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

Article type: Research Article

Authors: Luchsinger, José A.^{a; b; *} | Perez, Thania^a | Chang, Helena^c | Mehta, Pankaj^d | Steffener, Jason^e | Pradabhan, Gnanavalli^{f; g} | Ichise, Masanori^h | Manly, Jennifer^e | Devanand, Davangere P.^{f; g} | Bagiella, Emilia^c

Affiliations: [a] Department of Medicine, Columbia University Medical Center, New York, NY, USA | [b] Department of Epidemiology, Columbia University Medical Center, New York, NY, USA | [c] Department of Statistics, Mt. Sinai Medical Center, New York, NY, USA | [d] New York Institute for Basic Research, Staten Island, NY, USA | [e] Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA | [f] Department of Psychiatry, Columbia University Medical Center, New York, NY, USA | [g] Division of Geriatric Psychiatry, New York State Psychiatric Institute, New York, NY, USA | [h] Department of Radiology, Columbia University Medical Center, New York, NY, USA

Correspondence: [*] Correspondence to: Jose A. Luchsinger, MD, MPH, PH9 Center, room 210, 630 West 168th Street, New York, NY 10032, USA. Tel.: +1212 305 4730; Fax: +1212 305 9349; E-mail: [email protected].

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.

Keywords: Amnestic mild cognitive impairment, insulin, memory, metformin, randomized clinical trial

DOI: 10.3233/JAD-150493

Journal: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 501-514, 2016