PreDiabetesPhase 3NCT03309007
A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-Autophagy Effects of Metformin in Adults With Prediabetes
A Phase 3 study testing Metformin in people with PreDiabetes and Aging, run by University of New Mexico at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 30 to 70 years
- Conditions the study is for
- PreDiabetes, Aging
- What is being tested?
- Metformin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 25 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Sep 2017to 20 Aug 2020
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 30 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adults with prediabetes (defined as an A1c of 5.7-6.4%)
- BMI between 27 and 40 kg/m2 (inclusive).
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
University of New Mexico Clincal & Translational Science Center
Albuquerque, New Mexico, 87131
About this study
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.
Read more
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.
Read the 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
- Being tested
- Metformin, Placebo Oral Tablet
- Keywords
- Autophagy
- Medical subject headings
- Prediabetic State
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminDrug
Also called Glucophage
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 TabletDrug
Also called Calcium Carbonate
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.
| Study group | Role | What they receive |
|---|---|---|
| Metformin | Experimental | 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. Receives: Drug: Metformin |
| Placebo Oral Tablet | Placebo comparator | 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. Receives: Drug: Placebo Oral Tablet |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Data will be collected at 0 and 12 weeks and analyzed within 8 weeks of sample collection.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Oct 2017
- Study start1 Sep 2017
- Primary completion20 Aug 2020
- Study completion20 Aug 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for PreDiabetesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- This is a double-blind, approximate placebo-controlled trial of 12 weeks of metformin vs. CaCO3 (Placebo) among adult patients with prediabetes.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 25 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of New Mexico
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Mark R Burge, MD, Principal investigator, Professor Medicine, UNM HSC Endocrinology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03309007
- Sponsor's protocol ID
- 17-214
- Status last verified
- Dec 2023
- First submitted
- 7 Jul 2017
- Last updated
- 11 Dec 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: De-identified data will be made available for data sharing as is consistent with current NIH guidelines.
Study at a glance
From the registry record, last updated by the sponsor on 11 Dec 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-Autophagy Effects of Metformin in Adults With Prediabetes
- ClinicalTrials.gov ID
- NCT03309007
- Acronym / sponsor ID
- 17-214
- Conditions
- PreDiabetes, Aging
- Keywords
- Autophagy
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 25 participants (actual)
- Lead sponsor
- University of New MexicoUniversity, hospital or other
- Study start
- 1 Sep 2017 (actual)
- Primary completion
- 20 Aug 2020 (actual)
- Study completion
- 20 Aug 2020 (actual)
- First posted
- 13 Oct 2017 (actual)
- Results
- Posted 11 Dec 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- This is a double-blind, approximate placebo-controlled trial of 12 weeks of metformin vs. CaCO3 (Placebo) among adult patients with prediabetes.
| Arm | Type | Receives |
|---|---|---|
| Metformin | Experimental | Drug: MetforminMetformin 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. |
| Placebo Oral Tablet | Placebo comparator | Drug: Placebo Oral TabletNear-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. |
Who may qualify
- Ages
- 30 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Adults with prediabetes (defined as an A1c of 5.7-6.4%)
- BMI between 27 and 40 kg/m2 (inclusive).
Key exclusion criteria (8 listed)
- 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,
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MetforminAlso: GlucophageTotal 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. | Drug | Metformin |
| Placebo Oral TabletAlso: Calcium CarbonateTotal 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. | Drug | Placebo Oral Tablet |
Primary outcome
Change in Leucocyte LC3 Score
Time frame: Data will be collected at 0 and 12 weeks and analyzed within 8 weeks of sample collection.
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Dec 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: Yes. De-identified data will be made available for data sharing as is consistent with current NIH guidelines.
Related trials for PreDiabetes
Recruiting
Effects of Lean Pork Loin Intake on Protein Homeostasis and Glucose Regulation in Prediabetic Adults
Hyperglycaemia (Non Diabetic), Prediabetes
RecruitingObservational study
Food-i-Sense Analytics: Integrating AI Into Continuous Glucose Monitoring Data Analysis for Precision Nutrition.
Prediabetes (Insulin Resistance, Impaired Glucose Tolerance), Artificial Intelligence Mobile Application
RecruitingPhase 3
A Study of Orforglipron in Participants With Overweight at Risk of Development of Obesity-Related Complications or Progression to Class 1 Obesity
Overweight, Prediabetic State
Enrolling by invitationEarly Phase 1
Truway Diagnostic Tools in Primary Care
Chronic Disease, Type 2 Diabetes Mellitus (T2DM), Obesity, Overweight
Recruiting
CGM-Enhanced DPP to Prevent Type 2 Diabetes in Adults With Prediabetes
PreDiabetes
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mark R Burge, MD principal investigator
Professor Medicine, UNM HSC Endocrinology
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Metformin in people with PreDiabetes and Aging, run by University of New Mexico at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 Dec 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Leucocyte LC3 Score (time frame: Data will be collected at 0 and 12 weeks and analyzed within 8 weeks of sample collection.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Dec 2023.