AgingPhase 3ANTHEMNCT04264897
Antecedent Metabolic Health and Metformin Aging Study
A Phase 3 study testing Metformin in people with Aging and Insulin Sensitivity, run by Oklahoma Medical Research Foundation at 2 sites in United States.
Trial summary
Aging is the number one risk factor for the majority of chronic diseases. There are no pharmaceutical treatments to slow aging and prolong healthspan. The anti-diabetic drug metformin is considered a likely pharmaceutical candidate to slow aging. Read more about this study
- Who is it for?
- Ages 40 to 75 yearsHealthy volunteers can take part
- Conditions the study is for
- Aging, Insulin Sensitivity, Chronic Disease
- 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
- 166 participants
- Where
- 2 sitesUnited States
- Study dates
- 29 Jul 2020to 12 Mar 2025
- 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 40 to 75 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 40-75 years of age (inclusive)
- Free of chronic disease
- Comprehension of the protocol as indicated by an ability to respond to questions about the study after reading the consent form.
- Able to use and be contacted by telephone.
- Able to speak, read, and understand English, and complete a questionnaire in English
- Independently mobile
Who cannot join
- Pregnancy
- Heart disease (history, abnormal ECG, abnormal stress ECG)
- Cerebrovascular disease (history)
- Cancer (history)
- Chronic respiratory disease (history, forced expiratory volume at one second/forced vital capacity [FEV1/FVC] < 70, FEV1 < 80% predicted)
- Chronic liver disease (history, alanine transaminase [ALT] > 52 IU/L)
Show all 16Show fewer
- Diabetes (history, HbA1C ≥ 6.5, fasting blood glucose≥126 mg/dl, oral glucose tolerance test [OGTT] ≥ 200 mg/dl at 2 hrs)
- Impaired kidney function (eGFR ,45 mL/min)
- B12 lab values outside of normal range (<193 or >982 pg/mL)
- Alzheimer's (history)
- Chronic kidney disease (history, abnormal blood kidney panel including serum creatinine > 1.4)
- Problems with bleeding, on medication that prolongs bleeding time (if subject cannot safely stop prior to biopsy)
- Those on glucose lowering drugs
- Those planning to have imaging that requires intravenous contrast dye (within 6 weeks) or are on any of the following medications since they are contraindicated with the use of metformin: Dofetilide, Lamotrigine, Pegvisomant, Somatropin, Trimethoprim, Trospium, Gatifloxacin, Cephalexin, Cimetidine, Dalfampridine
- Tobacco use
- Allergies to lidocaine or metformin
Trial locations and contacts
2 sites in 1 country.
United States2 sites
University of Wisconsin-Madison
Madison, Wisconsin, 53705
University of Oklahoma Health Sciences Center, Oklahoma Shared Clinical and Translational Resources
Oklahoma City, Oklahoma, 73104
About this study
Official title: Does Insulin Sensitivity Impact the Potential of Metformin to Slow Aging
Aging is the number one risk factor for the majority of chronic diseases. There are no pharmaceutical treatments to slow aging and prolong healthspan. The anti-diabetic drug metformin is considered a likely pharmaceutical candidate to slow aging. In this study, the investigators hypothesize that metformin treatment in subjects free of type 2 diabetes will improve insulin sensitivity and glucoregulation in insulin resistant individuals, but will decrease insulin sensitivity and glucoregulation in insulin sensitive subjects. Further, the investigators hypothesize that long-term metformin treatment will remodel mitochondria in a way that decreases mitochondrial function in subjects that are insulin sensitive, but improves mitochondrial function in subjects that are insulin resistant. The investigators will use a dual-site, 12- week drug intervention trial performed in a double-blind, placebo-controlled manner on 148 subjects recruited from two separate sites (Oklahoma Medical Research Foundation (OMRF) and University of Wisconsin-Madison (UWM)). After consent and initial subject screening for chronic disease, subjects will be stratified to insulin sensitive (IS) or insulin resistant (IR) groups. Over a 12- week intervention, half of each group will take metformin and half will take a placebo. Pre- and post--intervention, subjects will complete a series of procedures to assess insulin sensitivity, glucose regulation, and biomarkers of aging. The same subjects will provide a skeletal muscle biopsy pre-- and post-intervention to assess the change in mitochondrial function and mitochondrial remodeling with and without metformin treatment. By completion of this project, the investigators expect to provide evidence that helps further delineate who may benefit from metformin treatment to slow aging.
Read the detailed description
Although there is epidemiological support for health benefits of metformin in patient populations, it is not clear if these protective effects extend to those free of disease. Therefore, there is a need to perform human studies determining which subjects free of chronic disease benefit from metformin treatment. Retrospective analysis of a randomized, double-blinded clinical trial in our lab revealed that subjects who were insulin sensitive had no effect or negative effects on insulin sensitivity when taking metformin during an exercise training program. These data suggest that in some subjects, metformin has detrimental metabolic outcomes that could accelerate aging. There are data both in support of and refuting that metformin inhibits mitochondrial complex I action and/or mitochondrial remodeling. The overall objective of this trial is to determine if subjects currently free of disease benefit from metformin treatment. There are two critical questions that remain unanswered in human subjects: 1) does antecedent metabolic health influence responses to metformin, and 2) does long-term treatment with metformin lead to mitochondrial remodeling and changes in function. To better understand the translational potential of a clinically relevant dose of metformin for the prevention of chronic conditions, this proposal aims to determine how antecedent metabolic health affects the response to metformin treatment, and identify the relationship between skeletal muscle mitochondrial remodeling and mitochondrial function with metformin treatment. The hypotheses are that: 1) metformin treatment in subjects free of Type 2 diabetes will improve insulin sensitivity and glucoregulation in insulin resistant individuals, but will decrease insulin sensitivity and glucoregulation in insulin sensitive subjects, and 2) long-term metformin treatment will remodel mitochondria in a way that decreases mitochondrial function in subjects that are insulin sensitive, but improves mitochondrial function in subjects that are insulin resistant. To test these hypotheses, a 12-week randomized, double-blind clinical trial will be performed in subjects 40-75 yrs of age, free of disease, and stratified by insulin sensitivity (insulin sensitive and insulin resistant). Pre- and post-training assessments include the hyperinsulinemic- euglycemic clamp to measure hepatic and peripheral insulin sensitivity, continuous glucose monitoring to determine glucoregulation, and proposed blood-based biomarkers of aging. Further, the use of novel stable isotope labeling with proteomic analysis will determine individual and complex-specific mitochondrial remodeling. This approach will be combined with analysis of protein modification and turnover to comprehensively analyze mitochondrial effects of metformin treatment in skeletal muscle. By completion of this project, it is expected that there will be evidence that helps further delineate who may benefit from metformin treatment to slow aging.
- Conditions
- Aging, Insulin Sensitivity, Chronic Disease, Mitochondria, Insulin Resistance
- Being tested
- Metformin, Placebo oral tablet
- Keywords
- Blood Glucose Regulation, 5' adenosine monophosphate-activated protein kinase, Healthspan, Skeletal muscle, Mitochondria
- Medical subject headings
- Insulin Resistance, Chronic Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminDrug
Also called Glucophage, Glucophage extended-release, Fortamet, Glumetza
Metformin (Hunter Pharmacy) following a "ramp up" dosing protocol with a targeted dose of 1500 mg/day for 12 weeks.
Placebo oral tabletDrug
Also called Placebo
Silicified microcrystalline cellulose, Micosolle®, K30 povidone, sodium starch glycolate, and magnesium stearate
| Study group | Role | What they receive |
|---|---|---|
| Metformin - Insulin Sensative | Experimental | The investigators use a "ramp up" dosing protocol in which the amount of metformin (Hunter Pharmacy) will begin at 500 mg/day in week 1, increase to 1000 mg/day in week 2, and then to 1500 mg/day in week 3, as tolerated. At week 3 and for the remaining 9 weeks, the dose will remain at 1500 mg/day, which is a standard clinical dose (1500-2000 mg/day). If a subject has gastrointestinal discomfort with 1500 mg/day the dose, the investigators will lower the dose to 1000 mg/day. The investigators will split the dose with 1/2 given in the a.m. and 1/2 in the p.m. and taken with meals to minimize GI discomfort. Receives: Drug: Metformin |
| Placebo - Insulin Sensitive | Placebo comparator | Subjects assigned to the placebo group will receive visually identical pills (silicified microcrystalline cellulose, Micosolle®, K30 povidone, sodium starch glycolate, and magnesium stearate).
The same dosing schedule will be followed as for metformin. The investigators use a "ramp up" dosing protocol in which the amount of placebo (Hunter Pharmacy) will begin at 500 mg/day in week 1, increase to 1000 mg/day in week 2, and then to 1500 mg/day in week 3, as tolerated. At week 3 and for the remaining 9 weeks, the dose will remain at 1500 mg/day. If a subject has gastrointestinal discomfort with 1500 mg/day the dose, the investigators will lower the dose to 1000 mg/day. The investigators will split the dose with 1/2 given in the a.m. and 1/2 in the p.m. and taken with meals to minimize GI discomfort. Receives: Drug: Placebo oral tablet |
| Metformin - Insulin Resistant | Experimental | The investigators use a "ramp up" dosing protocol in which the amount of metformin (Hunter Pharmacy) will begin at 500 mg/day in week 1, increase to 1000 mg/day in week 2, and then to 1500 mg/day in week 3, as tolerated. At week 3 and for the remaining 9 weeks, the dose will remain at 1500 mg/day, which is a standard clinical dose (1500-2000 mg/day). If a subject has gastrointestinal discomfort with 1500 mg/day the dose, the investigators will lower the dose to 1000 mg/day. The investigators will split the dose with 1/2 given in the a.m. and 1/2 in the p.m. and taken with meals to minimize GI discomfort. Receives: Drug: Metformin |
| Placebo - Insulin Resistant | Placebo comparator | Subjects assigned to the placebo group will receive visually identical pills (silicified microcrystalline cellulose, Micosolle®, K30 povidone, sodium starch glycolate, and magnesium stearate).
The same dosing schedule will be followed as for metformin. The investigators use a "ramp up" dosing protocol in which the amount of placebo (Hunter Pharmacy) will begin at 500 mg/day in week 1, increase to 1000 mg/day in week 2, and then to 1500 mg/day in week 3, as tolerated. At week 3 and for the remaining 9 weeks, the dose will remain at 1500 mg/day. If a subject has gastrointestinal discomfort with 1500 mg/day the dose, the investigators will lower the dose to 1000 mg/day. The investigators will split the dose with 1/2 given in the a.m. and 1/2 in the p.m. and taken with meals to minimize GI discomfort. Receives: Drug: Placebo oral tablet |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mean Change in Insulin Sensitivity Index
Insulin Sensitivity Index = M / I x 1000. M = Glucose disposal rate (mg/min), normalized to fat-free mass (kg). I = insulin concentration (mU/L) during steady state of the clamp (based on glucose infusion rate). We rely on the delta (post-pre) of the insulin sensitivity index as our primary outcome. Positive delta values indicate improved insulin sensitivity (a positive outcome), while negative delta values indicate lower insulin sensitivity (a negative outcome). Insulin sensitivity cannot be physiologically zero or negative.
Maximum negative change insulin sensitivity index = -52.31 mg/kg FFM/min/mU/L. Maximum positive insulin sensitivity index = 42.32 mg/kg FFM/min/mU/L.
Measured: Change from baseline to 12 weeks
Mean Change in Mitochondrial Function of the Electron Transport System Measured by Complex I Activity
Mitochondrial respiration was measured using permeabilized muscle fibers from the vastus lateralis using high-resolution respirometry. We rely on the delta (change from post-pre) of the Complex I mitochondrial respiratory capacity. Positive values indicate an increase in mitochondrial respiratory capacity and improved outcomes, while negative values indicate a reduction in mitochondrial respiratory capacity and a negative outcome. There is no minimum or maximum reported for mitochondrial respiratory capacity of CI, but mitochondrial respiratory capacity of CI cannot physiologically be zero or negative. We and others have previously reported maximal complex I linked oxidative phosphorylation at approximately 250 pmol/mg of tissue/s in ultra-endurance athletes.
Measured: Change from baseline to 12 weeks
Secondary outcomes (2)
Mean Change in Daily Average Glucose Measure
We measured blood glucose using a Dexcom Continuous Glucose Monitor (CGM) over seven days. We rely on the delta (change from pre to post) in mean glucose (mg/dL) levels. Positive values indicate an increase in blood glucose and a negative outcome, while negative values indicate a reduction in mean blood glucose and a positive outcome. Glucose values of 70-140 mg/dL generally represent a normal physiological range; values below 70 mg/dL indicate hypoglycemia excursions, while values above 180 mg/dL indicate hyperglycemia excursions.
Measured: Change from baseline to 12 weeks
Mean Change in Blood-based Biomarker Measures of Aging
This blood-based biomarker panel, developed by LeBrasseur and colleagues, measures changes in senescence-associated secretory phenotype proteins. This panel is associated with chronological age, biological age, and adverse clinical outcomes. Changes in the protein levels of biomarkers reflect changes in biological age. A greater abundance in these biomarkers is associated with greater frailty or biological aging. We rely on the delta (change from post-pre) of the biological markers. A positive value is associated with a negative outcome, while a negative value is associated with a positive outcome.
Measured: Change from baseline to 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Feb 2020
- Study start29 Jul 2020
- Primary completion12 Mar 2025
- Study completion12 Mar 2025
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.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for AgingStudies 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
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- This is a randomized, controlled clinical trial of healthy older male and female subjects 40-75 years of age. Subjects will be randomized into one of two groups (metformin or placebo) for a 12-week intervention. The study is double-blinded on placebo versus metformin. The randomization sequence will be stratified by study center (OUHSC or UWM) and baseline insulin status (HOMA-IR \<=2.2 \[sensitive\] versus \>=2.5 \[resistant\]) and will be created using randomly chosen block sizes of four or six. At each center, there will be four groups: insulin sensitive (IS) placebo, IS metformin, insulin resistant (IR) placebo, and IR metformin.
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 166 participants (actual)
Sponsor and investigators
- Lead sponsor
- Oklahoma Medical Research Foundation
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Aging (NIA), University of Oklahoma, University of Wisconsin, Madison
- Responsible party
- Sponsor
- Investigators
- Benjamin F Miller, PhD, Principal investigator, Oklahoma Medical Research FoundationAdam Konopka, PhD, Principal investigator, University of Wisconsin, Madison
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04264897
- Sponsor's protocol ID
- 10699
- Other IDs
- R01AG064951
- Acronym
- ANTHEM
- Status last verified
- Jun 2026
- First submitted
- 7 Feb 2020
- Last updated
- 5 Nov 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Results from the trial will be disseminated through presentations at professional meetings and through peer-reviewed publications. Data and other resources will be shared as required by NIH Resource Sharing policies.
Publications
Kumari S, Bubak MT, Schoenberg HM, Davidyan A, Elliehausen CJ, Kuhn KG, VanWagoner TM, Karaman R, Scofield RH, Miller BF, Konopka AR. Antecedent Metabolic Health and Metformin (ANTHEM) Aging Study: Rationale and Study Design for a Randomized Controlled Trial. J Gerontol A Biol Sci Med Sci. 2022 Dec 29;77(12):2373-2377. doi: 10.1093/gerona/glab358.
PubMed 34865016
Study at a glance
From the registry record, last updated by the sponsor on 5 Nov 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Does Insulin Sensitivity Impact the Potential of Metformin to Slow Aging
- ClinicalTrials.gov ID
- NCT04264897
- Acronym / sponsor ID
- ANTHEM / 10699
- Conditions
- Aging, Insulin Sensitivity, Chronic Disease, Mitochondria, Insulin Resistance
- Keywords
- Blood Glucose Regulation, 5' adenosine monophosphate-activated protein kinase, Healthspan, Skeletal muscle, Mitochondria
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 166 participants (actual)
- Lead sponsor
- Oklahoma Medical Research FoundationUniversity, hospital or other
- Collaborators
- National Institute on Aging (NIA), University of Oklahoma, University of Wisconsin, Madison
- Study start
- 29 Jul 2020 (actual)
- Primary completion
- 12 Mar 2025 (actual)
- Study completion
- 12 Mar 2025 (actual)
- First posted
- 11 Feb 2020 (actual)
- Results
- Posted 2 Jul 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Aging is the number one risk factor for the majority of chronic diseases. There are no pharmaceutical treatments to slow aging and prolong healthspan. The anti-diabetic drug metformin is considered a likely pharmaceutical candidate to slow aging. In this study, the investigators hypothesize that metformin treatment in subjects free of type 2 diabetes will improve insulin sensitivity and glucoregulation in insulin resistant individuals, but will decrease insulin sensitivity and glucoregulation in insulin sensitive subjects. Further, the investigators hypothesize that long-term metformin treatment will remodel mitochondria in a way that decreases mitochondrial function in subjects that are insulin sensitive, but improves mitochondrial function in subjects that are insulin resistant. The investigators will use a dual-site, 12- week drug intervention trial performed in a double-blind, placebo-controlled manner on 148 subjects recruited from two separate sites (Oklahoma Medical Research Foundation (OMRF) and University of Wisconsin-Madison (UWM)). After consent and initial subject screening for chronic disease, subjects will be stratified to insulin sensitive (IS) or insulin resistant (IR) groups. Over a 12- week intervention, half of each group will take metformin and half will take a placebo. Pre- and post--intervention, subjects will complete a series of procedures to assess insulin sensitivity, glucose regulation, and biomarkers of aging. The same subjects will provide a skeletal muscle biopsy pre-- and post-intervention to assess the change in mitochondrial function and mitochondrial remodeling with and without metformin treatment. By completion of this project, the investigators expect to provide evidence that helps further delineate who may benefit from metformin treatment to slow aging.
Detailed description
Although there is epidemiological support for health benefits of metformin in patient populations, it is not clear if these protective effects extend to those free of disease. Therefore, there is a need to perform human studies determining which subjects free of chronic disease benefit from metformin treatment. Retrospective analysis of a randomized, double-blinded clinical trial in our lab revealed that subjects who were insulin sensitive had no effect or negative effects on insulin sensitivity when taking metformin during an exercise training program. These data suggest that in some subjects, metformin has detrimental metabolic outcomes that could accelerate aging. There are data both in support of and refuting that metformin inhibits mitochondrial complex I action and/or mitochondrial remodeling. The overall objective of this trial is to determine if subjects currently free of disease benefit from metformin treatment. There are two critical questions that remain unanswered in human subjects: 1) does antecedent metabolic health influence responses to metformin, and 2) does long-term treatment with metformin lead to mitochondrial remodeling and changes in function. To better understand the translational potential of a clinically relevant dose of metformin for the prevention of chronic conditions, this proposal aims to determine how antecedent metabolic health affects the response to metformin treatment, and identify the relationship between skeletal muscle mitochondrial remodeling and mitochondrial function with metformin treatment. The hypotheses are that: 1) metformin treatment in subjects free of Type 2 diabetes will improve insulin sensitivity and glucoregulation in insulin resistant individuals, but will decrease insulin sensitivity and glucoregulation in insulin sensitive subjects, and 2) long-term metformin treatment will remodel mitochondria in a way that decreases mitochondrial function in subjects that are insulin sensitive, but improves mitochondrial function in subjects that are insulin resistant. To test these hypotheses, a 12-week randomized, double-blind clinical trial will be performed in subjects 40-75 yrs of age, free of disease, and stratified by insulin sensitivity (insulin sensitive and insulin resistant). Pre- and post-training assessments include the hyperinsulinemic- euglycemic clamp to measure hepatic and peripheral insulin sensitivity, continuous glucose monitoring to determine glucoregulation, and proposed blood-based biomarkers of aging. Further, the use of novel stable isotope labeling with proteomic analysis will determine individual and complex-specific mitochondrial remodeling. This approach will be combined with analysis of protein modification and turnover to comprehensively analyze mitochondrial effects of metformin treatment in skeletal muscle. By completion of this project, it is expected that there will be evidence that helps further delineate who may benefit from metformin treatment to slow aging.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 4
- Model description
- This is a randomized, controlled clinical trial of healthy older male and female subjects 40-75 years of age. Subjects will be randomized into one of two groups (metformin or placebo) for a 12-week intervention. The study is double-blinded on placebo versus metformin. The randomization sequence will be stratified by study center (OUHSC or UWM) and baseline insulin status (HOMA-IR <=2.2 [sensitive] versus >=2.5 [resistant]) and will be created using randomly chosen block sizes of four or six. At each center, there will be four groups: insulin sensitive (IS) placebo, IS metformin, insulin resistant (IR) placebo, and IR metformin.
| Arm | Type | Receives |
|---|---|---|
| Metformin - Insulin Sensative | Experimental | Drug: MetforminThe investigators use a "ramp up" dosing protocol in which the amount of metformin (Hunter Pharmacy) will begin at 500 mg/day in week 1, increase to 1000 mg/day in week 2, and then to 1500 mg/day in week 3, as tolerated. At week 3 and for the remaining 9 weeks, the dose will remain at 1500 mg/day, which is a standard clinical dose (1500-2000 mg/day). If a subject has gastrointestinal discomfort with 1500 mg/day the dose, the investigators will lower the dose to 1000 mg/day. The investigators will split the dose with 1/2 given in the a.m. and 1/2 in the p.m. and taken with meals to minimize GI discomfort. |
| Placebo - Insulin Sensitive | Placebo comparator | Drug: Placebo oral tabletSubjects assigned to the placebo group will receive visually identical pills (silicified microcrystalline cellulose, Micosolle®, K30 povidone, sodium starch glycolate, and magnesium stearate). The same dosing schedule will be followed as for metformin. The investigators use a "ramp up" dosing protocol in which the amount of placebo (Hunter Pharmacy) will begin at 500 mg/day in week 1, increase to 1000 mg/day in week 2, and then to 1500 mg/day in week 3, as tolerated. At week 3 and for the remaining 9 weeks, the dose will remain at 1500 mg/day. If a subject has gastrointestinal discomfort with 1500 mg/day the dose, the investigators will lower the dose to 1000 mg/day. The investigators will split the dose with 1/2 given in the a.m. and 1/2 in the p.m. and taken with meals to minimize GI discomfort. |
| Metformin - Insulin Resistant | Experimental | Drug: MetforminThe investigators use a "ramp up" dosing protocol in which the amount of metformin (Hunter Pharmacy) will begin at 500 mg/day in week 1, increase to 1000 mg/day in week 2, and then to 1500 mg/day in week 3, as tolerated. At week 3 and for the remaining 9 weeks, the dose will remain at 1500 mg/day, which is a standard clinical dose (1500-2000 mg/day). If a subject has gastrointestinal discomfort with 1500 mg/day the dose, the investigators will lower the dose to 1000 mg/day. The investigators will split the dose with 1/2 given in the a.m. and 1/2 in the p.m. and taken with meals to minimize GI discomfort. |
| Placebo - Insulin Resistant | Placebo comparator | Drug: Placebo oral tabletSubjects assigned to the placebo group will receive visually identical pills (silicified microcrystalline cellulose, Micosolle®, K30 povidone, sodium starch glycolate, and magnesium stearate). The same dosing schedule will be followed as for metformin. The investigators use a "ramp up" dosing protocol in which the amount of placebo (Hunter Pharmacy) will begin at 500 mg/day in week 1, increase to 1000 mg/day in week 2, and then to 1500 mg/day in week 3, as tolerated. At week 3 and for the remaining 9 weeks, the dose will remain at 1500 mg/day. If a subject has gastrointestinal discomfort with 1500 mg/day the dose, the investigators will lower the dose to 1000 mg/day. The investigators will split the dose with 1/2 given in the a.m. and 1/2 in the p.m. and taken with meals to minimize GI discomfort. |
Who may qualify
- Ages
- 40 to 75 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 40-75 years of age (inclusive)
- Free of chronic disease
- Comprehension of the protocol as indicated by an ability to respond to questions about the study after reading the consent form.
- Able to use and be contacted by telephone.
- Able to speak, read, and understand English, and complete a questionnaire in English
Key exclusion criteria (16 listed)
- Pregnancy
- Heart disease (history, abnormal ECG, abnormal stress ECG)
- Cerebrovascular disease (history)
- Cancer (history)
- Chronic respiratory disease (history, forced expiratory volume at one second/forced vital capacity [FEV1/FVC] < 70, FEV1 < 80% predicted)
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: Glucophage, Glucophage extended-release, Fortamet, GlumetzaMetformin (Hunter Pharmacy) following a "ramp up" dosing protocol with a targeted dose of 1500 mg/day for 12 weeks. | Drug | Metformin - Insulin Resistant, Metformin - Insulin Sensative |
| Placebo oral tabletAlso: PlaceboSilicified microcrystalline cellulose, Micosolle®, K30 povidone, sodium starch glycolate, and magnesium stearate | Drug | Placebo - Insulin Resistant, Placebo - Insulin Sensitive |
Primary outcome
Mean Change in Insulin Sensitivity Index
Time frame: Change from baseline to 12 weeks
Insulin Sensitivity Index = M / I x 1000. M = Glucose disposal rate (mg/min), normalized to fat-free mass (kg). I = insulin concentration (mU/L) during steady state of the clamp (based on glucose infusion rate). We rely on the delta (post-pre) of the insulin sensitivity index as our primary outcome. Positive delta values indicate improved insulin sensitivity (a positive outcome), while negative delta values indicate lower insulin sensitivity (a negative outcome). Insulin sensitivity cannot be physiologically zero or negative. Maximum negative change insulin sensitivity index = -52.31 mg/kg FFM/min/mU/L. Maximum positive insulin sensitivity index = 42.32 mg/kg FFM/min/mU/L.
Mean Change in Mitochondrial Function of the Electron Transport System Measured by Complex I Activity
Time frame: Change from baseline to 12 weeks
Mitochondrial respiration was measured using permeabilized muscle fibers from the vastus lateralis using high-resolution respirometry. We rely on the delta (change from post-pre) of the Complex I mitochondrial respiratory capacity. Positive values indicate an increase in mitochondrial respiratory capacity and improved outcomes, while negative values indicate a reduction in mitochondrial respiratory capacity and a negative outcome. There is no minimum or maximum reported for mitochondrial respiratory capacity of CI, but mitochondrial respiratory capacity of CI cannot physiologically be zero or negative. We and others have previously reported maximal complex I linked oxidative phosphorylation at approximately 250 pmol/mg of tissue/s in ultra-endurance athletes.
2 secondary outcomes
Mean Change in Daily Average Glucose Measure
Time frame: Change from baseline to 12 weeks
Mean Change in Blood-based Biomarker Measures of Aging
Time frame: Change from baseline to 12 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Nov 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 34865016Kumari S, Bubak MT, Schoenberg HM, Davidyan A, Elliehausen CJ, Kuhn KG, VanWagoner TM, Karaman R, Scofield RH, Miller BF, Konopka AR. Antecedent Metabolic Health and Metformin (ANTHEM) Aging Study: Rationale and Study Design for a Randomized Controlled Trial. J Gerontol A Biol Sci Med Sci. 2022 Dec 29;77(12):2373-2377. doi: 10.1093/gerona/glab358.
- Individual participant dataSharing planned: Yes. Results from the trial will be disseminated through presentations at professional meetings and through peer-reviewed publications. Data and other resources will be shared as required by NIH Resource Sharing policies.
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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.
Benjamin F Miller, PhD principal investigator
Oklahoma Medical Research Foundation
Adam Konopka, PhD principal investigator
University of Wisconsin, Madison
2 sites 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 Aging and Insulin Sensitivity, run by Oklahoma Medical Research Foundation at 2 sites 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 6 inclusion and 16 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 5 Nov 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites 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 2 Jul 2026). 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?
Mean Change in Insulin Sensitivity Index (time frame: Change from baseline to 12 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04264897, which also lists 1 linked publication.
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 5 Nov 2026; AzTrials last refreshed its copy on 6 Nov 2026.