A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-Autophagy Effects of Metformin in Adults With Prediabetes

NCT ID: NCT03309007

Last Updated: 2023-12-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-09-01
• Study Completion Date: 2020-08-20

Brief Summary

The goal of this pilot and feasibility study is to investigate the effects of a short course of metformin therapy on a surrogate marker of cellular senescence and autophagy among adult patients with prediabetes. The overall hypothesis is that metformin will have beneficial effects on longevity and quality of life by inducing autophagy downstream of activating adenosine monophosphate-activated protein kinase (AMPK) and inhibiting mechanistic target of rapamycin (mTOR) through potential effects of reduced inflammation, reduced degeneration of muscle and tendon tissue, antineoplastic effects, reduced obesity and hyperglycemia, preserved cardiovascular functions, and/or the prevention of neurodegeneration (such as age-associated dementia). This pilot study will address the following aim:

Demonstrate that metformin therapy will increase cellular autophagy as an inverse correlate of aging as measured by increases in Microtubule-associated protein 1A/1B-light chain 3 (LC3) scores.

Hypothesis 1: In addition to beneficial effects on glycemia, body weight, and body composition, metformin therapy exerts beneficial effects on surrogate measures of autophagy and aging.

Primary outcome: Increased levels of LC3 in leukocytes.

Detailed Description

Anti-aging medicine is a burgeoning field. Accumulating evidence implicates the cellular process of autophagy as a primary mechanism of normal aging and the diseases associated with it. Autophagy is a process of "cellular recycling" and is known to affect a spectrum of health and disease states associated with aging, including inflammatory disorders, metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer, and neurodegeneration. The dynamics of autophagy are controlled by autophagy-related genes and by one of the central regulators of metabolism, AMPK (the target of metformin). Autophagy also affects stem cells and cellular senescence. When the process of autophagy fails, the result is a state of chronic inflammation and degeneration in many organ systems.

Numerous studies have documented the metabolic benefits conferred by the glucose lowering agent metformin. In animal models, metformin has been shown to increase both lifespan and health-span, and a clinical trial (NCT02432287) is currently ongoing to determine whether this effect translates to humans, with additional investigation into how the medication alters the adult human transcriptome. In vitro studies demonstrate metformin's ability to mitigate aging- and disease-related inflammation, oxidative damage, and diminished autophagy. Additionally, there are numerous cohort, case-control and meta-analysis studies confirming metformin's reduction in cancer-related death via hypothesized activity in the relevant mTOR, human epidermal growth factor receptor 2 (HER2), micro-Ribosomal Nucleic Acid (miRNA) and transcription growth factor alpha (TGF-alpha) pathways and processes. As such, the National Institutes of Health (NIH) has issued an Funding Opportunity Announcement (FOA) parent announcement PA-17-073 (https://grants.nih.gov/grants/guide/pa-files/PA-17-073.html) to solicit additional clinical studies that will evaluate metformin's effects on aging and age-related conditions.

The long term goal of this study is to develop a Phase III study in response to this FOA using leucocyte LC3, transcription factor EB (TFEB) scores, total DNA methylation and galectin-3 to gauge the magnitude of metformin's effects on autophagy and cellular senescence as proxies for aging in adults with prediabetes. This study will provide preliminary data for such a proposal, and it will fill a knowledge gap regarding the use of validated biomarkers in this arena. It will also contribute significantly to the anti-aging literature. The primary objective of this proposal is to validate the autophagy-related experimental design by using leucocyte LC3 as a marker of autophagy and cellular senescence in humans.

Aim: Demonstrate that metformin therapy will increase cellular autophagy as an inverse correlate of aging as measured by increases in LC3 scores.

Hypothesis 1: In addition to beneficial effects on glycemia, body weight, and body composition, metformin therapy exerts beneficial effects on surrogate measures of autophagy and aging.

Primary outcome: Increased levels of LC3.

FUTURE DIRECTIONS Confirmation of improvement in markers of autophagy resulting from treatment with metformin will justify the submission of grant proposals for more definitive clinical trials examining the effect of metformin on actual clinical outcomes (as opposed to surrogate measures) in pursuit of a potential Food and Drug Administration (FDA) indication for metformin as an anti-aging therapy.

Conditions

PreDiabetes; Aging

Keywords

Autophagy

Study Design

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

Study Groups

Metformin

Metformin started at 500 mg po twice daily (BID), and then titrated up to 1000 mg po q morning (AM) and 500 po q evening (PM) over the course of 1 month, as tolerated.

Group Type: EXPERIMENTAL

Metformin

Intervention Type: DRUG

Total daily dose titrated up to 1500 mg po q day over the course of 4 weeks and continued for a total exposure of 12 weeks.

Placebo Oral Tablet

Near-identical CaCO3 as a Placebo Oral Tablet will be started at 648 mg po BID, and then titrated up to 1296 mg po q AM and 648 mg po q PM over the course of 1 month, as tolerated.

Group Type: PLACEBO_COMPARATOR

Placebo Oral Tablet

Intervention Type: DRUG

Total daily dose titrated up to 1944 mg po q day over the course of 4 weeks and continued for a total exposure of 12 weeks.

Interventions

Metformin

Total daily dose titrated up to 1500 mg po q day over the course of 4 weeks and continued for a total exposure of 12 weeks.

Intervention Type: DRUG

Placebo Oral Tablet

Total daily dose titrated up to 1944 mg po q day over the course of 4 weeks and continued for a total exposure of 12 weeks.

Intervention Type: DRUG

Other Intervention Names

Glucophage; Calcium Carbonate

Eligibility Criteria

Inclusion Criteria

• Adults with prediabetes (defined as an A1c of 5.7-6.4%)
• BMI between 27 and 40 kg/m2 (inclusive).

Exclusion Criteria

• Prior treatment with metformin or other diabetes medications,
• Pregnancy,
• Significant renal dysfunction (Serum Creatinine > 1.3 mg/dl for women, > 1.4 mg/dl for men),
• Severe hepatic dysfunction (aspartate amnotransferease [AST] or alanine aminotransferase [ALT] > 3 times the upper limit of normal),
• Ongoing alcohol or substance abuse,
• Inflammatory bowel disease,
• Ongoing glucocorticoid therapy,
• Or inability to render informed consent.

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of New Mexico

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mark R Burge, MD

Role: PRINCIPAL_INVESTIGATOR

Professor Medicine, UNM HSC Endocrinology

Locations

University of New Mexico Clincal & Translational Science Center

Albuquerque, New Mexico, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

17-214

Identifier Type: -

Identifier Source: org_study_id