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Cited by 285Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsDiabetes Treatment and Management

Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial

Open access
Luchsinger, José A., Perez, Thania, Chang, Helena, Mehta, Pankaj, Steffener, Jason, Pradabhan, Gnanavalli, Ichise, Masanori, Manly, Jennifer +2 more·2016·Journal of Alzheimer's Disease
DOI 10.3233/jad-150493PMC PMC5079271
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Abstract

Diabetes and hyperinsulinemia may be risk factors for Alzheimer's disease (AD). We conducted a pilot study of metformin, a medication efficacious in treating and preventing diabetes while reducing hyperinsulinemia, among persons with amnestic mild cognitive impairment (aMCI) with the goal of collecting preliminary data on feasibility, safety, and efficacy. Participants were 80 men and women aged 55 to 90 years with aMCI, overweight or obese, without treated diabetes. We randomized participants to metformin 1000 mg twice a day or matching placebo for 12 months. The co-primary clinical outcomes were changes from baseline to 12 months in total recall of the Selective Reminding Test (SRT) and the score of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). The secondary outcome was change in relative glucose uptake in the posterior cingulate-precuneus in brain fluorodeoxyglucose positron emission tomography. Change in plasma Aβ42 was an exploratory outcome. The mean age of participants was 65 years. Fifty percent of participants were women. The only baseline variable that was different between the arms was the ADAS-Cog. Metformin could not be tolerated by 7.5% of participants; 15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum dose. There were no serious adverse events related to metformin. The 7.5% of persons who did not tolerate metformin reported gastrointestinal symptoms. After adjusting for baseline ADAS-cog, changes in total recall of the SRT favored the metformin group (9.7±8.5 versus 5.3±8.5; p = 0.02). Differences for other outcomes were not significant. A larger trial seems warranted to evaluate the efficacy and cognitive safety of metformin in prodromal AD.

AI snapshot

Written from the paper’s full text.

TL;DR

In a 12-month pilot randomized placebo-controlled trial of metformin in 80 overweight/obese adults with amnestic mild cognitive impairment, metformin was feasible and safe but poorly tolerated at the maximum dose. After adjustment for baseline ADAS-cog, metformin improved Selective Reminding Test total recall versus placebo, while ADAS-cog, imaging, and plasma Aβ42 outcomes did not differ significantly.

Key findings

  • Metformin was not tolerated by 7.5% of participants; 15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum 2000 mg/day. No serious adverse events related to metformin were reported; the 7.5% who did not tolerate it reported gastrointestinal symptoms.
  • After adjusting for baseline ADAS-cog, SRT total recall favored metformin (9.7 ± 8.5 vs. 5.3 ± 8.5; p = 0.02), with a metformin-vs-placebo difference in change of 4.4 ± 8.5 words. The highest metformin dose was associated with 5.3 ± 10.0 more words in SRT total recall (p = 0.03) in post hoc analysis.
  • ADAS-cog differences were not significant after adjustment; the posterior cingulate-precuneus rCMRgl difference favored metformin but was not significant (2.0 ± 6.3% vs. 0.0 ± 6.0%; p = 0.36). Plasma Aβ42 changes were not significant (metformin 0.69 ± 18.5 pg/ml vs. placebo −4.40 ± 23.51 pg/ml; p = 0.3).
  • Fasting insulin increased more in placebo than metformin (13.8 vs. 4.7 IU/ml; p = 0.09), and hsCRP decreased with metformin but increased with placebo (−0.3 vs. 1.0 mg/dl; p = 0.07).

Methods

  • Double-blind, placebo-controlled randomized pilot trial at a single site (Columbia University Medical Center); 80 men and women aged 55–90 years with amnestic MCI by Petersen criteria, BMI ≥25 kg/m², and without treated diabetes were randomized 1:1 to metformin 1000 mg twice daily or matching placebo for 12 months, stratified by APOE-ε4.
  • Co-primary clinical outcomes were 12-month changes in Selective Reminding Test total recall and ADAS-cog; secondary imaging outcome was change in posterior cingulate-precuneus relative glucose uptake on FDG PET/MRI; plasma Aβ42 was exploratory.
  • Analysis used ANCOVA with intent-to-treat and last-observation-carried-forward imputation, adjusting for baseline variables that differed between arms; post hoc analyses examined metformin dose and strata by age, APOE-ε4, BMI, HbA1c, and fasting insulin.

Limitations

  • Stated: the study was a pilot with a relatively small sample size, results may be due to chance, findings were inconsistent between SRT and ADAS-cog, post hoc analyses are subject to chance, and the study was not powered to detect imaging differences.
  • Stated: recruitment was challenging, requiring 32 months and screening 1426 by telephone and 331 in person; most participants could not achieve the maximum metformin dose, and some could not tolerate metformin at all.
  • Evident from the text: it was a single-site study; 65 of 80 participants completed 12 months, and imaging follow-up was completed in 33 of 40 invited participants, which further limits precision and generalizability.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3233/jad-150493

Cites

106 of 106 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 53 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The 7.5% of persons who did not tolerate metformin reported gastrointestinal symptoms.

    “The 7.5% of persons who did not tolerate metformin reported gastrointestinal symptoms.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Differences for outcomes other than SRT total recall were not significant.

    “Differences for other outcomes were not significant.”
    Quote in the paperSubstantial claim
  • Findingown data

    There were no serious adverse events related to metformin.

    “There were no serious adverse events related to metformin.”
    • Also stated in: § Compliance with metformin and adverse events · plain
      “In terms of safety, there were no serious adverse events related to metformin and the 7.5% of persons who were not able to tolerate metformin reported gastrointestinal symptoms.”
    Quote in the paperSubstantial claim
  • Findingown data

    Metformin could not be tolerated by 7.5% of participants.

    “Metformin could not be tolerated by 7.5% of participants”
    Quote in the paperNot a substantial claim
  • Findingown data

    After adjusting for baseline ADAS-cog, changes in total recall of the Selective Reminding Test favored the metformin group.

    “After adjusting for baseline ADAS-cog, changes in total recall of the SRT favored the metformin group (9.7 ± 8.5 vs. 5.3 ± 8.5; p = 0.02).”
    • Also stated in: § Changes in the clinical outcomes · plain
      “after adjustment for baseline ADAS-Cog the metformin group showed significantly greater improvement in SRT total recall compared to placebo (difference in changes in total recall of the SRT of metformin vs. placebo= 4.4 ± 8.5 words)”
    Quote in the paperSubstantial claim
  • May combine two claims. 42
  • Classified as probably not a substantial claim. 31

  • May combine two claims.

    Findingown data

    The tolerated metformin doses were distributed as 15% at 500 mg/day, 35% at 1000 mg/day, 32.5% at 1500 mg/day, and 10% at the maximum dose.

    “15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum dose.”
    • Also stated in: § Compliance with metformin and adverse events · plain
      “15% remained on 500 mg a day (1 tablet), 35% remained on 1000 mg a day (2 tablets), 32.5% remained on 1500 mg a day (3 tablets), and 10% tolerated the maximum dose of 2,000 mg a day (4 tablets).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The pilot randomized trial of metformin in persons with amnestic mild cognitive impairment was feasible and safe.

    “We found in a pilot study that conducting a randomized trial of metformin in persons with AMCI was feasible and safe.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Crude analyses showed a greater improvement in the Selective Reminding Test in the metformin group, but the difference for the ADAS-Cog favored the placebo group.

    “Crude analyses showed a greater improvement in the SRT in the metformin group, but the difference for the ADAS-Cog favored the placebo group.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Weight decreased more in the metformin group than in the placebo group, but this difference was not statistically significant.

    “Weight decreased more in the metformin group (-2.7 ± 6.4 Kg) compared with the placebo group (-1.6 ± 4.5 Kg) but this difference was not statistically signficant (p = 0.63).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There were no differences between metformin and placebo in changes in digit span backwards, the neuropsychiatric inventory, the MMSE, paragraph recall, or CGIC-MCI.

    “There were no differences between metformin and placebo in changes in digit span backwards, the neuropsychiatric inventory, the MMSE, paragraph recall, or CGIC-MCI (Supplemental table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Fasting insulin increased appreciably more in the placebo group compared with the metformin group, and this difference was close to statistical significance.

    “Fasting insulin increased appreciably more in the placebo group compared with the metformin group as expected, and this difference was close to statistical significance (13.8 vs. 4.7 IU/ml; p = 0.09).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For delayed recall of the Selective Reminding Test, the gain in words was higher in the metformin group than in the placebo group and was close to statistical significance.

    “The results were similar for delayed recall of the SRT, in which the gain in words was higher in the metformin group (2.3 ± 2.5) compared to the placebo group (1.3 ± 2.3) and was close to statistical significance (p=0.06).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The study found preliminary evidence of efficacy for one primary outcome, total recall in the Selective Reminding Test, but not the other, the ADAS-Cog, after adjusting for the baseline difference in the ADAS-Cog.

    “We also found preliminary evidence of efficacy for one of the primary outcomes, total recall in the Selective Reminding Test, but not the other, the ADAS-Cog, after adjusting for the baseline difference in the ADAS-Cog.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Secondary ROIs including hippocampus, para-hippocampus, and entorhinal cortex favored metformin but were not statistically significant.

    “Secondary ROIs including hippocampus (2.4 ± 4.7% vs. 1.0 ± 5.1%; p =0.73), para-hippocampus (3.3 ± 5.5% vs. 2.0 ± 5.1%; p =0.76), and entorhinal cortex (5.3± 9.0% vs. 1.3 ± 6.0; p =0.16) favored metformin but were not statistically significant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    HbA1c decreased modestly more in the metformin group than in the placebo group, but this difference was not statistically significant.

    “HbA1c decreased modestly more in the metformin group (-0.3 ± 0.7 %) compared with the placebo group (- 0.2 ± 0.5), but this difference was not statistically significant (p=0.64).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Differences between metformin and placebo in changes in the primary and exploratory biomarker outcomes were not significantly different, but the direction of the difference modestly favored metformin and supported the finding for the Selective Reminding Test.

    “Differences between metformin and placebo in changes in the primary and exploratory biomarker outcomes were not significantly different but the direction of the difference modestly favored metformin and supported the finding for the SRT.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Post hoc analyses suggest that the benefit on the Selective Reminding Test total recall is higher with the highest metformin dose, among younger subjects, among those without APOE-ε4, among those with the lower HbA1c, and those with the highest baseline fasting insulin.

    “Post hoc analyses suggest that the benefit on the SRT total recall is higher with the highest metformin dose, among younger subjects, among those without APOE-ε4, among those with the lower HbA1c, and those with the highest baseline fasting insulin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both the Selective Reminding Test and ADAS-Cog scores improved in the placebo and metformin groups.

    “Both the SRT and ADAS-COG scores improved in the placebo and metformin groups (increases in SRT total recall, decreases in ADAS-COG scores).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    None of the differences in changes in plasma Aβ-42 were statistically significant; plasma Aβ-42 increased in the metformin group and decreased in the placebo group.

    “None of the differences in changes in plasma Aβ-42 were statistically significant. Plasma Aβ-42 increased in the metformin group (0.69 ± 18.5 pg/ml) and decreased in the placebo group (-4.40 ± 23.51 pg/ml; p=0.3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Metformin showed better performance compared with placebo in younger persons, those without APOE-ε4, those with lower HbA1c, and those with higher insulin levels.

    “Metformin showed better performance compared with placebo in younger persons, those without APOE-ε4, those with lower HbA1c, and those with higher insulin levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    hsCRP decreased in the metformin group and increased in the placebo group, with a difference close to statistical significance.

    “hsCRP, a measure of inflammation and vascular risk [63], and a correlate of memory impairment in our center[64] decreased in the metformin group and increased in the placebo group (-0.3 vs. 1.0 mg/dl; p = 0.07).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    We found a result benefiting metformin for the SRT but not for the ADAS-Cog.

    “we found a result benefiting metformin for the the SRT but not for the ADAS-Cog.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    The side effects and safety for metformin in our trial were similar to published research and clinical experience.

    “The side effects and safety for metformin in our trial were similar to published research and clinical experience.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The difference for the ADAS-cog favoring placebo disappeared after adjusting for the significant differences in baseline ADAS-cog, while the differences in the SRT persisted.

    “The difference for the ADAS-cog favoring placebo dissapeared after adjusting for the significant differences in baseline ADAS-cog, while the differences in the SRT persisted.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    We encountered a long recruitment period due in part to a large number of subjects needed to be screened.

    “These challenges included a long recruitment period due in part to a large number of subjects needed to be screened”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Our study showed improvements in both clinical outcomes, contrary to the idea that cognition declines with time.

    “our study showed improvements in both clinical outcomes, contrary to the idea that cognition declines with time.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Amnestic mild cognitive impairment is considered a high risk group for dementia and has become a common target for secondary prevention.

    “Thus, AMCI is considered a high risk group for dementia [6] and has become a common target for secondary prevention.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Petersen, 2009, Mild cognitive impairment: Ten years later, Arch Neurol source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Metformin is efficacious in treating and preventing diabetes while reducing hyperinsulinemia.

    “metformin, a medication efficacious in treating and preventing diabetes while reducing hyperinsulinemia”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Luchsinger, 2004, Hyperinsulinemia and risk of Alzheimer disease, Neurology source

      Not checked in the free run.

    • cites [26] Peila, 2004, Fasting insulin and incident dementia in an elderly population of Japanese-American men, Neurology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The natural history of Alzheimer's disease starts slowly in late middle age with mild memory deficits that progress to amnestic mild cognitive impairment, which in turn progresses to dementia.

    “The natural history of AD starts slowly in late middle age with mild memory deficits that progress to amnestic mild cognitive impairment (AMCI) [6], which in turn progresses to dementia [7].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Petersen, 2009, Mild cognitive impairment: Ten years later, Arch Neurol source

      Not checked in the free run.

    • cites [7] Cummings, 2004, Alzheimer’s disease, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Diabetes and hyperinsulinemia may be risk factors for Alzheimer's disease.

    “Diabetes and hyperinsulinemia may be risk factors for Alzheimer's disease (AD).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10] Luchsinger, 2010 source

      Not checked in the free run.

    • cites [11] Luchsinger, 2010, Type 2 diabetes, related conditions, in relation and dementia: An opportunity for prevention?, J Alzheimers Dis source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    An expert panel from NIH concluded in 2010 that there was insufficient evidence to recommend treatment of amnestic mild cognitive impairment or prevention for Alzheimer's disease.

    “an expert panel from NIH concluded in 2010 that there was insufficient evidence to recommend treatment of AMCI or prevention for AD [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] (2010) NIH consensus development conference statement on preventing Alzheimer’s disease and cognitive decline. NIH Consensus and State-of-the-Art Statements, volume 27, number 4.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Premisecitation

    It has been hypothesized that pharmacologic strategies effective in preventing diabetes while decreasing insulin resistance may prevent Alzheimer's disease.

    “it has been hypothesized that pharmacologic strategies effective in preventing diabetes while decreasing insulin resistance may prevent AD [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Ferrannini, 2014, The target of metformin in type 2 diabetes, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The study was approved by the Institutional Review Board of Columbia University Medical Center and registered in ClinicalTrials.gov.

    “This study was approved by the Institutional Review Board of Columbia University Medical Center (AAAC7231) and was registered in ClinicalTrials.gov (ID NCT00620191).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The insulin assay intra- and inter-assay coefficients of variation are 4.7% and 8.2%, respectively.

    “Intra- and inter-assay coefficients of variation are 4.7% and 8.2%, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    65 subjects (81%) completed 12 months, 6 subjects (7.5%) completed 9 months, and 9 subjects (11.2%) had less than 9 months of follow-up.

    “65 subjects (81%) completed 12 months, 6 subjects (7.5 %) completed 9 months, and 9 subjects (11.2%) had less than 9 months of follow-up.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The study was a double-blind placebo-controlled randomized pilot trial of metformin 1000 mg twice a day versus matching placebo for 12 months in 80 subjects with amnestic mild cognitive impairment.

    “This study was a double-blind placebo-controlled randomized pilot trial of metformin 1000 mg twice a day vs. matching placebo for 12 months in 80 subjects with AMCI.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    APOE genotyping was performed with allele-specific PCR with universal molecular beacons, and DNA sequencing of positive control DNA samples was completed to assure correct assignment of alleles.

    “Genotyping of APOE polymorphisms rs7412 and rs429358 was performed at PreventionGenetics (www.preventiongenetics.com) with an array tape [58] using allele-specific PCR with universal molecular beacons [59, 60]. DNA sequencing of positive control DNA samples were completed to assure correct assignment of alleles.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [58] Tuan, 2003, Usefulness of plasma glucose and insulin concentrations in identifying patients with insulin resistance, Am J Cardiol source

      Not checked in the free run.

    • cites [59] Ridker, 2004, High-sensitivity C-reactive protein, inflammation, and cardiovascular risk: From concept to clinical practice to clinical benefit, Am Heart J source

      Not checked in the free run.

    • cites [60] Ridker, 2007, Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: Implications for longevity, Nutr Rev source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The study was powered to detect a large difference of 0.75 standard deviations in change in outcomes at 12 months with a sample size of 30 persons per group, later increased from 60 to 80 participants.

    “it was powered to detect a large difference (0.75 standard deviations) in the change in the outcomes at 12 months with a sample size of 30 persons per group (Total 60 groups). We obtained supplementary funding and increased the sample size from 60 to 80 participants.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The finding that diabetes and insulin resistance are related to an increased risk of Alzheimer's dementia has prompted the exploration of related strategies for treatment and prevention of Alzheimer's disease.

    “The finding that diabetes and insulin resistance are related to an increased risk of Alzheimer's dementia has prompted the exploration of related strategies for treatment and prevention of AD [11].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Luchsinger, 2010, Type 2 diabetes, related conditions, in relation and dementia: An opportunity for prevention?, J Alzheimers Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lifestyle interventions (exercise and diet) are the best insulin sensitizers, but require substantial support and resources in clinical trials that are difficult to sustain in the long term and replicate in real-world settings.

    “Lifestyle interventions (exercise and diet) are the best insulin sensitizers, but require substantial support and resources in clinical trials that are difficult to sustain in the long term and replicate in “real world” settings [65].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Kahn, 2006, Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Study design and conductreasoning

    Given the pilot nature of the study with a relatively small sample size and the potential for chance findings, the preliminary evidence of efficacy should be taken with caution.

    “However, given the pilot nature of our study with a relatively small sample size and the potential for chance findings, our preliminary evidence of efficacy should be taken with caution.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Allocation concealment was maintained by randomly alternating block sizes.

    “Allocation concealment was maintained by randomly alternating block sizes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Thiazolidinediones (PPAR-gamma agonists) are powerful insulin sensitizers effective in lowering insulin resistance and preventing type 2 diabetes, with efficacy similar to lifestyle strategies and greater than metformin.

    “Among the pharmacologic strategies, the thiazolidenidiones, also known as PPAR-gamma agonists, are powerful insulin sensitizers effective in lowering insulin resistance [66] and preventing T2D [67], with efficacy similar to lifestyle strategies and greater than metformin [68].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [66] Nathan, 2007, Trials that matter: Rosiglitazone, ramipril, and the prevention of type 2 diabetes, Ann Intern Med source

      Not checked in the free run.

    • cites [67] Nathan, 2007, Rosiglitazone and cardiotoxicity –weighing the evidence, N Engl J Med source

      Not checked in the free run.

    • cites [68] Risner, 2006, Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease, Pharmacogenomics J source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The test-retest reliability of the measurement of plasma Aβ42 is excellent, with a Cronbach's alpha coefficient of 0.91.

    “The test–retest reliability of the measurement of plasma Aβ42 is excellent (Cronbach's α coefficient = 0.91).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    No interim analyses were planned or conducted during the conduct of the clinical trial.

    “No interim analyses were planned or conducted during the conduct of the clinical trial.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    The data coordinating center generated the random allocation sequence, and only the statistician had access to it; the assistant assigning participants and staff recruiting and evaluating participants did not have access.

    “The data coordinating center at Department of Biostatistics at Columbia University Medical Center generated the random allocation sequence.”
    • Also stated in: § Statistical Analyses · plain
      “Only the statistician had access to the randomization sequence. The assistant assigning the participants to interventions and the staff recruiting and evaluating participants did not have access to the randomizaion sequence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The only statistically significant difference between the groups at baseline was the ADAS-Cog score, which was lower (better) in the metformin group.

    “The only statistically significant difference between the groups at baseline (Table 2) was the ADAS-Cog score, which was lower (better) in the metformin group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Metformin is a safe, inexpensive medication available in generic form with proven efficacy in treating and preventing type 2 diabetes through reduction of peripheral glucose and insulin levels.

    “Metformin is a safe, inexpensive medication available in generic form with proven efficacy in treating and preventing T2D though the reduction of peripheral glucose and insulin levels [25, 26].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Luchsinger, 2004, Hyperinsulinemia and risk of Alzheimer disease, Neurology source

      Not checked in the free run.

    • cites [26] Peila, 2004, Fasting insulin and incident dementia in an elderly population of Japanese-American men, Neurology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Initial analyses were conducted blinded to true treatment allocation, and treatment unblinding was conducted after analyses were checked for quality.

    “Initial analyses were conducted blinded to true treatment allocation. Treatment unblinding was conducted after analyses were checked for quality.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Compliance with metformin was 7.5% stopped metformin but continued in the study following intent-to-treat, 15% remained on 500 mg a day, 35% on 1000 mg a day, 32.5% on 1500 mg a day, and 10% tolerated the maximum dose of 2,000 mg a day.

    “Compliance with metformin was as follows: 7.5% stopped metformin but continued in the study following ITT, 15% remained on 500 mg a day (1 tablet), 35% remained on 1000 mg a day (2 tablets), 32.5% remained on 1500 mg a day (3 tablets), and 10% tolerated the maximum dose of 2,000 mg a day (4 tablets).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Imputation with last-observation-carried-forward was used to account for missing follow-up data.

    “Imputation with last-observation-carried-forward (LOCF) was used to account for missing follow-up data.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Follow-up MRI and PET were completed in 33 out of 40 participants, with 82.5% completion overall.

    “Follow-up MRI and PET were completed in 33 out of 40 participants (15 in the metformin group, 18 in the placebo group, 82.5% completion overall).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    Randomization was stratified and blocked, with APOE-ε4 genotype as the only stratification variable.

    “To balance factors that may influence treatment outcome, randomization was stratified and blocked. The only stratification variable was the presence or absence of APOE-ε4 genotype.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Analysis of Covariance was used to compare outcomes between treatment groups following an Intent-to-treat approach adjusting for variables that were different at baseline if necessary.

    “Analysis of Covariance (ANCOVA) was used to compare outcomes between the treatment groups following an Intent-to-treat (ITT) approach adjusting for variables that were different at baseline if necessary.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The coordinators conducting outcomes assessments were blinded from these data.

    “The coordinators conducting outcomes assessments were blinded from these data.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the DPP, metformin was more effective than lifestyle intervention in preventing T2D after 10 years.

    “In the DPP, metformin was more effective than lifestyle intervention in preventing T2D after 10 years [65].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Kahn, 2006, Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rosiglitazone was tested for secondary prevention of cognitive decline in mild AD among persons without T2D and was found to be non-efficacious in a phase III trial after promising results in a pilot study.

    “The thiazolidinedione rosiglitazone was tested for secondary prevention of cognitive decline in mild AD among persons without T2D and was found to be non-efficacious in a phase III trial[71] after promising results in a pilot study [72].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [71] Tian, 2004, Association between apolipoprotein E e4 allele and arteriosclerosis, cerebral amyloid angiopathy, and cerebral white matter damage in Alzheimer’s disease, J Neurol Neurosurg Psychiatry source

      Not checked in the free run.

    • cites [72] The Diabetes Prevention Program Research, Group, 2005, Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance, Diabetes source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Metformin reduces the risk of T2D in persons at risk.

    “T2D[77] in persons at risk”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Watson, 2004, Modulation of memory by insulin and glucose: Neuropsychological observations in Alzheimer’s disease, Eur J Pharmacol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Metformin reduces inflammation and thrombosis.

    “inflammation and thrombosis[75]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Nathan, 2002, Initial management of glycemia in type 2 diabetes mellitus, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Metformin has been reported to increase production of Aβ in a cell culture model.

    “metformin has been reported to increase production of Aβ in a cell culture model [84]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Li, 2012, Metformin attenuates Alzheimer’s disease-like neuropathology in obese, leptin-resistant mice, Pharmacol Biochem Behav source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Thiazolidinediones have concerning side effects including edema, congestive heart failure, and in the case of rosiglitazone, myocardial infarction, which led to a black box warning from the FDA.

    “However, they have concerning side effects including edema, congestive heart failure (CHF), and in the case of rosiglitazone, myocardial infarction (MI) [69], which led to a black box warning from the Food and Drug Administration (FDA) [70].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [69] Watson, 2005, Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: A preliminary study, Am J Geriatr Psychiatry

      Not checked in the free run.

    • cites [70] Dunn, 1995, A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus, Drugs source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Study design and conductnone given

    The results of post-hoc analyses are subject to chance.

    “the results of post-hoc analyses are are subject to chance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    It seems safe and feasible to conduct a randomized trial of metformin among persons with MCI although we encountered important challenges.

    “It seems safe and feasible to conduct a randomized trial of metformin among persons with MCI although we encountered important challenges.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An epidemiologic study showed that metformin is related to lower AD risk among persons with T2D.

    “an epidemiologic study that showed that metformin is related to lower AD risk among persons with T2D [89].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Skinner, 2012, The Alzheimer’s Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-Plus): An expansion of the ADAS-Cog to improve responsiveness in MCI, Brain Imaging Behav source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Decreases in plasma Aβ-42 predict future AD.

    “decreases in plasma Aβ-42 predict future AD[94].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Cohen, 1988

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    We cautiously believe that preliminary findings justify the conduct of a larger clinical trial.

    “we cautiously believe that there are preliminary findings justify the conduct of larger clinical trial.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Our results must be interpreted with caution because of the inconsistency of the results for the SRT and ADAS-cog.

    “We acknowledge that our results must be interpreted with caution because of the inconsistency of the results for the SRT and ADAS-cog”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Metformin reduces the risk of the metabolic syndrome.

    “the risk of the metabolic syndrome[76]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Park, 2001, Cognitive effects of insulin in the central nervous system, Neurosci Biobehav Rev source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Two retrospective studies reported that among persons with T2D, a diagnosis of dementia was associated with metformin use.

    “two retrospective studies reported that among persons with T2D, a diagnosis of dementia was associated with metformin use[85, 86].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [85] Gupta, 2011, Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes, Neuropharmacology source

      Not checked in the free run.

    • cites [86] Hsu, Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin, J Alzheimers Dis source

      Not checked in the free run.

64 of 64

  • The paper relies on this without support.

    The posterior cingulate-precuneus and precuneus share the same pathological features in Alzheimer's disease.

    “This ROI included the Precuneus & Posterior Cingulate gyrus together, because they share the same pathological features in AD.”

  • The paper relies on this without support.

    Persons with an HbA1c of 6.5% or less are unlikely to receive pharmacologic treatment for type 2 diabetes, including metformin, during the 12 months of the study.

    “We chose the cutoff of 6.5% in HbA1c because persons with this level of HbA1c seemed unlikely to receive pharmacologic treatment for T2D, including metformin, during the 12 months of the study.”

  • The paper relies on this without support.

    A Telephone Interview for Cognitive Status score greater than 34 out of 41 indicates normal cognition and persons with this score are unlikely to have memory impairment.

    “A TICS Score > 34 out of 41 was considered normal cognition. Persons with this score were not invited to participate.”

  • The paper relies on this without support.

    A 2-week washout period is sufficient to ensure that changes in rCMRgl are not due to acute changes in glucose due to metformin.

    “However, we conducted a washout period of 2 weeks [54] at the end of the trial before performing FDG PET to ensure that changes in rCMRgl were not due to acute changes in glucose due to metformin.”

  • The authors state this as an assumption.

    Metformin acts on the AD process through reduction of peripheral insulin levels that affect brain clearance of Aβ.

    “we postulate that it acts on the AD process through reduction of peripheral insulin levels that affect brain clearance of Aβ [79-81].”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Glucose metabolism amelioration in the CNS is supposed to improve cognitive decline in early and late amnestic MCI patients or prevent cognitive decline in obese people.

    “Glucose metabolism amelioration in the Central Nervous System (CNS) is supposed to improve the cognitive decline of early and late amnestic Mild Cognitive Impairment patients or prevent the cognitive decline in obese people [3,105,106].”

    From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [105]

    The Results (Changes in the clinical outcomes; page not provided) report greater improvement in a memory-recall test with metformin than with placebo among overweight or obese people with amnestic MCI. But the Results (Changes in Biomarker outcomes) found no statistically significant improvement in measured brain glucose uptake. The paper does not establish a benefit separately for early and late amnestic MCI or prevention of cognitive decline in obese people generally. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting accounts of who was invited for brain imaging

    Minor

    The design section says half of the 80 participants were invited to the imaging sub-study, then says all participants were invited for brain imaging.

1 of 1

Cites

Flagged first, then by citations

7 of the 113 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

  1. Perez, 2011, II clinical trial of metformin in amnestic MCI: Rationale, methods, and barriers and enablers of successful recruitment, J Nutr Health Aging, 15, S14
  2. Weschler, 1987, Wechsler Memory Scale-revised manual
  3. Weschler, 1981, Manual for the adult Weschler intelligence scale-Revised

Cited by

Sorted by citations

Related

Authors
Luchsinger, J. A., Perez, T., Chang, H., Mehta, P., Steffener, J., Pradabhan, G., Ichise, M., Manly, J., Devanand, D. P., & Bagiella, E.
Affiliations
  • Department of Medicine, Columbia University Medical Center, New York, NY, USA
  • Columbia University Irving Medical Center (US)
  • Mount Sinai Hospital (US)
  • New York Institute for Basic Research, Staten Island, NY, USA
  • Columbia University (US)
  • New York State Psychiatric Institute (US)
ORCID
Venue
Journal of Alzheimer's Disease
Publisher
SAGE Publications
Published
2016-03-15
Volume
51
Issue
2
Pages
501-514
ISSN
  • 1387-2877 (ISSN-L)
  • 1875-8908
DOI
10.3233/jad-150493
PMC
PMC5079271
OpenAlex
W2315843281
Semantic Scholar
051353655bd022160343f181e1c8e5bd3de5377e
Cited by
285
References
113
Citations by year
2026: 22 · 2025: 33 · 2024: 29 · 2023: 40 · 2022: 42 · 2021: 32 · 2020: 29 · 2019: 20 · 2018: 24 · 2017: 11 · 2016: 3
FWCI
17.17
Type
journal article
Language
en
Open access
Locations
  • Journal of Alzheimer s Disease (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Alzheimer's Drug Discovery Foundation
  • National Institutes of Health (UL1TR000040)
  • National Institute on Aging (R01AG026413)
  • National Center for Research Resources (UL1RR024156)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
metformin, amnestic mild cognitive impairment
MeSH terms
Aged, Aged, 80 and over, Brain, Double-Blind Method, Female, Follow-Up Studies, Glucose, Humans, Male, Metformin, Middle Aged, Peptide Fragments, Pilot Projects, Psychological Tests, Severity of Illness Index, Amyloid beta-Peptides, Treatment Outcome, Nootropic Agents, Positron-Emission Tomography, Overweight, Cognitive Dysfunction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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