Therapeutics

Metformin

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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 in people using it to treat diabetes, 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., 2018; Chin-Hsiao, 2019; Sluggett et al., 2020; Imfeld et al., 2012; Porter et al., 2019). More recent, and larger, studies bear out a reduction in all-cause dementia in people with diabetes who use metformin, and indicate a dose-response relationship (e.g., Doran et al., 2024; Sun et al., 2023; Zimmerman et al., 2023). This finding is not universal (see Wu et al., 2024). In one study, metformin effects varied among subgroups defined by use of antidepressants, NSAIDs, or with neuropsychiatric disorders (Tang et al., 2024).

Likewise, results for studies of metformin in Alzheimer’s disease are mixed. One meta-analysis of published studies suggested a reduced risk of cognitive decline, but not of Alzheimer’s, in people with diabetes who used metformin (Zhang et al., 2022). Other studies found no reduction of AD risk or slowing of decline in people with AD (Luo et al., 2022; Wu et al., 2020; Xue and Xie, 2023). One study reported the potential for a higher risk of AD among Asians using metformin (Ha et al., 2021). In an autopsy study of 1,584 participants, there was no difference in the level of AD pathology or evidence of strokes between metformin users and non-users (Sood et al., 2024).

Among positive studies, metformin was associated with a reduced risk of all types of dementia, but only if it was initiated before dementia began (Ji et al., 2022). In the Alzheimer's Disease Neuroimaging Initiative study, metformin was associated with better cognitive performance, and CSF and imaging biomarkers in AD patients, if treatment started early (Pomilio et al., 2022). In the same study population, non-demented metformin users had less atrophy in some brain regions (Nabizadeh et al., 2022). A Swedish study found slower cognitive decline in people with AD who took metformin (Secnik et al., 2021).

A genetic analysis of variants in genes that affect blood sugar levels and metformin target genes linked several variants to a reduction in the risk of AD (Zheng et al., 2022). This and other studies support the idea that metformin prevents cognitive aging by mechanisms other than glycemic control (e.g., see Charpignon et al., 2022; Zheng et al., 2023; Chen et al., 2023).

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; Chen et al., 2021; Lu et al., 2020; Zhao et al., 2023). Metformin was reported to normalize expression of some genes in the brain, induce the Aβ protease IDE, and activate chaperone-mediated autophagy of APP to reduce Aβ levels (Qiu-Yue et al., 2022; Lu et al., 2020; Xu et al., 2021). Not all studies were positive: One found that metformin treatment in the P301S mouse tauopathy model reduced hyperphosphorylated tau but increased tau aggregation (Barini et al., 2016). In a study of long-term treatment in 3XTG-AD mice, one year of metformin led to memory impairment, and increased Aβ plaques and tau pathology (Cho et al., 2024).

In people with Huntington's disease, metformin treatment was linked to better cognitive function and, in mouse models of HD, to longer survival and milder symptoms (Hervás et al., 2017; Arnoux et al., 2018; Sanchis et al., 2019). Metformin was claimed to reduce production of toxic peptides from the C9orf72 expansion, and mitigate symptoms in a mouse model of ALS/FTD (Zu et al., 2020). In C9orf72-expressing cells, metformin protected against mitochondria damage (Feng et al., 2024).

An intranasal formulation improved cognitive function in a streptozotocin-induced diabetes-like AD mouse model (Kazkayasi et al., 2022).

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).

Starting in October 2019, a small imaging study embedded in the long-running Diabetes Prevention Program Outcomes Study (DPPOS) in New York City was recruiting 10 people on metformin and 10 on placebo for amyloid plaque and neurofibrillary tangle PET imaging. The participants were to be scanned with 11C-PIB and 18F-MK-6240, and undergo MRI measurement of hippocampal volume and cortical white-matter lesions. As of July 2021, the study was enrolling; its current status is unknown.

In October 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 was to run through March 2022. As of March 2021, the enrollment was reduced to 10.

A multicenter, Phase 2/3 prevention trial began in March 2021. The Metformin in Alzheimer’s Dementia Prevention (MAP) study is enrolling 326 people at more than 20 academic medical centers in the U.S. 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 were to take up to 2,000 mg per day extended-release metformin or placebo for two years; this was shortened to 18 months mid-trial. 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, white-matter hyperintensity volume, and plasma measures of amyloid, tau, and neurofilament light. Half the participants will have amyloid and tau PET scans at baseline and after treatment. The trial will run through 2026.

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. It has recruited 18 participants, and expects to finish in early 2024.

In December 2021, a Phase 3 trial began testing one year of daily 1,700 mg metformin against cognitive decline in 60 people with Huntington's. The trial is running at multiple sites in Spain through August 2024.

In February 2022, the MetMemory trial began recruiting 242 people with mild cognitive impairment to test three years of metformin for its effects on cognitive decline and neuroimaging biomarkers. Participants who are overweight or obese, without diabetes, will be randomized to 500-2000 mg daily metformin, against primary outcomes of changes in memory and executive function. Thirteen secondary outcomes span measures of other cognitive domains, changes in total brain and hippocampal volume, white-matter hyperintensities, cerebral blood flow, cerebral amyloid, fMRI, and biomarkers of glucose and insulin status. The trial, in two sites in Australia, is expected to finish in December 2027.

In January 2023, a trial began testing metformin in the context of the FINGER study of multidomain lifestyle interventions to reduce the risk of dementia in older adults. FINGER 2.0 is enrolling 600 people age 60-79, with a CAIDE Dementia risk score greater than six, and average to slightly low cognitive performance for their age. Participants will be randomized to a structured, intensive lifestyle intervention including diet, physical activity, cognitive training, and cardiovascular/metabolic risk monitoring, or a program that gives only lifestyle advice. Within the intervention group, participants at increased risk of diabetes will be assigned randomly to metformin 2000 or 1000 mg daily, or placebo. The intervention lasts for two years, with a primary outcome of change in a z score for cognition based on an extended Neuropsychological Test Battery. The list of 39 secondary and exploratory outcomes includes other cognitive measures, CDR-SB and measures of function, blood lipids, diabetes, hypertension, blood biomarkers of amyloid, tau, and neurofilament light. The trial is to run in Finland, Sweden, and the United Kingdom through December 2026. The protocol is published (Barbera et al., 2024).

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: 23 Feb 2024

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References

News Citations

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

Paper Citations

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External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Bendlin BB. Antidiabetic therapies and Alzheimer disease. Dialogues Clin Neurosci. 2019 Mar;21(1):83-91. PubMed.
  2. Tahmi M, Luchsinger JA. Metformin in the Prevention of Alzheimer's Disease and Alzheimer's Disease Related Dementias. J Prev Alzheimers Dis. 2023;10(4):706-717. PubMed.
  3. Birajdar SV, Mazahir F, Alam MI, Kumar A, Yadav AK. Repurposing and clinical attributes of antidiabetic drugs for the treatment of neurodegenerative disorders. Eur J Pharmacol. 2023 Dec 15;961:176117. Epub 2023 Oct 30 PubMed.
  4. Top WM, Kooy A, Stehouwer CD. Metformin: A Narrative Review of Its Potential Benefits for Cardiovascular Disease, Cancer and Dementia. Pharmaceuticals (Basel). 2022 Mar 4;15(3) PubMed.
  5. Khezri MR, Yousefi K, Mahboubi N, Hodaei D, Ghasemnejad-Berenji M. Metformin in Alzheimer's disease: An overview of potential mechanisms, preclinical and clinical findings. Biochem Pharmacol. 2022 Mar;197:114945. Epub 2022 Feb 5 PubMed.
  6. Cummings J, Ortiz A, Castellino J, Kinney J. Diabetes: Risk factor and translational therapeutic implications for Alzheimer's disease. Eur J Neurosci. 2022 Feb 6; PubMed.
  7. Katsenos AP, Davri AS, Simos YV, Nikas IP, Bekiari C, Paschou SA, Peschos D, Konitsiotis S, Vezyraki P, Tsamis KI. New treatment approaches for Alzheimer's disease: preclinical studies and clinical trials centered on antidiabetic drugs. Expert Opin Investig Drugs. 2022 Jan;31(1):105-123. Epub 2022 Jan 2 PubMed.
  8. Samaras K, Makkar S, Crawford JD, Kochan NA, Wen W, Draper B, Trollor JN, Brodaty H, Sachdev PS. Metformin Use Is Associated With Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults With Type 2 Diabetes: The Sydney Memory and Ageing Study. Diabetes Care. 2020 Nov;43(11):2691-2701. Epub 2020 Sep 23 PubMed.
  9. Kumar H, Chakrabarti A, Sarma P, Modi M, Banerjee D, Radotra BD, Bhatia A, Medhi B. Novel therapeutic mechanism of action of metformin and its nanoformulation in Alzheimer's disease and role of AKT/ERK/GSK pathway. Eur J Pharm Sci. 2023 Feb 1;181:106348. Epub 2022 Dec 7 PubMed.
  10. Ponce-Lopez T, González Álvarez Tostado JA, Dias F, Montiel Maltez KH. Metformin Prevents NDEA-Induced Memory Impairments Associated with Attenuating Beta-Amyloid, Tumor Necrosis Factor-Alpha, and Interleukin-6 Levels in the Hippocampus of Rats. Biomolecules. 2023 Aug 24;13(9) PubMed.
  11. Saffari PM, Alijanpour S, Takzaree N, Sahebgharani M, Etemad-Moghadam S, Noorbakhsh F, Partoazar A. Metformin loaded phosphatidylserine nanoliposomes improve memory deficit and reduce neuroinflammation in streptozotocin-induced Alzheimer's disease model. Life Sci. 2020 Aug 15;255:117861. Epub 2020 May 28 PubMed.
  12. Birajdar SV, Mazahir F, Yadav AK. Transferrin functionalized poloxamer-chitosan nanoparticles of metformin: physicochemical characterization, in-vitro, and Ex-vivo studies. Drug Dev Ind Pharm. 2023 Dec;49(12):734-747. Epub 2023 Dec 20 PubMed.
  13. Tang X, Brinton RD, Chen Z, Farland LV, Klimentidis Y, Migrino R, Reaven P, Rodgers K, Zhou JJ. Use of oral diabetes medications and the risk of incident dementia in US veterans aged ≥60 years with type 2 diabetes. BMJ Open Diabetes Res Care. 2022 Sep;10(5) PubMed.
  14. Fan Z, Ren T, Wang Y, Jin H, Shi D, Tan X, Ge D, Hou Z, Jin X, Yang L. Aβ-responsive metformin-based supramolecular synergistic nanodrugs for Alzheimer's disease via enhancing microglial Aβ clearance. Biomaterials. 2022 Apr;283:121452. Epub 2022 Mar 11 PubMed.
  15. Oliveira WH, Braga CF, Lós DB, Araújo SM, França MR, Duarte-Silva E, Rodrigues GB, Rocha SW, Peixoto CA. Metformin prevents p-tau and amyloid plaque deposition and memory impairment in diabetic mice. Exp Brain Res. 2021 Sep;239(9):2821-2839. Epub 2021 Jul 20 PubMed.