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

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.

Study Overview

• Status: Completed
• Conditions: PreDiabetes; Aging
• Intervention / Treatment: Drug: Metformin; Drug: Placebo Oral Tablet

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.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico Clincal & Translational Science Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: 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.; Other Names: Glucophage
Placebo Comparator: 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.	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.; Other Names: Calcium Carbonate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Leucocyte LC3 Score	During the process of autophagy, autophagosomes engulf cytoplasmic components and concomitantly, the cytosolic form of LC3 (LC3-I) is conjugated to phosphatidyl ethanolamine, resulting in the autophagosomal membrane-bound form (LC3-II). LC3-II is a widely used marker to monitor autophagosome formation by quantitation of the number of LC3-labeled puncta (autophagosomes, or "dots") per cell detected by fluorescence microscopy. An increase in LC3 puncta formation denotes an increase in autophagic activity.	Data will be collected at 0 and 12 weeks and analyzed within 8 weeks of sample collection.

Collaborators and Investigators

• Sponsor: University of New Mexico
• Investigators: Principal Investigator: Mark R Burge, MD, Professor Medicine, UNM HSC Endocrinology

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2017
• Primary Completion (Actual): August 20, 2020
• Study Completion (Actual): August 20, 2020

Study Registration Dates

• First Submitted: July 7, 2017
• First Submitted That Met QC Criteria: October 11, 2017
• First Posted (Actual): October 13, 2017

Study Record Updates

• Last Update Posted (Estimated): December 11, 2023
• Last Update Submitted That Met QC Criteria: December 7, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Autophagy
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperglycemia; Prediabetic State; Glucose Intolerance; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Antacids; Metformin; Calcium Carbonate
• Other Study ID Numbers: 17-214

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data will be made available for data sharing as is consistent with current NIH guidelines.
• IPD Sharing Time Frame: After the study is completed and published. The data should be available in perpetuity in the University of New Mexico (UNM) Digital Repository.
• IPD Sharing Access Criteria: No restrictions.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No