Metformin to Augment Strength Training Effective Response in Seniors (MASTERS)

• ClinicalTrials.gov Identifier: NCT02308228
• Recruitment Status: Completed
• First Posted: December 4, 2014
• Results First Posted: September 17, 2019
• Last Update Posted: September 17, 2019
• Sponsor: Philip Kern
• Collaborator: University of Alabama at Birmingham
• Information provided by (Responsible Party): Philip Kern, University of Kentucky

Study Description

Brief Summary:

The purpose of this study is to determine whether a commonly prescribed drug, metformin, can enhance the benefits seen during resistance exercise such as increased muscle mass and strength.

Condition or disease	Intervention/treatment	Phase
Aging	Behavioral: Progressive Resistance Training; Drug: Metformin	Early Phase 1

Detailed Description:

Muscle mass and strength are critical determinants not only of a person's quality of life and functional independence, but also metabolic health, as muscle is the organ primarily responsible for insulin-mediated glucose uptake. The elderly suffer obligatory losses of muscle mass and strength, exacerbated by illness and physical inactivity. Progressive resistance exercise training (PRT) is the most effective intervention identified to improve muscular strength, and combat the muscle atrophy of aging (sarcopenia); however, overall the muscle response to PRT is blunted in the elderly and variability of response increased, with some individuals actually losing muscle mass. The Bamman and Peterson labs have independently been studying the molecular and cellular mechanisms underlying the "non-responder" phenotype, with the goal of identifying novel intervention strategies to promote mass and strength gains to improve function. We hypothesize that the abundance of anti-inflammatory, alternatively activated M2 macrophages in muscle predicts response to PRT in the elderly; those with the highest number of M2 macrophages and lowest inflammatory gene expression prior to the start of training gained the most mass. Further, we determined that metformin treatment increased M2 macrophage abundance, and decreased inflammatory cytokine gene expression. These provocative findings have led us to our central hypothesis that adjuvant metformin may improve the responses to PRT in the elderly by altering the muscle tissue inflammatory environment, thereby enhancing mechanisms that drive PRT-induced myofiber hypertrophy.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 109 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: Novel Actions of Metformin to Augment Resistance Training Adaptations in Older Adults
• Actual Study Start Date: January 14, 2015
• Actual Primary Completion Date: December 14, 2017
• Actual Study Completion Date: June 28, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Metformin; Participants will be randomized to receive Metformin (1700 mg/day) for a period of 16 weeks; 2 weeks of Metformin only followed by 14 weeks of continued Metformin use in combination with progressive resistance training.	Behavioral: Progressive Resistance Training; Participants will complete 14 weeks (42 sessions, 3x/week) of progressive resistance training which will consist of 8 constant load movements to train all major muscle groups bilaterally.; Other Name: Strength Training; Drug: Metformin; Participants will be randomized to receive metformin in conjunction with their strength training program.; Other Name: Glucophage XR
Placebo Comparator: Placebo, Sugar Pill; Participants will be randomized to receive placebo sugar pills (1700 mg/day) for a period of 16 weeks; 2 weeks of placebo only followed by 14 weeks of continued placebo use in combination with progressive resistance training. Placebos will be almost identical to the Metformin medication.	Behavioral: Progressive Resistance Training; Participants will complete 14 weeks (42 sessions, 3x/week) of progressive resistance training which will consist of 8 constant load movements to train all major muscle groups bilaterally.; Other Name: Strength Training

Outcome Measures

Primary Outcome Measures :

1. Percent Change in Type 2 Myofiber Cross Sectional Area [ Time Frame: 16 weeks ]
   The ability of metformin to improve the hypertrophic response to resistance training will be determined. Muscle biopsies of the vastus lateralis will be used to quantify myofiber cross-sectional area. The percent change in type 2 myofiber size between week 16 and week 0 was used.

Secondary Outcome Measures :

1. Percent Change in Normal Density Muscle Size by Computed Tomography [ Time Frame: 16 weeks ]
   The ability of metformin to improve the hypertrophic response at the whole muscle level will be quantified by computed tomography. Percent change in normal density muscle area will be calculated as the difference between week 16 and week 0.

Other Outcome Measures:

1. Percent Change in Muscle Strength [ Time Frame: Week 4 and week 16 ]
   Determine if metformin treatment augments strength gains in conjunction with progressive resistance training by one repetition maximum assessments. Maximum (1RM) leg extension muscle strength was assessed at week 4 (to account for neurological adaptations during the initial stages of the resistance program) and week 16. The percent change from week 4 to week 16 is reported.
2. Percent Change in Total Body Lean Mass by DXA [ Time Frame: 16 weeks ]
   To determine if metformin improves changes in body composition associated with progressive resistance training. Percent change in total body lean mass in kg was calculated as the difference between week 16 and week 0 from a total body DXA scan.
3. Insulin Sensitivity [ Time Frame: 16 weeks ]
   A standard OGTT will be used to determine insulin sensitivity using the Matsuda Index.

Eligibility Criteria

• Ages Eligible for Study: 65 Years and older (Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• ≥65 years of age.
• Independently mobile with a SPPB score 3-12.
• Access to transportation.
• Capable of providing informed consent (cognitively intact).

Exclusion Criteria:

• Obesity (BMI>30)
• Serum creatinine >1.4 because of risk of lactic acidosis with metformin.
• History of regular resistance training within the past year.
• History (or ECG evidence) of previous myocardial infarction, history of congestive heart failure.
• Current angina pectoris or symptoms of myocardial ischemia or congestive heart failure.
• Chronic aspirin or NSAID use (unless it can be safely stopped prior to the biopsies), and any other use of an anticoagulant (e.g., Coumadin) or history of bleeding.
• History of alcoholism or liver disease.
• History of hypo- or hyper-coagulation disorders including subjects taking Coumadin.
• Any end-stage disease and/or a life expectancy less than one year.
• Neurological, musculoskeletal, or other disorder that would preclude them from completing resistance training and all performance tests.
• Uncontrolled hypertension.
• Diabetes mellitus as demonstrated with- HgbA1C>6.5, or fasting glu>126 mg/dl.
• Any other medical condition that would interfere with testing or increase one's risk of complications during exercise, as judged by the study physicians.
• Any other condition or events considered exclusionary by the PI and/or physician, such as non-compliance.
• Lidocaine allergy (1% lidocaine is the local anesthetic used during the muscle biopsy procedure).

Contacts and Locations

Locations

United States, Alabama

University of Alabama Birmingham

Birmingham, Alabama, United States, 35294

United States, Kentucky

University of Kentucky

Lexington, Kentucky, United States, 40536

Sponsors and Collaborators

Philip Kern

University of Alabama at Birmingham

Investigators

• Principal Investigator: Charlotte Peterson, Ph.D.; University of Kentucky
• Principal Investigator: Philip Kern, M.D.; University of Kentucky
• Principal Investigator: Marcas Bamman, Ph.D; University of Alabama at Birmingham

  Study Documents (Full-Text)

Documents provided by Philip Kern, University of Kentucky:

Study Protocol and Statistical Analysis Plan  [PDF] October 16, 2018

Informed Consent Form  [PDF] February 17, 2014

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Walton RG, Dungan CM, Long DE, Tuggle SC, Kosmac K, Peck BD, Bush HM, Villasante Tezanos AG, McGwin G, Windham ST, Ovalle F, Bamman MM, Kern PA, Peterson CA. Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double-blind, placebo-controlled, multicenter trial: The MASTERS trial. Aging Cell. 2019 Dec;18(6):e13039. doi: 10.1111/acel.13039. Epub 2019 Sep 26.

Long DE, Villasante Tezanos AG, Wise JN, Kern PA, Bamman MM, Peterson CA, Dennis RA. A guide for using NIH Image J for single slice cross-sectional area and composition analysis of the thigh from computed tomography. PLoS One. 2019 Feb 7;14(2):e0211629. doi: 10.1371/journal.pone.0211629. eCollection 2019.

Long DE, Peck BD, Martz JL, Tuggle SC, Bush HM, McGwin G, Kern PA, Bamman MM, Peterson CA. Metformin to Augment Strength Training Effective Response in Seniors (MASTERS): study protocol for a randomized controlled trial. Trials. 2017 Apr 26;18(1):192. doi: 10.1186/s13063-017-1932-5.

• Responsible Party: Philip Kern, M.D., University of Kentucky
• ClinicalTrials.gov Identifier: NCT02308228
• Other Study ID Numbers: 1R01AG046920-01A1 ( U.S. NIH Grant/Contract )
• First Posted: December 4, 2014
• Results First Posted: September 17, 2019
• Last Update Posted: September 17, 2019
• Last Verified: August 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Philip Kern, University of Kentucky:

Aging; Hypertrophy; Metformin; Strength; Muscle

Additional relevant MeSH terms:

Metformin; Hypoglycemic Agents; Physiological Effects of Drugs