes, or how well diabetes is controlled [8]. Also, metformin is often used to treat mild diabetes, so patients taking other anti-diabetic drugs may have more severe diabetes, which may be associated with worse brain health. Additionally, long-term metformin use can decrease vitamin B12 levels, which may be a potential risk factor for Alzheimer’s disease. One study reported that when controlling for vitamin B12 levels, metformin was no longer significantly associated with risk of Alzheimer’s disease [6; 9].

It is currently unknown whether metformin is protective against cognitive decline or Alzheimer’s disease in people without type 2 diabetes. For people who have type 2 diabetes, keeping it under control is important for reducing your risk for Alzheimer’s disease, whether with metformin or another intervention. If you are taking metformin, you should speak to your doctor about monitoring your vitamin B12 levels.

APOE4 Carriers:

In an observational study of 1,192 people with normal cognition and 807 people with Alzheimer’s disease from the National Alzheimer’s Coordinating Center database, the relationships between metformin treatment and cognitive outcomes were different between APOE4 carriers and non-carriers [10]. Among cognitively healthy APOE4 non-carriers, metformin treatment was associated with better memory over time, but this association was not observed among APOE4 carriers. But for people with Alzheimer’s disease, metformin use was associated with a faster rate of memory decline in APOE4 carriers, but not non-carriers. It is not known why these differences are observed between APOE4 carriers and non-carriers. Because this study was an observational one, it was not designed to prove cause and effect. For more information on what the APOE4 gene allele means for your health, read our APOE4 information page.

For Dementia Patients

In two clinical studies in non-diabetic patients with mild cognitive impairment or mild Alzheimer’s disease, metformin treatment improved some aspects of cognition, but not others. There were no effects on biological markers of Alzheimer’s disease [11; 12]. However, both studies were likely too small and short to show a clinical benefit. In a clinical trial of patients with abnormal glucose metabolism and vascular cognitive impairment (but without dementia), adding metformin to their treatment regimen for one year improved several measures of cognitive function compared to the comparator group (receiving a different antidiabetic drug as an add-on) [13].

Safety

The most common side effect metformin users experience is gastrointestinal discomfort—which can lead to weight loss—but this discomfort may decrease over time [14]. Some evidence suggests that metformin may decrease levels of vitamin B12, thus increasing the risk of nerve problems [15]. Additionally, some reports suggest that metformin may increase the risk of lactic acidosis, a buildup of lactate which can decrease the blood’s pH [16]. Metformin has, however, been available for many decades and has a good safety profile. It does have many drug interactions that should be discussed with your doctor before use.

NOTE: This is not a comprehensive safety evaluation or complete list of potentially harmful drug interactions. It is important to discuss safety issues with your physician before taking any new supplement or medication.

How to Use

Metformin (sold as Glucophage or Glucophage XR – extended release) is available by prescription. For diabetes patients, it is usually started at 500 mg twice per day and increased up to 2000 mg per day in divided doses.

Learn More

More information on side effects and drug interactions is available on Drugs.com.

Full scientific report (PDF) on Cognitive Vitality Reports

References

  1. Zhang Y, Zhang Y, Shi X et al. (2022) Metformin and the risk of neurodegenerative diseases in patients with diabetes: A meta-analysis of population-based cohort studies. Diabetic medicine : a journal of the British Diabetic Association, e14821.
  2. Zhang QQ, Li WS, Liu Z et al. (2020) Metformin therapy and cognitive dysfunction in patients with type 2 diabetes: A meta-analysis and systematic review. Medicine 99, e19378.
  3. Tabatabaei Malazy O, Bandarian F, Qorbani M et al. (2022) The effect of metformin on cognitive function: A systematic review and meta-analysis. Journal of psychopharmacology, 2698811211057304.
  4. Imfeld P, Bodmer M, Jick SS et al. (2012) Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: a population-based case-control study. Journal of the American Geriatrics Society 60, 916-921.
  5. Kuan YC, Huang KW, Lin CL et al. (2017) Effects of metformin exposure on neurodegenerative diseases in elderly patients with type 2 diabetes mellitus. Progress in neuro-psychopharmacology & biological psychiatry 79, 77-83.
  6. Moore EM, Mander AG, Ames D et al. (2013) Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care 36, 2981-2987.
  7. Guo M, Mi J, Jiang QM et al. (2014) Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus. Clinical and experimental pharmacology & physiology 41, 650-656.
  8. Goodarzi MO (2014) Comment on Moore et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes care 2013; 36:2981-2987. Diabetes Care 37, e150.
  9. Moore EM, Mander AG, Ames D et al. (2014) Response to comment on Moore et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes care 2013; 36:2981-2987. Diabetes Care 37, e151.
  10. Wu CY, Ouk M, Wong YY et al. (2020) Relationships between memory decline and the use of metformin or DPP4 inhibitors in people with type 2 diabetes with normal cognition or Alzheimer's disease, and the role APOE carrier status. Alzheimer's & dementia : the journal of the Alzheimer's Association 16, 1663-1673.
  11. Koenig AM, Mechanic-Hamilton D, Xie SX et al. (2017) Effects of the Insulin Sensitizer Metformin in Alzheimer Disease: Pilot Data From a Randomized Placebo-controlled Crossover Study. Alzheimer disease and associated disorders 31, 107-113.
  12. Luchsinger JA, Perez T, Chang H et al. (2016) Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. Journal of Alzheimer's disease : JAD 51, 501-514.
  13. Lin Y, Wang K, Ma C et al. (2018) Evaluation of Metformin on Cognitive Improvement in Patients With Non-dementia Vascular Cognitive Impairment and Abnormal Glucose Metabolism. Frontiers in aging neuroscience 10, 227.
  14. Diabetes Prevention Program Research G (2012) Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care 35, 731-737.
  15. Aroda VR, Edelstein SL, Goldberg RB et al. (2016) Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. The Journal of clinical endocrinology and metabolism 101, 1754-1761.
  16. Huang W, Castelino RL, Peterson GM (2017) Lactate Levels with Chronic Metformin Use: A Narrative Review. Clinical drug investigation 37, 991-1007.