Metformin in Amnestic Mild Cognitive Impairment (MCI)

• Total Recall in the Selective Reminding Test [ Time Frame: 12 MONTHS ] [ Designated as safety issue: No ]
• ADAS-cog [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  Alzheimer's Disease Assessment Scale-cognitive subscale

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, we hypothesize the 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. We 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.

1. SPECIFIC AIMS:

   The goal of this study is to conduct a phase II placebo controlled randomized trial of metformin lasting 12 months in the prevention of memory decline in 80 persons with amnestic MCI in order to collect preliminary data on efficacy, safety, and feasibility.

   • Our primary aim is to compare changes in total recall of the Selective Reminding Test and changes in the modified Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-COG) between metformin and placebo on an intent to treat basis..
   • Our secondary aim is to compare relative glucose uptake (rCMRgl) in the posterior cingulate-precuneus measured with brain [18]F-labeled 2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET).
   • Our exploratory aim is to compare plasma amyloid beta (Aβ) 42 between metformin and placebo.

2. BACKGROUND AND SIGNIFICANCE:

   • Burden of Alzheimer's disease. 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. We propose to use these criteria with slight modification to recruit persons for a pilot trail of AD prevention in persons with amnestic MCI.
   • Hyperinsulinemia, diabetes, and risk of AD. 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. We 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
   • Choice of metformin as treatment agent:. The Diabetes prevention program (DPP) is a trial of metformin vs. lifestyle intervention (diet and exercise) vs. Placebo in the prevention of onset of diabetes in 3,234 individuals without diabetes at baseline. It found that both metformin and lifestyle intervention were successful in preventing diabetes vs. placebo in 3 years of follow-up and in reducing insulin levels. Serious adverse events of metformin including hospitalizations and hypoglycemia were similar to placebo. More recently, another agent that lowers insulin levels, rosiglitazone, was tested in similar fashion for the prevention of diabetes and found effective, and is now being tested in AD given its insulin decreasing properties. However, rosiglitazone's safety profile is not as good as metformin- it can cause, edema and heart failure(21), and is not widely using in clinical practice in persons without diabetes, as metformin is.

3. METHODS. PARTICIPANTS: In general the participants are persons who meet criteria for Amnestic Mild Cognitive Impairment, do not have treated diabetes, and are overweight or obese (BMI >25 Kg/m2).

   • 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.


     • Age range: 55 years to 90 years. The main rationale for this inclusion criteria is to follow the standard set by the ADCS
     • Sex distribution: men and women.
- Languages: fluent in English or Spanish.
- MMSE equal or more than 20. The rationale for this cutoff is that the population of Washington Heights is heterogeneous in educational and cultural background. Persons with low educational attainment may have a score of 20 without having dementia.


     • Subjects must fulfill criteria for amnestic mild cognitive impairment (MCI) according to criteria developed for the population of Northern Manhattan by one of the co-investigators in this study Jennifer Manly. The diagnosis of mild cognitive impairment is reached by consensus between Drs. Luchsinger and Dr. Manly based on information from the neuropsychological battery, the presence of memory complaints, and the clinical dementia rating. This is the standard procedure used in the Washington Heights Inwood Columbia Aging Project (WHICAP) for the diagnosis of amnestic 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).
For the logical memory II delayed paragraph recall the cutoffs are:

       1. less than or equal to 8 for 16 or more years of education.
       2. less than or equal to 4 for 8-15 years of education; 
c) less than or equal to 2 for 0-7 years of education. For the SRT subjects must score below a predetermined cut-off score. The cutoffs for the SRT are calculated for each individual based on their age, gender, and education level. For example, for a 75-year old African American woman with 6 years of education, an SRT total recall score of 25 yields a T-score of 42, which is in the normal range, while for an AA woman of the same age with a master's degree (18 years of school), the T-score is 34 which is in the impaired range. This woman would be classified as MCI if she met the criteria for function.
     • Global CDR score must be 0.5 at screening. The memory box score must be 0.5 or 1.0, with no more than two box scores other than memory rated as high as 1.0 and no box score rated greater than 1.0.
- *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 HbA1c is > 6.5. In addition, a diagnosis of diabetes can be made if the HbA1c is 6.5% or more (American Diabetes Association, January 2010). The reason our study does not include persons with diabetes is that some medications to treat diabetes (sulfonylureas, insulin) INCREASE insulin levels. This would interfere with our study, which is based on the premise that lowering insulin levels with metformin will decrease the risk of memory impairment. The ADA recommends a target of < 7 of HbA1c for diabetes treatment. Thus, persons with a HbA1c < 7 with a new diagnosis of diabetes do not require pharmacologic treatment. We propose to include in our study persons with a new or previous diagnosis of diabetes, never treated with any drug, who have a HbA1c of 6.9% or less. The rationale for this cutoff is that we want to diminish the chances that someone enrolled in the study with new diabetes or old diabetes without pharmacologic treatment will require treatment during the 12 months of the study. We will provide all participants with the results of their testing including HbA1c. The participants and their physicians will have the discretion to start diabetes treatment. If this happens we will record such information and continue following the participants as randomized. These participants (those diagnosed with diabetes started on treatment outside of the study) would still be considered in Intent-to-treat analyses. All other inclusion and exclusion criteria still apply to these participants including body mass index.

     • Overweight or obese by National Heart, Lung, and Blood Institute (NHLBI) criteria (BMI of more or equal of 25 kg/ m2)(33). The main rationale for the use of this criteria is that they predict insulin resistance in the general population and we need to use criteria that are generalizable and standard for a phase III trial. Measurement of insulin for the diagnosis of insulin resistance is not standard in clinical practice, and there are no absolute definitions of what constitutes insulin resistance. Using BMI criteria as a surrogate of insulin resistance is an acceptable alternative used in research and clinical practice. Glucose intolerance is not necessarily a proxy for insulin resistance and may be a sign of insulin deficiency. Thus, we will not use glucose intolerance as a criterion for entering the study.

     • 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
- At the time of telephone contact for screening, we may conduct the Telephone Interview for Cognitive Status (TICS) if the potential participant agrees. This procedure is currently followed in other Studies at Columbia University to screen out persons who are unlikely to have any memory impairment (we are recruiting persons with mild cognitive impairment). A Score > 34 on the Telephone Interview for Cognitive Status (TICS) out of 41 is considered normal cognition. Persons with this score will not be invited to participate.

     • Subjects with neurologic diseases associated to neurologic deficits.

     • Subjects with current psychiatric diagnoses such as depression, bipolar disorder or schizophrenia.
- Normal individuals without cognitive complaints.

     • 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 hemoglobin A1c 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. We will also exclude subjects with a history of intolerance to metformin.
- Use of cholinesterase inhibitors. The rationale for this exclusion is that the ADCS showed a beneficial effect of donepezil at 12 months(16) which could confound our study. We do not have survey data on the use of cholinesterase inhibitors, but believe that their use is uncommon in persons with AMCI, particularly if they are recruited from the community.

   • Exclusion criteria for brain imaging study:


     • Presence of diabetes, even if the HbA1c is less or equal to 6.5. The reason for this is that FDG PET uptake will be affected by glucose levels.

     • Inability to lie down for any reason.

     • Presence of any metallic implant.

     • Claustrophobia.

     • Any contraindication to MRI or FDG PET as determined by the staff of the hatch center (MRI) or Kreitchman center (PET). A safety screen form from the MRI research center is attached.

SCREENING AND RECRUITMENT: We will advertise within the medical center, using free newsletters in the Community of Washington heights, using paid print media, using free and paid internet media, and using radio. If we are contacted for participation, we will screen for exclusion criteria. If persons feel comfortable with cognitive testing over the phone, we will administer the Telephone Interview for Cognitive Status (TICS). We will have access to WebCis, the internet based clinical information system from Columbia University Medical Center (CUMC), which we will use to ascertain exclusion criteria. If the person meets criteria for AMCI, they will be invited to participate in the study and randomized to metformin or placebo within one month.

The sources of the participants will be:1) The Associates in Internal Medicine (AIM) practice of Columbia University; 2) the Memory Disorders Clinic (MDC) at AIM; 3) The Community of Washington Heights. We expect that 50% of participants will be Hispanic, 30% Black, and 20% Non-Hispanic White, 70% women, and 30% men.

RANDOMIZATION. We propose the use of random permuted blocks as the method of randomization to ensure balance in the groups given the small sample size. If participants are included in the study we will do APOE-ε4 genotyping and use this information for block randomization.

SCHEDULE OF ASSESSMENTS. We will collect medical history and concomitant medication data at every visit. Participants will be examined at 3 month intervals. Imaging studies will be conducted only at baseline and after the 12 month visit.

METFORMIN AND PLACEBO. Metformin Dosing Schedule and side effects: Metformin and matching placebo will be provided by Merck-Lipha of France. The medication and placebo will be managed and dispensed by the Research Pharmacy at Columbia University Medical Center. Persons will first be given metformin 500 mg once a day at baseline. At day-7 the dose will be increased to 500 mg twice a day. At day 14, the dose will be increased to 500 mg three times a day. At day 21, the dose will be recommended to 1000 mg twice a day. At day 28, we will call the patient via telephone to ascertain that they are tolerating the dose of 1000 mg twice a day, the usual maximum dose recommended in clinical practice. If the participants report not tolerating a dose of metformin, they will be asked to remain at the lowest tolerated dose. The most common side effect of metformin is gastrointestinal intolerance. At baseline, 3 month, 6 month, 9 month visit and at the end of the study we will measure renal function, liver function, and complete blood count to monitor side effects. This information will be made available to the data safety monitoring board of the study.

NEUROPSYCHOLOGICAL BATTERY. All measures will be available in English and Spanish. The neuropsychological battery includes our 2 co-primary outcomes, the Buschke Selective Reminding test, and the modified ADAS-Cog. In addition, our battery includes the ADCS Clinical Global Impression of Change-Mild cognitive impairment, the Clinical Dementia Rating, the Digit Span Backwards, the Hamilton Rating Scale for Depression, the Logical Memory Test, the Mini Mental State Examination, and the neuropsychiatric inventory.

OTHER ASSESSMENTS:

We will assess body mass index (BMI), blood pressure, heart rate, respiratory rate, and conduct a physical exam to search for contraindications to metformin including cardiac disease. Will also perform an EKG at baseline.

LABORATORY MEASURES. Plasma Aβ40 and Aβ42 have been suggested as markers of AD and high Aβ42 has been shown to predict AD progression in Northern Manhattan . They will be measured in all participants at baseline and at the end of the study from EDTA plasma stored a -80 degrees F using published procedures.

General chemistry, liver function tests, and complete blood count will be done as shown in the timetable to monitor for contraindications and side effects of metformin. In persons with no available information on TSH, B12, and RPR, necessary measures to rule out secondary cognitive impairment, we will obtain them at baseline. HsCRP, insulin, lipids, adiponectin, and HbA1c are inflammatory and metabolic intermediate variables and will be measured to ascertain the effects of metformin and to explore mechanisms for a benefit of metformin on the outcomes. APOE-ε4 genotyping will also be conducted.

BRAIN IMAGING. A subsample of the study will compare on an intention-to-treat basis between the metformin and placebo group mean changes from the beginning to end of the trial in uptake of fluorodeoxyglucose (FDG) in the posterior cingulate-precuneous measured with brain positron emission tomography (PET) in 40 non-diabetic patients out of the 80 study subjects. PET imaging will be performed with a HR+ scanner at Columbia Kreitchman PET Center. All image analysis will be performed with MEDX and FSL (FMRIB) Software Library). There will also be a brain magnetic resonance imaging (MRI). MRI images co-registered to the PET images allow accurate structural localization of metabolic changes and correction of brain atrophy. Participants will be scanned on a 1.5T Philips Intera dedicated research scanner. Four sets of structural images will be obtained from each subject during their MRI scanning session. The total imaging time will be 30 minutes. As part of standard procedures, a neuroradiologist conducts a clinical evaluation to rule out tumors, strokes, and other lesions. Any significant abnormality is discussed with the study investigator, who then takes appropriate action, including discussion of the abnormality with the participant, and with the participant's permission, with the participant's physician of choice. If the participant has no physician, we will facilitate one at Columbia University Medical Center. PET and MR images will be spatially normalized to a custom template image in standard Montreal Neurological Institute (MNI) space. The spatial normalization will allow assessing any changes in the metabolic rate of glucose as a result of the intervention through a statistical parametric mapping approach. These spatial parameters will be applied to the co-registered PET images thereby transforming them into standardized space.

STATISTICAL ANALYSES. The primary analyses will be conducted on an intention-to-treat basis. We will use ANACOVA to compare changes from baseline to 12 months in all outcomes between metformin and placebo. We will adjust for variables found to be different between the metformin and placebo groups at baseline. The primary analyses are those for the primary aim, secondary aim, and exploratory aim.

We will also secondary analyses examining completers, and also examining changes in metabolic markers and other cognitive measures.

I

• Drug: metformin
  metformin 1000 mg twice a day titrated from 500 mg once a day
  Other Name: glucophage
• Drug: placebo
  placebo identical to metformin 2 tablets twice a day titrated from one table once a day
  Other Name: placebo

• Placebo Comparator: P
  placebo identical to metformin.
  Intervention: Drug: placebo
• Experimental: metformin
  metformin 1000 mg twice a day
  Intervention: Drug: metformin

Inclusion Criteria:

• Age range: 55 to 90 years;
• Sex distribution: men and women;
• Languages: fluent in English or Spanish.

• Subjects must score below a pre-determined cut-off score on the logical memory II delayed paragraph recall sub-test of the Wechsler Memory Scale Revised (WMS-R)26:

  1. less than or equal to 8 for 16 or more years of education.;
  2. less than or equal to 4 for 8-15 years of education;
  3. less than or equal to 2 for 0-7 years of education.
• Global Clinical dementia rating (CDR) score must be 0.5 at screening. The memory box score must be 0.5 or 1.0, with no more than two box scores other than memory rated as high as 1.0 and no box score rated greater than 1.0.
• 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 HbA1c is > 6.5.
• BMI ≥ 25 kg/m2
• No contraindications to metformin treatment.
• 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:

• Subjects with uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 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;
• Abnormal TSH, B12, and RPR.
• Contraindications to metformin use include a creatinine of > 1.5, liver disease by history or by elevated transaminases, congestive heart failure, and alcohol abuse.
• We will also exclude subjects with a history of intolerance to metformin.

• Institute for the Study of Aging (ISOA)
• National Institute on Aging (NIA)