Therapeutics

Metformin

Overview

Name: Metformin
Synonyms: Glucophage, Glucophage XR
Chemical Name: N,N-Dimethylimidodicarbonimidic diamide
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2/3)
Approved for: Type 2 Diabetes

Background

Metformin is a prescription drug widely used to treat Type 2 diabetes. It lowers blood glucose and restores insulin sensitivity. Type 2 diabetes is a risk factor for dementia, and insulin sensitivity may be altered in Alzheimer's patients.

Metformin has been reported to reduce inflammation and oxidative stress, and to promote neurogenesis. Its ability to stimulate AMP-activated protein kinase (AMPK) has been linked to anti-aging activity in animal models, but also to increased Aβ generation via upregulation of BACE1. In people, metformin use is associated with reduced mortality, cardiovascular disease, and cancer, independent of its effects on diabetes (Campbell et al., 2017). This has led some to promote it as a potential anti-aging drug in people (Barzilai et al., 2016).

Some epidemiological studies suggest metformin reduces Alzheimer's risk, but others have found long-term use may increase it. Long-term metformin use can lead to vitamin B12 deficiency, which can cause symptoms of dementia (Campbell et al., 2018Chin-Hsiao, 2019Sluggett et al., 2019Imfeld et al., 2012).

In multiple preclinical models of Alzheimer’s and Parkinson’s diseases, metformin was reported to improve behavioral phenotypes while decreasing Aβ pathology and tau phosphorylation (for a meta-analysis of animal results, see Craig et al., 2019).

Findings

From 2008 to 2012, a pilot study was conducted at Columbia University, New York City, in 80 people with amnestic mild cognitive impairment. Participants were overweight but did not have diabetes. They received a maximum of 2,000 mg metformin per day, split into two doses, or placebo for one year. Primary outcomes were the Selective Reminding Test (SRT) for memory, and the ADAS-Cog. Glucose uptake in the posterior cingulate/precuneus by FDG-PET was the secondary outcome; plasma Aβ42 was also measured. After one year, the metformin group scored significantly better on the SRT than the placebo group. The ADAS-Cog, glucose uptake, and plasma Aβ42 did not differ between groups (Luchsinger et al., 2016). Only 10 percent of people tolerated the highest metformin dose, with most taking 1,000 or 1,500 mg daily. There were no serious adverse events.

In 2013 to 2015, a small trial at the University of Pennsylvania investigated the effect of metformin on biomarkers of AD in 20 non-diabetic people with mild cognitive impairment or dementia due to AD. Diagnosis of AD was confirmed by MRI, FDG-PET, or amyloid biomarkers. In a crossover design, each participant received metformin at a maximum dose of 2,000 mg/day for eight weeks, then placebo for eight weeks, or vice versa. Outcomes included cognitive testing in multiple learning and memory domains, executive functioning, attention, language, and motor speed using the ADAS-Cog and CANTAB batteries; CSF concentration of Aβ, total tau, and phosphorylated tau; and blood flow in the brain as measured by arterial spin labeling. The trial found a statistically significant increase in the Trails B measure of executive function, and trends toward improvement on learning, memory, and attention in the treated group. Metformin did not change blood flow in prespecified regions of interest. The drug was detectable in CSF, but AD biomarkers were unchanged (Nov 2015 conference news; Koenig et al., 2017).

A small imaging study embedded in the long-running Diabetes Prevention Program Outcomes Study (DPPOS) in New York City is recruiting 10 people on metformin and 10 on placebo for amyloid plaque and neurofibrillary tangle PET imaging. The participants will be scanned with 11C-PIB and 18F-MK-6240, and undergo MRI measurement of hippocampal volume and cortical white-matter lesions. 

In February 2020, Swedish investigators started evaluating the effect of one year of metformin plus exercise and diet on memory in 80 people with Type 2 diabetes and mild cognitive impairment. Primary outcomes are recruitment, adherence, and retention rates, while secondary measures are metabolic change and memory function. The study will run through December 2021.

A multicenter, Phase 2/3 prevention trial is slated to begin in August 2020. The Metformin in Alzheimer’s Dementia Prevention (MAP) study will enroll 370 people at nine academic medical centers in the United States. Participants must be between 55 and 90, be overweight or obese without diabetes, and have early or late MCI. People of normal weight are less likely to have a metabolic response to metformin, and will be excluded. Participants will take 2,000 mg per day extended-release metformin or placebo for two years. The primary outcome is change on the Free and Cued Selective Reminding Test; secondary outcomes are change on the Alzheimer's Disease Cooperative Study Preclinical Alzheimer's Cognitive Composite (PACC-ADCS), hippocampal volume, and white-matter hyperintensity volume. The trial will run through 2024.

In January 2020, a small, open-label study began to assess safety and efficacy of metformin in people with amyotrophic lateral sclerosis due to C9ORF72 expansions.

Metformin is also being studied for Fragile X Syndrome, age-related macular degeneration, various types of cancer, and other conditions. For details on metformin trials for dementia, see clinicaltrials.gov.

Last Updated: 06 Mar 2020

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References

News Citations

  1. Truly New to Déjà Vu: For Five Hopefuls, Lights Go Out After Phase 2

Paper Citations

  1. . Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. J Alzheimers Dis. 2016;51(2):501-14. PubMed.
  2. . Effects of the Insulin Sensitizer Metformin in Alzheimer Disease: Pilot Data From a Randomized Placebo-controlled Crossover Study. Alzheimer Dis Assoc Disord. 2017 Apr-Jun;31(2):107-113. PubMed.
  3. . Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis. Ageing Res Rev. 2017 Nov;40:31-44. Epub 2017 Aug 10 PubMed.
  4. . Metformin as a Tool to Target Aging. Cell Metab. 2016 Jun 14;23(6):1060-1065. PubMed.
  5. . Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis. J Alzheimers Dis. 2018;65(4):1225-1236. PubMed.
  6. . Metformin and the Risk of Dementia in Type 2 Diabetes Patients. Aging Dis. 2019 Feb;10(1):37-48. PubMed.
  7. . Metformin and Risk of Alzheimer's Disease Among Community-Dwelling People With Diabetes: A National Case-Control Study. J Clin Endocrinol Metab. 2020 Apr 1;105(4) PubMed.
  8. . Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: a population-based case-control study. J Am Geriatr Soc. 2012 May;60(5):916-21. Epub 2012 Mar 28 PubMed.
  9. . A systematic literature review of the effect of insulin sensitizers on the cognitive symptoms of Alzheimer's Disease in transgenic mice. Behav Brain Res. 2019 Oct 17;372:112015. Epub 2019 Jun 27 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. . Antidiabetic therapies and Alzheimer disease. Dialogues Clin Neurosci. 2019 Mar;21(1):83-91. PubMed.