Prediabetes
Conditions
Keywords
metformin, muscle, insulin resistance, sarcopenia, older adults, impaired fasting glucose
Brief summary
Sarcopenia is the loss of muscle mass, strength and function with aging and is associated with increased disability, falls and fractures. Older adults with diabetes and prediabetes are insulin resistant and have a higher risk of developing sarcopenia. This study examines the use of metformin, an antidiabetic drug, for preventing the development of sarcopenia in older adults with prediabetes.
Detailed description
The proposed study utilizes clinical and translational research approaches to study sarcopenia. Sarcopenia is common in older adults and is associated with decreased strength, increased disability, falls and fractures. There are currently few interventions to prevent or treat sarcopenia and a poor understanding of the mechanisms for sarcopenia. Given the growing number of Veterans over the age of 65, studies to prevent sarcopenia and resulting disability are important for the health, independence and well-being of this population. The investigators' preliminary studies have shown that older adults with diabetes have an accelerated loss in muscle mass and gait speed, except when treated with metformin. Older adults with prediabetes also have a greater decline in muscle mass and higher incidence of disability. Therefore, this study further investigates these findings by addressing the following aims: (1) to determine whether metformin can prevent the loss in muscle mass and physical performance and (2) to examine changes in muscle histologic characteristics associated with metformin treatment in older adults with prediabetes.
Interventions
DRUGmetformin
Metformin will be given at a dose of 850 mg orally once daily for 1 month with titration up to 850 mg orally twice daily for the remainder of the study.
DRUGplacebo
One placebo capsule by mouth once daily for 1 month followed by one placebo capsule by mouth twice daily for the remainder of the study.
Sponsors
Oregon Health and Science University
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The investigators will enroll 120 sedentary, weight-stable, ambulatory Veterans aged 65 years and older with prediabetes identified with fasting glucose values 100 mg/dL or greater but under 126 mg/dL with no use of diabetes medications. * Participants must demonstrate that they are able to ambulate 400 meters without assistance.
Exclusion criteria
* Chronic medical conditions affecting muscle mass or function like active non-skin cancer and hypogonadism * Medications affecting muscle mass or function like glucocorticoids and androgen/antiandrogens * Contraindications to metformin such as renal dysfunction defined as creatinine \>= 1.5 mg/dL for men or \>=1.4 mg/dL for women or estimated glomerular filtration rate (eGFR)\<60 mL/min; liver dysfunction defined as alanine aminotransferase (ALT)\>48 U/L, aspart aminotransferase (AST)\>41 U/L or alkaline phosphatase (AlkPhos)\>141 U/L; B12 deficiency defined as B12 level \<180 pg/dL; congestive heart failure; known hypersensitivity to metformin; excessive alcohol intake (average of 2 or more alcoholic beverages/day over a month) For the muscle biopsy substudy, additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total Lean Mass From Baseline | 3 years | At baseline, 1, 2, and 3 year follow-up visits, participants will have whole body dual x-ray absorptiometry scans (DXA) with a Hologic QDR 4500W DXA scanner by a certified DXA operator to determine total body lean mass and appendicular lean mass (Kg). The changes in appendicular and total lean mass were calculated by determining the change from baseline to the three year data point. If participants withdrew from the study prior to collection of 3 year data, the final time point available was used. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Physical Performance - 400 Meter Walk Speed | 3 years | At baseline, 1, 2, and 3 year follow-up visits, participants will have physical performance assessed using a 400 meter timed walk. We report the 400 meter timed walk speed as the change from baseline in seconds. The change in walk speed from baseline to the three year time point was used for analysis. For participants who withdrew from the study early, the walk speed from the final data point collected was used. |
| Change in Muscle Characteristics | 6 months | At baseline and 6 month follow-up visits, 32 subjects will undergo a muscle biopsy of the vastus lateralis muscle 15 cm above the patella using the modified Bergstrom technique under local anesthesia. The muscle biopsy specimens will be used for the histochemical and transcriptome analyses |
Countries
United States
Participant flow
Recruitment details
Participants were recruited via advertisement flyers, primary care referral and letters to subjects in the research data warehouse within the Portland VA Healthcare System between May 2014 and August 2015. The first participant was enrolled in the study on May 27,2014 and the last participant was enrolled on August 12, 2015.
Pre-assignment details
Of the 431 assessed for eligibility, 120 met inclusion criteria and were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 60 participants will be randomized to placebo pills.
placebo: One placebo capsule by mouth once daily for 1 month followed by one placebo capsule by mouth twice daily for the remainder of the study. | 43 |
| Metformin 60 enrolled participants will be randomized to metformin.
metformin: Metformin will be given at a dose of 850 mg orally once daily for 1 month with titration up to 850 mg orally twice daily for the remainder of the study. | 77 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 10 |
| Overall Study | Decreased interest/personal | 4 | 5 |
| Overall Study | Enrollment in dual studies | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Moved out of area | 0 | 7 |
| Overall Study | Other health concerns | 2 | 7 |
| Overall Study | other MD recommended | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Metformin | Placebo |
|---|---|---|---|
| 400 Meter Walk Time (seconds) | 295.7 seconds STANDARD_DEVIATION 49.1 | 297.3 seconds STANDARD_DEVIATION 48.8 | 292.9 seconds STANDARD_DEVIATION 50.2 |
| Age, Continuous | 71.3 years STANDARD_DEVIATION 5.6 | 71.2 years STANDARD_DEVIATION 5.1 | 71.4 years STANDARD_DEVIATION 6.5 |
| BMI | 29.347 kg/m2 STANDARD_DEVIATION 4.61 | 29.246 kg/m2 STANDARD_DEVIATION 4.86 | 29.527 kg/m2 STANDARD_DEVIATION 4.177 |
| DEXA Appendicular Lean Mass (g) | 24834.0 grams STANDARD_DEVIATION 3700.7 | 24923.5 grams STANDARD_DEVIATION 3599.3 | 24676.7 grams STANDARD_DEVIATION 3913.7 |
| Dual-energy X-ray absorptiometry (DEXA) Total Lean Mass (g) | 59227.8 grams STANDARD_DEVIATION 7526.4 | 59412.4 grams STANDARD_DEVIATION 7366 | 58902.9 grams STANDARD_DEVIATION 7882.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) White | 113 Participants | 71 Participants | 42 Participants |
| Sex: Female, Male Female | 5 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 115 Participants | 76 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 43 | 1 / 77 |
| other Total, other adverse events | 24 / 43 | 52 / 77 |
| serious Total, serious adverse events | 25 / 43 | 52 / 77 |
Outcome results
Primary
Change in Total Lean Mass From Baseline
At baseline, 1, 2, and 3 year follow-up visits, participants will have whole body dual x-ray absorptiometry scans (DXA) with a Hologic QDR 4500W DXA scanner by a certified DXA operator to determine total body lean mass and appendicular lean mass (Kg). The changes in appendicular and total lean mass were calculated by determining the change from baseline to the three year data point. If participants withdrew from the study prior to collection of 3 year data, the final time point available was used.
Time frame: 3 years
Population: A simple adaptive randomization scheme was developed to balance gender, age and BMI. 120 subjects were randomized to treatment conditions according to 64% to 36% allocation probabilities. Subjects were followed for up to 3 years, with walk time and lean mass measured annually. The study experienced roughly 38% loss-to-follow up at year 3.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Total Lean Mass From Baseline | Appendicular Lean Mass Decrease from Baseline | 322.8 grams lean mass | Standard Deviation 1342.3 |
| Placebo | Change in Total Lean Mass From Baseline | Total Lean Mass Decrease from Baseline | 392.4 grams lean mass | Standard Deviation 2583.8 |
| Metformin | Change in Total Lean Mass From Baseline | Appendicular Lean Mass Decrease from Baseline | 697.6 grams lean mass | Standard Deviation 2318.8 |
| Metformin | Change in Total Lean Mass From Baseline | Total Lean Mass Decrease from Baseline | 548.0 grams lean mass | Standard Deviation 2339.4 |
p-value: 0.45t-test, 2 sided
p-value: 0.79t-test, 2 sided
Secondary
Change in Muscle Characteristics
At baseline and 6 month follow-up visits, 32 subjects will undergo a muscle biopsy of the vastus lateralis muscle 15 cm above the patella using the modified Bergstrom technique under local anesthesia. The muscle biopsy specimens will be used for the histochemical and transcriptome analyses
Time frame: 6 months
Population: Due to loss of sample and unmatched (time 0 and 6 month) sample availability as well as poor sample integrity, no interpretable histology data is available. No histology data was collected/analyzed from any samples for this Outcome measure.
Secondary
Change in Physical Performance - 400 Meter Walk Speed
At baseline, 1, 2, and 3 year follow-up visits, participants will have physical performance assessed using a 400 meter timed walk. We report the 400 meter timed walk speed as the change from baseline in seconds. The change in walk speed from baseline to the three year time point was used for analysis. For participants who withdrew from the study early, the walk speed from the final data point collected was used.
Time frame: 3 years
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Physical Performance - 400 Meter Walk Speed | -2.82 seconds | Standard Deviation 51.35 |
| Metformin | Change in Physical Performance - 400 Meter Walk Speed | 0.46 seconds | Standard Deviation 29.98 |
p-value: 0.48t-test, 2 sided