Metformin in Amnestic Mild Cognitive Impairment

NCT ID: NCT00620191

Last Updated: 2020-10-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-06-01
• Study Completion Date: 2012-02-29

Brief Summary

Hyperinsulinemia and type 2 diabetes (T2D) are important potential risk factors for cognitive decline and Alzheimer's disease (AD). Two thirds of the US adult population are at risk for hyperinsulinemia and T2D, and half of the population 85 years and older have AD. Peripheral hyperinsulinemia can impair the clearance of amyloid beta in the brain, the main culprit in AD. Thus, the investigators hypothesize that lowering peripheral insulin in overweight persons with amnestic mild cognitive impairment (AMCI), a transition state between normal cognition and AD, can decrease the risk of cognitive decline and progression to AD. The investigators propose to conduct a phase II double blinded placebo controlled randomized clinical trial of metformin, a safe and effective medication that prevents hyperinsulinemia and diabetes, to test this hypothesis among 80 overweight persons aged 55 to 90 years with AMCI. The main outcome of the study will be changes in performance in a memory test (total recall of the Selective Reminding Test) and the Score a test of general cognitive function used in clinical trials (the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog)). Another aim is to compare brain function in an area affected by Alzheimer's disease between the metformin and placebo group mean changes from beginning to end among 40 participants using a PET scan.

Detailed Description

The prevalence of Alzheimer's disease (AD) is expected to quadruple by the year 2047. There are no known curative or preventive measures for AD. Current treatment options for AD only address symptoms, and no treatments are available that focus on delaying the actual disease process. One of the currently accepted hypothesis of the pathogenesis of AD is that the main culprit is the accumulation of Aβ in the brain, and this process has become a target for treatments and preventive measures. Amnestic mild cognitive impairment (MCI) has been used to describe a transitional state between normal cognitive function and AD, and has thus been targeted for interventions. Persons with MCI progress to AD at the rate of nearly 10% to 15% per year. The criteria most commonly used for the definition of AD dementia from MCI. The investigators propose to use these criteria with slight modification to recruit persons for a pilot trail of AD prevention in persons with amnestic MCI.

Peripheral hyperinsulinemia (high insulin levels) potentially impair Aβ clearance, and in this study we are proposing to use metformin, an insulin lowering agent, to prevent AD by improving Aβ clearance in the brain. The insulin resistance syndrome and hyperinsulinemia are common in individuals with and without diabetes, and are related to increased risk of cardiovascular and cerebrovascular outcomes. Hyperinsulinemia predicts the development of diabetes; therefore, diabetes can be considered a consequence and a marker of past hyperinsulinemia. According to NHANES III data, more than 40% of the population over the age of 60 years has problems of glucose intolerance or diabetes, all related to insulin resistance and hyperinsulinemia. The investigators have found that the risk of AD in individuals without diabetes increases with increasing levels of fasting insulin, and that high insulin levels are related to a faster decline in memory scores. The high prevalence of hyperinsulinemia and diabetes (49% of the elderly in Northern Manhattan) and its biological plausibility as a risk factor for cognitive decline and AD has attracted increasing attention. In this application we are targeting hyperinsulinemia, the most important risk factor for AD identified in the elderly population of Northern Manhattan. The risk of AD attributable to hyperinsulinemia or diabetes in Northern Manhattan was 39%, and is higher in Hispanics and African-Americans, who have a higher prevalence of diabetes and insulin resistance, and will comprise the majority of our sample.

Conditions

Mild Cognitive Impairment

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Matching Placebo

Placebo identical to metformin

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo identical to metformin 2 tablets twice a day titrated from one table once a day

Metformin

Metformin 1000 mg twice a day

Group Type: EXPERIMENTAL

Metformin

Intervention Type: DRUG

Metformin 1000 mg twice a day titrated from 500 mg once a day

Interventions

Metformin

Metformin 1000 mg twice a day titrated from 500 mg once a day

Intervention Type: DRUG

Placebo

Placebo identical to metformin 2 tablets twice a day titrated from one table once a day

Intervention Type: DRUG

Other Intervention Names

Glucophage

Eligibility Criteria

Inclusion Criteria

• Memory complaint expressed by the participant and recognized by the informant. The memory complaint must represent a change from previous functioning based on information provided by both subject and informant.
• Fluent in English or Spanish.
• Mini-Mental State Examination (MMSE) equal or more than 20.
• Subjects must fulfill criteria for amnestic mild cognitive impairment (MCI). Guidelines for the diagnosis of MCI: Subjects must score below a predetermined cut-off score on the logical memory II delayed paragraph recall sub-test of the Wechsler Memory Scale Revised (WMS-R) or the selective reminding test (SRT).
• Global Clinical Dementia Rating (CDR) score must be 0.5 at screening.
• Subjects without a known history of diabetes or diabetes that has never been treated with medications. If diabetes is diagnosed during screening or they have a history of diabetes not treated in the last 12 months they will be excluded if their Hemoglobin A1c (HbA1c) is > 6.5. In addition, a diagnosis of diabetes can be made if the HbA1c is 6.5% or more.
• Overweight or obese by National Heart, Lung, and Blood Institute (NHLBI) criteria (Body Mass Index (BMI) of more or equal of 25 kg/ m2).
• No contraindications to metformin treatment.
• Hachinski score less or equal to 4.
• Hamilton score less or equal to 12 on the 17 item scale.
• General cognition and functional performance such that a diagnosis of dementia cannot be made at the time of screening based on DSM-IV criteria.
• Vision and hearing must be sufficient for compliance with testing procedures.

Exclusion Criteria

• Individuals with dementia
• MMSE < 20
• Subjects with neurologic diseases associated to neurologic deficits.
• Subjects with current psychiatric diagnoses such as depression, bipolar disorder or schizophrenia.
• Subjects with uncontrolled hypertension (systolic blood pressure more than 160 mmHg or diastolic blood pressure more than 95 mmHg.
• Subjects with a history of active cancer or cancer within last five years, with the exception of squamous or basal cell carcinoma of the skin.
• Subjects who for any reason may not complete the study as judged by the study physician.
• Subjects with a known history of diabetes treated with medications.
• Subjects with a new or old diagnosis of diabetes, never treated, with a HbA1c of more than 6.5 .
• Contraindications to metformin: Contraindications to metformin use include a creatinine of > 1.5, liver disease by history or by elevated transaminases, congestive heart failure, and alcohol abuse.
• Use of cholinesterase inhibitors.

• Presence of diabetes, even if the HbA1c is less or equal to 6.5.
• Inability to lie down for any reason.
• Presence of any metallic implant.
• Claustrophobia.
• Any contraindication to magnetic resonance imaging (MRI) or fluorodeoxyglucose (FDG) positron emission tomography (PET).

• Minimum Eligible Age: 55 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Institute for the Study of Aging (ISOA)

OTHER

Sponsor Role: collaborator

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

Columbia University

OTHER

Sponsor Role: lead

Responsible Party

José A. Luchsinger

Associate Professor of Medicine and Epidemiology at NYPH/CUMC

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jose A Luchsinger, MD

Role: PRINCIPAL_INVESTIGATOR

Columbia University

Locations

Columbia University Medical Center

New York, New York, United States

Countries

United States

References

Luchsinger JA, Perez T, Chang H, Mehta P, Steffener J, Pradabhan G, Ichise M, Manly J, Devanand DP, Bagiella E. Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. J Alzheimers Dis. 2016;51(2):501-14. doi: 10.3233/JAD-150493.

Reference Type: RESULT

PMID: 26890736 (View on PubMed)

Other Identifiers

R01AG026413

Identifier Type: NIH

Identifier Source: secondary_id

View Link

270901

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

AAAC7231

Identifier Type: -

Identifier Source: org_study_id