Antecedent Metabolic Health and Metformin Aging Study

NCT04264897 | Completed Phase 3 DMC FDA Drug

• 2 other identifiers: 10699R01AG064951
• Study Type: interventional
• Target: 101
• Locations: 1 country
• Sites: 2

Brief 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. 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.

Conditions

Aging; Chronic Disease; Insulin Sensitivity; Mitochondria; Insulin Resistance

Keywords

Blood Glucose Regulation; 5' adenosine monophosphate-activated protein kinase; Healthspan; Skeletal muscle; Mitochondria

Outcome Measures

Primary Outcomes (2)

• Mean change in insulin sensitivity measure

  Change in insulin sensitivity as determined by a hyperinsulinemic-euglycemic clamp

  Change from baseline to 12 weeks

• Mean change in mitochondrial function of the electron transport system measured by complex I activity

  Mitochondrial function of the electron transport system

  Change from baseline to 12 weeks

Secondary Outcomes (2)

• Mean change in daily average glucose measure

  Change from baseline to 12 weeks

• Mean change in blood-based biomarker measures of aging

  Change from baseline to 12 weeks

Study Arms (4)

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.

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.

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.

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.

Drug: Placebo oral tablet

Interventions

Placebo oral tablet DRUG

Silicified microcrystalline cellulose, Micosolle®, K30 povidone, sodium starch glycolate, and magnesium stearate

Also known as: Placebo

Placebo - Insulin Resistant; Placebo - Insulin Sensitive

Metformin DRUG

Metformin (Hunter Pharmacy) following a "ramp up" dosing protocol with a targeted dose of 1500 mg/day for 12 weeks.

Also known as: Glucophage, Glucophage extended-release, Fortamet, Glumetza, Riomet

Metformin - Insulin Resistant; Metformin - Insulin Sensative

Eligibility Criteria

• Age: 40 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)
• 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

Sponsors & Collaborators

• Oklahoma Medical Research Foundation: lead
• National Institute on Aging (NIA): collaborator
• University of Oklahoma: collaborator
• University of Wisconsin, Madison: collaborator

Study Sites (2)

University of Oklahoma Health Sciences Center, Oklahoma Shared Clinical and Translational Resources

Oklahoma City, Oklahoma, 73104, United States

Location

University of Wisconsin-Madison

Madison, Wisconsin, 53705, United States

Location

Related Publications (1)

• 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.

  PMID: 34865016 DERIVED

MeSH Terms

Conditions

Insulin Resistance; Chronic Disease

Interventions

Metformin

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Benjamin F Miller, PhD

  Oklahoma Medical Research Foundation

  PRINCIPAL INVESTIGATOR

• Adam Konopka, PhD

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Subjects assigned to the placebo group will receive visually identical pills (silicified microcrystalline cellulose, Micosolle®, K30 povidone, sodium starch glycolate, and magnesium stearate). Only the study statistician and pharmacist will know the metformin versus placebo assignment.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: February 7, 2020
• First Posted: February 11, 2020
• Study Start: July 29, 2020
• Primary Completion: March 12, 2025
• Study Completion: March 12, 2025
• Last Updated: April 23, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: De-identified data will be shared following the publication of the primary manuscripts for each specific aim from the trial by the trial investigators.
• Access Criteria: Researchers interested in accessing de-identified data will contact the trial principal investigators to complete data use agreements and paper/presentation proposals needed for consideration of the proposed research.

Locations

US (2)