Metformin Effect on Brain Function in Insulin Resistant Elderly People

NCT ID: NCT03733132

Last Updated: 2024-06-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-03-15
• Study Completion Date: 2023-04-05

Brief Summary

Alzheimer's disease (AD) and other forms of dementia are rapidly increasing with the aging of the population, and show a clear preponderance among people with insulin resistance. Metformin, an insulin sensitizer, is being examined in clinical trials as an anti-aging drug. However, very little objective data is available regarding metformin's effect on the brain, a major organ affected by aging.

Detailed Description

Insulin resistance is highly prevalent with advancing age. Metformin is an insulin sensitizer and is currently being extensively investigated for its potential anti-aging effect. However, only very limited information is available on metformin effect on brain, which is a major organ affected by aging. With appropriate experimental design, the investigators are attempting to understand the mechanism of metformin treatment on the physiology of the brain as well as cognitive effects. These studies may uncover relationships that could be favorably manipulated to decrease health risks associated with insulin sensitivity and the effect on the brain.

The study results may lead to a breakthrough in providing either definitive data or sufficiently strong preliminary data regarding metformin's effect on elderly people with insulin resistance, on whether the drug enhances brain mitochondrial function in conjunction with improvement of brain functional network and cognitive function.

The overall hypothesis is that metformin administration to elderly people with insulin resistance enhances brain mitochondrial function in conjunction with improvement of brain function. To test this hypothesis, the investigators will address the following Specific Aims:

1. Determine whether 40 weeks of metformin administration in elderly people (> 65 years) with insulin resistance enhances brain mitochondrial ATP production. The investigators will measure brain ATP production by 31P-MRS.

2. Determine the effect of 40 weeks of metformin administration in elderly people (> 65 years) with insulin resistance on blood flow and functional network in different areas of brain. As a secondary outcome, the investigators will measure structural changes in white and grey matter areas of brain to determine whether metformin has any effect on brain structure.

3. Determine the effect of 40 weeks of metformin administration in elderly people (> 65 years) with insulin resistance on cognitive function. The investigators will utilize the computerized NIH Toolbox to measure cognitive outcomes.

The investigators will also associate outcomes from our specific aims with improvements in whole-body insulin sensitivity and skeletal muscle mitochondrial function.

The investigators propose to complete 40 weeks of study in 40 elderly (> 65 years) participants with fasting glucose between 100 to 140 mg/dl and abdominal girth of >102 cm in men and > 88 cm in women. All participants will be those who are not oral hypoglycemic agents including metformin. In this double-blind placebo trial, the investigators will randomly assign the participants to placebo or metformin in an escalated dose to reach a maximum of 2500 mg per day.

Conditions

Insulin Resistance; Obesity; Obesity, Abdominal

Study Design

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

Study Groups

Placebo

Participants in placebo group will receive Placebo Oral Tablets identical to the metformin tablets for 10 months.

Group Type: PLACEBO_COMPARATOR

Placebo Oral Tablet

Intervention Type: DRUG

Placebo treatment of identical tablets to metformin group

Metformin

Participants in placebo group will receive an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months.

Group Type: ACTIVE_COMPARATOR

Metformin Hydrochloride

Intervention Type: DRUG

Metformin treatment of 2500mg for 10 months in the Metformin group

Interventions

Metformin Hydrochloride

Metformin treatment of 2500mg for 10 months in the Metformin group

Intervention Type: DRUG

Placebo Oral Tablet

Placebo treatment of identical tablets to metformin group

Intervention Type: DRUG

Other Intervention Names

Metformin; Placebo

Eligibility Criteria

Inclusion Criteria

• Age >/= 65 years
• Abdominal girth > 102 cm in men and > 88 cm in women-
• Fasting glucose >/= 100-140 mg/dL
• Non-smoker
• English language proficiency

Exclusion Criteria

• Coronary artery disease or heart failure
• A known medical condition that in the judgment of the investigator might interfere with the completion of the protocol such as the following examples:

Inpatient psychiatric treatment in the past 6 months

• Presence of a known adrenal disorder
• Abnormal liver function test results (Transaminase >2 times the upper limit of normal); testing required for subjects taking medications known to affect liver function or with diseases known to affect liver function
• Abnormal renal function tests results (calculated GFR <60 mL/min/1.73m2); testing required for subjects with diabetes duration of greater than 5 years post onset of puberty
• Active gastroparesis
• If on antihypertensive, thyroid, anti-depressant or lipid lowering medication, lack of stability on the medication for the past 2 months prior to enrollment in the study
• Uncontrolled thyroid disease (TSH undetectable or >10 mlU/L): testing required within here months prior to admission for subjects with a goiter, positive antibodies, or who are on thyroid hormone replacement, and within one year otherwise
• Abuse of alcohol or recreational drugs
• Infectious process not anticipated to resolve prior to study procedures (e.g. meningitis, pneumonia, osteomyelitis)
• Uncontrolled arterial hypertension (Resting diastolic blood pressure >90 mmHg and/or systolic blood pressure >160 mmHg) at the time of screening
• Oral steroids
• A recent injury to body or limb, muscular disorder, use of any medication, any carcinogenic disease, or other significant medical disorder if that injury, medication or disease in the judgment of the investigator will affect the completion of the protocol
• Any metal in the body that could interfere with magnetic resonance imaging (MRI) including pacemaker or implanted defibrillator, neurostimulators, ear implants, metal fragments within the body, metal joints, rods, pins, plates or screws
• Medications that may impact study end points such as mitochondrial biology eg. beta blockers
• Anti-hyperglycemic drugs including metformin
• Any other medication that the investigator believes is a contraindication to the subject's participation

• Minimum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

Mayo Clinic

OTHER

Sponsor Role: lead

Responsible Party

K. Sreekumaran Nair

Professor of Medicine and Consultant in Endocrinology and Metabolism

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

K Sreekumaran Nair, M.D., Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

Locations

Mayo Clinic in Rochester

Rochester, Minnesota, United States

Countries

United States

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Related Links

https://www.mayo.edu/research/clinical-trials

Mayo Clinic Clinical Trials

Other Identifiers

1R21AG060139-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

18-004012

Identifier Type: -

Identifier Source: org_study_id