title: Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial.
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.
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, NY, USA.|Department of Epidemiology, Columbia University Medical Center, New York, NY, USA.
authors.forename: José A
authors.initials: JA
authors.lastname: Luchsinger
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, NY, USA.
authors.forename: Thania
authors.initials: T
authors.lastname: Perez
authors.affiliation: Department of Statistics, Mt. Sinai Medical Center, New York, NY, USA.
authors.forename: Helena
authors.initials: H
authors.lastname: Chang
authors.affiliation: New York Institute for Basic Research, Staten Island, NY, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Mehta
authors.affiliation: Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Steffener
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, New York, NY, USA.|Department of Radiology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Gnanavalli
authors.initials: G
authors.lastname: Pradabhan
authors.affiliation: Division of Geriatric Psychiatry, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Ichise
authors.affiliation: Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Manly
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, New York, NY, USA.|Department of Radiology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Davangere P
authors.initials: DP
authors.lastname: Devanand
authors.affiliation: Department of Statistics, Mt. Sinai Medical Center, New York, NY, USA.
authors.forename: Emilia
authors.initials: E
authors.lastname: Bagiella
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000097:blood; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D018697:Nootropic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D050177:Overweight / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D010446:Peptide Fragments / Q000097:blood; D010865:Pilot Projects; D049268:Positron-Emission Tomography; D011581:Psychological Tests; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D016229:Amyloid beta-Peptides; D018697:Nootropic Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D008687:Metformin; D005947:Glucose
keywords: Amnestic mild cognitive impairment; insulin; memory; metformin; randomized clinical trial