Trial Outcomes & Findings for Effect of Metformin on Vascular and Mitochondrial Function in Type 1 Diabetes (NCT NCT01813929)

Results Overview

Determine the effect of metformin on insulin sensitivity in T1D. Reported measure is glucose infusion rate during hyperinsulinemic euglycemic clamp normalized to total body weight. For this measure, insulin was infused at 40 mU/m2 surface area. Blood sugar wass checked every 5 minutes and glucose infusion adjusted to maintain glucose level at 90 mg/dL for 2 hours. The glucose infusion rate for the final 30 minutes is reported as GIR (aka M-value or glucose disposal rate) in mg glucose/kg\*min. A higher value corresponds to greater sensitivity to insulin. There is no strictly defined normal range.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

23 participants

Primary outcome timeframe

End of each 6 week intervention period

Results posted on

2022-01-21

Participant Flow

3 participants screen failed before starting the study. 3 more participants withdrew after randomization, but before starting the study.

Participant milestones

Participant milestones
Measure	Metformin, Then Placebo Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily. Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.	Placebo, Then Metformin Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention. Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.
Overall Study STARTED	5	12
Overall Study Completed Intervention 1	5	12
Overall Study Completed Washout (2weeks up to 2 Months)	5	11
Overall Study Started Intervention 2	5	11
Overall Study COMPLETED	5	11
Overall Study NOT COMPLETED	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Metformin, Then Placebo Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily. Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.	Placebo, Then Metformin Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention. Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.
Overall Study Withdrawal by Subject	0	1

Baseline Characteristics

Effect of Metformin on Vascular and Mitochondrial Function in Type 1 Diabetes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Metformin, Then Placebo n=5 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily. Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.	Placebo, Then Metformin n=12 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention. Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Total n=17 Participants Total of all reporting groups
Age, Continuous	43.0 years STANDARD_DEVIATION 14.4 • n=5 Participants	43.3 years STANDARD_DEVIATION 11.6 • n=7 Participants	43.2 years STANDARD_DEVIATION 12.0 • n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	5 Participants n=7 Participants	9 Participants n=5 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	7 Participants n=7 Participants	8 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	5 Participants n=5 Participants	10 Participants n=7 Participants	15 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	5 Participants n=5 Participants	12 Participants n=7 Participants	17 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	5 participants n=5 Participants	12 participants n=7 Participants	17 participants n=5 Participants

PRIMARY outcome

Timeframe: End of each 6 week intervention period

Determine the effect of metformin on insulin sensitivity in T1D. Reported measure is glucose infusion rate during hyperinsulinemic euglycemic clamp normalized to total body weight. For this measure, insulin was infused at 40 mU/m2 surface area. Blood sugar wass checked every 5 minutes and glucose infusion adjusted to maintain glucose level at 90 mg/dL for 2 hours. The glucose infusion rate for the final 30 minutes is reported as GIR (aka M-value or glucose disposal rate) in mg glucose/kg\*min. A higher value corresponds to greater sensitivity to insulin. There is no strictly defined normal range.

Outcome measures

Outcome measures
Measure	Metformin n=16 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=17 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Insulin Sensitivity by Hyperinsulinemic Euglycemic Clamp	3.27 mg/kg/min Standard Deviation 1.51	3.46 mg/kg/min Standard Deviation 2.15

PRIMARY outcome

Timeframe: End of each 6 week intervention period

Population: Not completed on last subjects -futility, concern re reliability, and difficulty getting US images analyzed.

Measure of endothelial function by brachial ultrasound of the percent dilation after 5 minutes of occlusion.

Outcome measures

Outcome measures
Measure	Metformin n=12 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=13 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Flow-mediated Brachial Artery Dilation	8.19 percent change in BA diameter Standard Deviation 3.85	7.45 percent change in BA diameter Standard Deviation 5.86

SECONDARY outcome

Timeframe: End of each 6 week intervention period

Pulse wave velocity by Sphygmacor as a measure of aortic stiffness in m/sec.

Outcome measures

Outcome measures
Measure	Metformin n=15 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=16 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Arterial Stiffness by PWV	8.64 m/sec Standard Deviation 2.76	8.56 m/sec Standard Deviation 3.02

SECONDARY outcome

Timeframe: End of each 6 week intervention period

Augmentation index by Sphygmacor is a measure of aortic arterial stiffness. AI@75 is the ratio of augmented pressure/pulse pressure adjusted to a heart rate of 75.

Outcome measures

Outcome measures
Measure	Metformin n=15 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=17 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Arterial Stiffness by AI@75	15.89 ratio Standard Deviation 9.08	14.96 ratio Standard Deviation 12.48

SECONDARY outcome

Timeframe: End of each 6 week intervention period

Oxygen consumption rate with various substrates and max uncoupled O2 consumption. Measure is performed on permeabilized muscle fibers from biopsy tissue from the vastus lateralis using the Oroboros OxygraphO2k high resolution respirometer. State 3 is full coupled oxygen flux using PMG or PMGS (pyruvate, malate, glutamate, +/- succinate) or OCMS (octanyl carnitine, malate, +/- succinate) as substrates. state 4 is after addition of oligomycin to inhibit the ATP synthase and thus corresponds to the maximum leak state where O2 consumption is limited by the buildup of the proton gradient and can only proceed as fast as the protons can leak back across the membrane. FCCP is added as an uncoupler, allowing free leakage of protons across the inner membrane, and thus measures maximum possible O2 flux. There are no defined normal ranges, but higher state 3 and uncoupled flux indicate better mitochondrial function, while state 4 is needed to correct state 3 to the fully coupled flux.

Outcome measures

Outcome measures
Measure	Metformin n=15 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=15 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Mitochondrial Measures: Oxygen Consumption PMG State 3 Oxygen Flux	28.3 pmoles/mg/s Standard Deviation 6.8	29.7 pmoles/mg/s Standard Deviation 11.0
Mitochondrial Measures: Oxygen Consumption PMGS State 3 Oxygen Flux	44.3 pmoles/mg/s Standard Deviation 16.5	41.5 pmoles/mg/s Standard Deviation 16.1
Mitochondrial Measures: Oxygen Consumption PMGS State 4 Oxygen Flux	14.6 pmoles/mg/s Standard Deviation 8.0	14.0 pmoles/mg/s Standard Deviation 6.3
Mitochondrial Measures: Oxygen Consumption PMGS Uncoupled Max Oxygen Flux	76.0 pmoles/mg/s Standard Deviation 26.3	76.4 pmoles/mg/s Standard Deviation 21.2
Mitochondrial Measures: Oxygen Consumption OCM State 3 Oxygen Flux	16.8 pmoles/mg/s Standard Deviation 7.0	18.0 pmoles/mg/s Standard Deviation 5.6
Mitochondrial Measures: Oxygen Consumption OCMS State 3 Oxygen Flux	43.8 pmoles/mg/s Standard Deviation 16.9	42.8 pmoles/mg/s Standard Deviation 13.1
Mitochondrial Measures: Oxygen Consumption OCMS State 4 Oxygen Flux	14.6 pmoles/mg/s Standard Deviation 7.4	15.1 pmoles/mg/s Standard Deviation 5.9
Mitochondrial Measures: Oxygen Consumption OCMS Uncoupled Max Oxygen Flux	67.1 pmoles/mg/s Standard Deviation 23.3	71.3 pmoles/mg/s Standard Deviation 18.8

SECONDARY outcome

Timeframe: End of each 6 week intervention period

Mito content by Western Blotting of electron transport chain complexes I, II, III, and V. complex 1 utilizes NADH from pyruvate/malate/glutamate while complex II utilizes FADH from succinate. complex III is the cytochrome c reductase while complex V is the ATP synthase.

Outcome measures

Outcome measures
Measure	Metformin n=11 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=11 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes complex I	1436 Arbitrary units Standard Deviation 981	1084 Arbitrary units Standard Deviation 718
Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes complex II	4375 Arbitrary units Standard Deviation 2022	4201 Arbitrary units Standard Deviation 1541
Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes complex III	10361 Arbitrary units Standard Deviation 5131	9001 Arbitrary units Standard Deviation 5451
Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes complex V	23118 Arbitrary units Standard Deviation 9281	23254 Arbitrary units Standard Deviation 8368

SECONDARY outcome

Timeframe: End of each 6 week intervention period

hsCRP (mg/L) by Beckman Coulter assay

Outcome measures

Outcome measures
Measure	Metformin n=16 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=17 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Inflammatory Marker: hsCRP	2.13 mg/L Standard Deviation 2.29	2.95 mg/L Standard Deviation 2.75

SECONDARY outcome

Timeframe: End of each 6 week intervention period

measure of autonomic function: ratio of fastest to slowest heart rate during valsalva maneuver

Outcome measures

Outcome measures
Measure	Metformin n=16 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=17 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Heart Rate Variability	1.55 ratio Standard Deviation 0.34	1.42 ratio Standard Deviation 0.18

SECONDARY outcome

Timeframe: Last Week of each 6 Week Intervention Period (over 7 days)

Mean Glucose \& Glucose Standard Deviation (Glycemic Variability) by Dexcom CGM

Outcome measures

Outcome measures
Measure	Metformin n=14 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=17 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Continuous Glucose Monitor Measures of Mean Glucose Mean 7 Day Glucose	162 mg/dL Standard Deviation 35	163 mg/dL Standard Deviation 26
Continuous Glucose Monitor Measures of Mean Glucose Glucose Standard Deviation (variability in glucoses throughout the 7 day period)	64 mg/dL Standard Deviation 14	68 mg/dL Standard Deviation 21

SECONDARY outcome

Timeframe: Last Week of each 6 Week Intervention Period (over 7 days)

Percent of time less than 70 mg/dL during the final week of each phase by Dexcom CGM.

Outcome measures

Outcome measures
Measure	Metformin n=14 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=17 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Continuous Glucose Monitor Measures of Hypoglycemia	8.4 percentage of time Standard Deviation 10.7	7.9 percentage of time Standard Deviation 6.9

SECONDARY outcome

Timeframe: End of each 6 week intervention period

Population: NS by paired t-test

Glucagon (pg/ml); baseline on AM of each phase final study visit.

Outcome measures

Outcome measures
Measure	Metformin n=16 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=17 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Metabolic Markers: Glucagon	95.5 pg/ml Standard Deviation 27.8	90.2 pg/ml Standard Deviation 45.6

SECONDARY outcome

Timeframe: End of each 6 week intervention period

Glucose (mg/dL), triglycerides (mg/dL), cholesterol (mg/dL) at baseline after each phase

Outcome measures

Outcome measures
Measure	Metformin n=16 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=17 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Metabolic Markers: Glucose, Triglycerides, Cholesterol Glucose	135 mg/dL Standard Deviation 45	124 mg/dL Standard Deviation 46
Metabolic Markers: Glucose, Triglycerides, Cholesterol Triglycerides	98 mg/dL Standard Deviation 50	78 mg/dL Standard Deviation 41
Metabolic Markers: Glucose, Triglycerides, Cholesterol total cholesterol	156 mg/dL Standard Deviation 38	154 mg/dL Standard Deviation 48

SECONDARY outcome

Timeframe: End of each 6 week intervention period

fatty acids (microeq/L) at baseline after each phase in the AM of the final visit

Outcome measures

Outcome measures
Measure	Metformin n=16 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=17 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Metabolic Markers: Fatty Acids	531 microEq/L Standard Deviation 174	446 microEq/L Standard Deviation 185

SECONDARY outcome

Timeframe: End of each 6 week intervention period

glycerol (micromol/L) at baseline after each phase in the AM of the final phase visit

Outcome measures

Outcome measures
Measure	Metformin n=16 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=17 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Metabolic Markers: Glycerol	95 microM/L Standard Deviation 33	87 microM/L Standard Deviation 31

SECONDARY outcome

Timeframe: End of each 6 week intervention period

insulin (microIU/ml) at baseline after each phase in the AM of the final phase visit

Outcome measures

Outcome measures
Measure	Metformin n=16 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=17 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Metabolic Markers: Insulin	33.9 microIU/ml Standard Deviation 34.3	49.1 microIU/ml Standard Deviation 56.8

SECONDARY outcome

Timeframe: End of each 6 week intervention period

lactate (mmol/L) at baseline after each phase in the AM of the final phase visit

Outcome measures

Outcome measures
Measure	Metformin n=16 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=17 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Metabolic Markers: Lactate	0.79 mmoles/L Standard Deviation 0.26	0.75 mmoles/L Standard Deviation 0.2

SECONDARY outcome

Timeframe: End of each 6 week intervention period

adiponection (microg/ml) at baseline after each phase in the AM of the final phase visit

Outcome measures

Outcome measures
Measure	Metformin n=16 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=17 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Metabolic Markers: Adiponection	13.5 microg/mL Standard Deviation 8.1	15.1 microg/mL Standard Deviation 9.4

SECONDARY outcome

Timeframe: End of each 6 week intervention period

endothelin-1 at baseline after each phase in the AM of the final phase visit by peninsula labs radioimmunoassay

Outcome measures

Outcome measures
Measure	Metformin n=13 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=14 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Vascular Markers: Endothelin-1 (pg/ml)	6.3 pg/mL Standard Deviation 4.8	5.8 pg/mL Standard Deviation 2.1

SECONDARY outcome

Timeframe: End of each 6 week intervention period

Population: 2 subjects complete data for metformin, but not placebo. (images not good) ME not reported for one placebo subject due to AnGly out of range.

Measured by 31P-mass spec. This ratio measures mitochondrial efficiency. The higher the ratio, the more efficiently the individual converts metabolic substrates into ATP, with the ATP then available for energy-demanding cellular processes such as protein synthesis and biomass production

Outcome measures

Outcome measures
Measure	Metformin n=11 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=8 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
In Vivo Mitochondrial Function: Ratio of the Amount of ATP Generated Per Unit of Oxygen Consumed	0.152 ratio Standard Deviation 0.067	0.116 ratio Standard Deviation 0.044

SECONDARY outcome

Timeframe: End of each 6 week intervention period

Measured by 31P-mass spec. ADP time constant and phosphocreatine time constant. ADP time constant is a measure of the time required to convert ADP → ATP and is a measure of muscle mitochondrial health (energy metabolism). A faster recovery is a better outcome; a slower recovery is a worse outcome. Similarly for phosphocreatine.

Outcome measures

Outcome measures
Measure	Metformin n=11 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=9 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
In Vivo Mitochondrial Function: Time Constants ADP time constant	18.4 seconds Standard Deviation 5.4	23.3 seconds Standard Deviation 10.3
In Vivo Mitochondrial Function: Time Constants Phosphocreatine time constant	32.9 seconds Standard Deviation 9.2	32.8 seconds Standard Deviation 12.5

SECONDARY outcome

Timeframe: End of each 6 week intervention period

Measured by 31P-mass spec. For each measure, a higher value indicates better mitochondrial function. All re calculated from multiple measures from the MRS spectra. These are relatively new research measures and normal values are not known or generally accepted. * QMax is theoretical maximum activity. * VPCr measures the rate at which PCr is regenerated.

Outcome measures

Outcome measures
Measure	Metformin n=11 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=9 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
In Vivo Mitochondrial Function: QMax, VPCr VPCr	0.24 mmoles/sec Standard Deviation 0.07	0.19 mmoles/sec Standard Deviation 0.08
In Vivo Mitochondrial Function: QMax, VPCr QMax	0.42 mmoles/sec Standard Deviation 0.14	0.38 mmoles/sec Standard Deviation 0.13

SECONDARY outcome

Timeframe: End of each 6 week intervention period

Measured by 31P-mass spec. A higher value indicates better mitochondrial function. All re calculated from multiple measures from the MRS spectra. These are relatively new research measures and normal values are not known or generally accepted. Oxidative Phosphorylation measures the rate at which electron transport activity generates phosphorylated energy sources (ATP and PCr)

Outcome measures

Outcome measures
Measure	Metformin n=11 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=9 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
In Vivo Mitochondrial Function: Oxidative Phosphorylation	0.19 mmol/L/s Standard Deviation 0.07	0.13 mmol/L/s Standard Deviation 0.06

SECONDARY outcome

Timeframe: End of each 6 week intervention period

Population: One placebo subject out of range for AnGly

Measured by 31P-mass spec. Anaerobic glycolysis measures the amount of anaerobic ATP generation for energy. It is generally felt that a higher value here reflects impaired mitochondrial function necessitating greater reliance on anaerobic metabolism.

Outcome measures

Outcome measures
Measure	Metformin n=11 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=8 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
In Vivo Mitochondrial Function:AnGly	0.22 mmol/L/s Standard Deviation 0.15	0.29 mmol/L/s Standard Deviation 0.21

SECONDARY outcome

Timeframe: End of each 6 week intervention period

Cardiac output

Outcome measures

Outcome measures
Measure	Metformin n=16 Participants Metformin: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.	Placebo n=17 Participants Placebo: Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Cardiac Function	5.52 L/min Standard Deviation 0.76	4.92 L/min Standard Deviation 0.62

OTHER_PRE_SPECIFIED outcome

Timeframe: after each 6 week intervention

exploratory measure looking at H2O2 production. not performed due to equipment not available.

Outcome measures

Outcome data not reported

Adverse Events

Metformin

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Irene Schauer, MD

University of Colorado Denver

Phone: 3037241111

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place