Metabolic Syndrome
Conditions
Brief summary
Health organizations recommend exercise in an intensity based manner to promote cardiovascular adaptation and prevent disease. Metformin is a common anti-diabetes medication that reduces future type 2 diabetes and cardiovascular disease (CVD) risk. However, the optimal dose of exercise to be combined with metformin for vascular health remains unknown. The purpose of this study is to evaluate whether combining high or low intensity exercise with metformin has the potential to outperform either exercise intensity alone on blood flow across the arterial tree as well as impact insulin action in individuals with metabolic syndrome. Identification of such outcomes will indicate 1) whether and how metformin should be combined with physical activity for CVD prevention, 2) provide the first indication of whether exercise intensity reduces CVD risk via multi-level vasculature function vs. metabolic insulin action, and 3) provide a rational early treatment for people with metabolic syndrome to prevent/treat type 2 diabetes and CVD.
Interventions
DRUGMetformin
Oral metformin 2000 mg/d for 16 weeks. Metformin dosage will follow 500 mg/d ramp up progression: Week 1 = 500 mg/d; Week 2 = 1,000 mg/d; Week 3 = 1500 mg/d; Week 4-16 = 2000 mg/d.
DRUGPlacebo
Oral placebo for 16 weeks. Placebo tablets will follow a four-stage progression: Week 1 = 1 tablet; Week 2 = 2 tablets; Week 3 = 3 tablets; Week 4-16 = 4 tablets.
BEHAVIORALLow Intensity Exercise
Low intensity exercise will consist of 16 weeks of walking at \ 55% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions.
BEHAVIORALHigh Intensity Exercise
High intensity exercise will consist of 16 weeks of walking at \ 85% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Rutgers University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Each subject will be randomly assigned to receive low intensity exercise training + placebo, high intensity exercise training + placebo, or these exercise programs with metformin.
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male or female ≥40 and ≤80 years old. * Has a body mass index ≥25 and ≤47 kg/m2. * Not diagnosed with Type 2 or Type 1 diabetes * Not currently engaged in \> 150 min/wk of exercise * Weight stable (\<2kg weight change in past 3 months) * Non-smoking \>5 years At minimum, subject will have abdominal obesity (increased waist circumference as defined below) and may have any additional National Cholesterol Education Adult Treatment Panel III Metabolic Syndrome criteria: * Increased waist circumference (≥102 cm in men; ≥88 cm in women) * Elevated triglycerides (≥150 mg/dl), or on medication for treating the condition * Reduced HDL-cholesterol (\<40mg/dl in men, \<50 mg/dl in women), or on medication for treating the condition * High blood pressure (≥130 mmHg systolic or ≥85mmHg diastolic), or on medication for treating the condition * Elevated fasting glucose (≥100 mg/dl), or on medication for treating the condition * Other major risk factors to be noted based on the Framingham Risk Score * HbA1c 5.7-6.4% * LDL \> 130 mg/dL * Family history of type 2 diabetes (immediate family, i.e. parent/sibling) * History of gestational diabetes * History of Polycystic Ovarian Syndrome * Family history of pre-mature cardiovascular disease (immediate family i.e. parent/sibling) before 55 for males or 65 for females that can include heart attack, peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery disease or clinical coronary heart disease) * Age ( \> 45 years old for men; \> 55 years old for women) * Black/African American, Mexican, Asian, and/or Hispanic * Subjects currently taking medications that affect heart rate and rhythm (i.e. Ca++ channel blockers, nitrates, alpha- or beta-blockers)
Exclusion criteria
* Subjects prescribed metformin or have taken metformin within 1 year. * Subjects with abnormal estimated glomerular filtration rate (eGFR). * Hypertriglyceridemic (\>400 mg/dl) and hypercholesterolemic (\>260 mg/dl) subjects * Hypertensive (\>160/100 mmHg) * Subjects with a history of significant metabolic, cardiac, congestive heart failure, cerebrovascular, hematological, pulmonary, gastrointestinal, liver, renal, or endocrine disease or cancer that in the investigator's opinion would interfere with or alter the outcome measures, or impact subject safety. * Pregnant (as evidenced by positive pregnancy test) or nursing women * Subjects with contraindications to participation in an exercise training program * Currently taking active weight suppression medication (e.g. phentermine,orlistat, lorcaserin, naltrexone-bupropion in combination, liraglutide, benzphetamine, diethylpropion, phendimetrazine) * Known hypersensitivity to perflutren (contained in Definity) * Subjects who are considered non-English speaking individuals
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Unscaled Flow Mediated Dilation (FMD) of the Brachial Artery | 0 and 16 weeks | Endothelial function assessed as a percentage change in brachial artery diameter from baseline to deflation (5 minutes after artery occlusion by blood pressure cuff inflation). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Metabolic Insulin Sensitivity. Glucose Infusion Rate Normalized to Steady-State Insulin (GIR). | 0 and 16 weeks | The glucose infusion rate (mg/kg/min) divided by steady-state insulin (uU/mL) during a 120 minute euglycemic-hyperinsulinemic clamp provides an index of metabolic insulin sensitivity. Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome. |
| Change in Fasting Augmentation Index | 0 and 16 weeks | Measure of Arterial Stiffness calculated by dividing the augmentation pressure by the pulse pressure, then multiplying by 100 and normalizing to a heart rate of 75 bpm (AIx75). Delta = Week 16 - Week 0. Lower values and negative change scores following the intervention indicate a better outcome. |
| Change in Insulin-stimulated Microvascular Blood Flow (MBF) of the Forearm. | 0 and 16 weeks | Product of microvascular blood volume (VI; video intensity units) and microvascular flow velocity (sec\^-1). Insulin-stimulated microvascular blood flow is the change during a 120 minute euglycemic-hyperinsulinemic clamp (120-0 minutes). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome. |
| Change in Insulin-stimulated Microvascular Flow Velocity (MFV) of the Forearm. | 0 and 16 weeks | Replenishment curves of the forearm flexor muscle acquired during steady-state infusion of Definity microbubbles. Insulin-stimulated microvascular flow velocity is the change during a 120 minute euglycemic-hyperinsulinemic clamp (120-0 minutes). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome. |
| Change in Insulin-stimulated Microvascular Blood Volume (MBV) of the Forearm. | 0 and 16 weeks | Replenishment curves of the forearm flexor muscle acquired during steady-state infusion of Definity microbubbles. Insulin-stimulated microvascular blood volume is the change during a 120 minute euglycemic-hyperinsulinemic clamp (120-0 minutes). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LoEx With Placebo Low intensity exercise with placebo.
Placebo: Oral placebo for 16 weeks. Placebo tablets will follow a four-stage progression: Week 1 = 1 tablet; Week 2 = 2 tablets; Week 3 = 3 tablets; Week 4-16 = 4 tablets.
Low Intensity Exercise: Low intensity exercise will consist of 16 weeks of walking at \
55% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. | 22 |
| HiEx With Placebo High intensity exercise with placebo.
Placebo: Oral placebo for 16 weeks. Placebo tablets will follow a four-stage progression: Week 1 = 1 tablet; Week 2 = 2 tablets; Week 3 = 3 tablets; Week 4-16 = 4 tablets.
High Intensity Exercise: High intensity exercise will consist of 16 weeks of walking at \
85% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. | 21 |
| LoEx With Metformin Low intensity exercise with metformin.
Metformin: Oral metformin 2000 mg/d for 16 weeks. Metformin dosage will follow 500 mg/d ramp up progression: Week 1 = 500 mg/d; Week 2 = 1,000 mg/d; Week 3 = 1500 mg/d; Week 4-16 = 2000 mg/d.
Low Intensity Exercise: Low intensity exercise will consist of 16 weeks of walking at \
55% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. | 24 |
| HiEx With Metformin High intensity exercise with metformin.
Metformin: Oral metformin 2000 mg/d for 16 weeks. Metformin dosage will follow 500 mg/d ramp up progression: Week 1 = 500 mg/d; Week 2 = 1,000 mg/d; Week 3 = 1500 mg/d; Week 4-16 = 2000 mg/d.
High Intensity Exercise: High intensity exercise will consist of 16 weeks of walking at \
85% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. | 24 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | COVID-19 | 3 | 2 | 3 | 3 |
| Overall Study | Lost to Follow-up | 1 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 0 | 3 |
Baseline characteristics
| Characteristic | LoEx With Placebo | HiEx With Placebo | LoEx With Metformin | HiEx With Metformin | Total |
|---|---|---|---|---|---|
| Age, Continuous | 56.5 years | 54.0 years | 56.0 years | 56.0 years | 56.0 years |
| Body Mass Index | 31.3 kg/m^2 | 33.8 kg/m^2 | 35.3 kg/m^2 | 36.0 kg/m^2 | 34.8 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 21 Participants | 24 Participants | 21 Participants | 88 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 0 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) White | 19 Participants | 18 Participants | 23 Participants | 16 Participants | 76 Participants |
| Sex: Female, Male Female | 17 Participants | 17 Participants | 19 Participants | 18 Participants | 71 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 5 Participants | 6 Participants | 20 Participants |
| VO2peak | 22.6 ml/kg/min | 23.0 ml/kg/min | 22.9 ml/kg/min | 21.1 ml/kg/min | 22.5 ml/kg/min |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 21 | 0 / 24 | 0 / 24 |
| other Total, other adverse events | 0 / 22 | 0 / 21 | 0 / 24 | 1 / 24 |
| serious Total, serious adverse events | 0 / 22 | 0 / 21 | 0 / 24 | 0 / 24 |
Outcome results
Primary
Change in Fasting Unscaled Flow Mediated Dilation (FMD) of the Brachial Artery
Endothelial function assessed as a percentage change in brachial artery diameter from baseline to deflation (5 minutes after artery occlusion by blood pressure cuff inflation). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome.
Time frame: 0 and 16 weeks
Population: Analysis includes only individuals that had both pre and post data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LoEx With Placebo | Change in Fasting Unscaled Flow Mediated Dilation (FMD) of the Brachial Artery | -0.45 Percent change in diameters |
| HiEx With Placebo | Change in Fasting Unscaled Flow Mediated Dilation (FMD) of the Brachial Artery | 0.76 Percent change in diameters |
| LoEx With Metformin | Change in Fasting Unscaled Flow Mediated Dilation (FMD) of the Brachial Artery | 3.50 Percent change in diameters |
| HiEx With Metformin | Change in Fasting Unscaled Flow Mediated Dilation (FMD) of the Brachial Artery | 5.28 Percent change in diameters |
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention 0 min unscaled FMD change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.04595% CI: [0.08, 6.99]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention 0 min unscaled FMD change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.50795% CI: [-2.42, 4.73]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention 0 min unscaled FMD change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.01495% CI: [1.14, 8.83]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention 0 min unscaled FMD change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.23795% CI: [-1.66, 6.42]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention 0 min unscaled FMD change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.48695% CI: [-2.8, 5.7]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention 0 min unscaled FMD change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.08195% CI: [-0.53, 8.19]ANCOVA
Secondary
Change in Fasting Augmentation Index
Measure of Arterial Stiffness calculated by dividing the augmentation pressure by the pulse pressure, then multiplying by 100 and normalizing to a heart rate of 75 bpm (AIx75). Delta = Week 16 - Week 0. Lower values and negative change scores following the intervention indicate a better outcome.
Time frame: 0 and 16 weeks
Population: Analysis includes only individuals that had both pre and post data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LoEx With Placebo | Change in Fasting Augmentation Index | -1.33 Percent of pulse pressure |
| HiEx With Placebo | Change in Fasting Augmentation Index | -4.65 Percent of pulse pressure |
| LoEx With Metformin | Change in Fasting Augmentation Index | 0.00 Percent of pulse pressure |
| HiEx With Metformin | Change in Fasting Augmentation Index | -1.20 Percent of pulse pressure |
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention AIx75 change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.67195% CI: [-5.68, 8.69]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention AIx75 change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.1795% CI: [-11.84, 2.19]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention AIx75 change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.83995% CI: [-7.29, 5.97]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention AIx75 change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.02495% CI: [0.86, 11.8]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention AIx75 change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.38595% CI: [-7.16, 2.83]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention AIx75 change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.0895% CI: [-0.53, 8.86]ANCOVA
Secondary
Change in Insulin-stimulated Microvascular Blood Flow (MBF) of the Forearm.
Product of microvascular blood volume (VI; video intensity units) and microvascular flow velocity (sec\^-1). Insulin-stimulated microvascular blood flow is the change during a 120 minute euglycemic-hyperinsulinemic clamp (120-0 minutes). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome.
Time frame: 0 and 16 weeks
Population: Analysis includes only individuals that had both pre and post data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LoEx With Placebo | Change in Insulin-stimulated Microvascular Blood Flow (MBF) of the Forearm. | 0.027 VI * sec^-1 |
| HiEx With Placebo | Change in Insulin-stimulated Microvascular Blood Flow (MBF) of the Forearm. | 0.041 VI * sec^-1 |
| LoEx With Metformin | Change in Insulin-stimulated Microvascular Blood Flow (MBF) of the Forearm. | -0.026 VI * sec^-1 |
| HiEx With Metformin | Change in Insulin-stimulated Microvascular Blood Flow (MBF) of the Forearm. | -0.065 VI * sec^-1 |
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBF change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.08895% CI: [-0.069, 0.005]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBF change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.9695% CI: [-0.059, 0.062]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBF change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.07595% CI: [-0.109, 0.006]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBF change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.25895% CI: [-0.094, 0.028]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBF change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.44395% CI: [-0.075, 0.035]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBF change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.14495% CI: [-0.126, 0.02]ANCOVA
Secondary
Change in Insulin-stimulated Microvascular Blood Volume (MBV) of the Forearm.
Replenishment curves of the forearm flexor muscle acquired during steady-state infusion of Definity microbubbles. Insulin-stimulated microvascular blood volume is the change during a 120 minute euglycemic-hyperinsulinemic clamp (120-0 minutes). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome.
Time frame: 0 and 16 weeks
Population: Analysis includes only individuals that had both pre and post data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LoEx With Placebo | Change in Insulin-stimulated Microvascular Blood Volume (MBV) of the Forearm. | 0.188 Video Intensity Units (VI) |
| HiEx With Placebo | Change in Insulin-stimulated Microvascular Blood Volume (MBV) of the Forearm. | 0.433 Video Intensity Units (VI) |
| LoEx With Metformin | Change in Insulin-stimulated Microvascular Blood Volume (MBV) of the Forearm. | -0.257 Video Intensity Units (VI) |
| HiEx With Metformin | Change in Insulin-stimulated Microvascular Blood Volume (MBV) of the Forearm. | -0.510 Video Intensity Units (VI) |
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.08695% CI: [-0.495, 0.035]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.60895% CI: [-0.354, 0.574]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.1195% CI: [-0.779, 0.09]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.14595% CI: [-0.818, 0.137]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.56595% CI: [-0.538, 0.309]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.1195% CI: [-1.025, 0.116]ANCOVA
Secondary
Change in Insulin-stimulated Microvascular Flow Velocity (MFV) of the Forearm.
Replenishment curves of the forearm flexor muscle acquired during steady-state infusion of Definity microbubbles. Insulin-stimulated microvascular flow velocity is the change during a 120 minute euglycemic-hyperinsulinemic clamp (120-0 minutes). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome.
Time frame: 0 and 16 weeks
Population: Analysis includes only individuals that had both pre and post data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LoEx With Placebo | Change in Insulin-stimulated Microvascular Flow Velocity (MFV) of the Forearm. | 0.006 sec^-1 |
| HiEx With Placebo | Change in Insulin-stimulated Microvascular Flow Velocity (MFV) of the Forearm. | 0.009 sec^-1 |
| LoEx With Metformin | Change in Insulin-stimulated Microvascular Flow Velocity (MFV) of the Forearm. | -0.007 sec^-1 |
| HiEx With Metformin | Change in Insulin-stimulated Microvascular Flow Velocity (MFV) of the Forearm. | -0.018 sec^-1 |
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MFV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.14795% CI: [-0.017, 0.003]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MFV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.94395% CI: [-0.016, 0.017]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MFV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.10895% CI: [-0.027, 0.003]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MFV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.31995% CI: [-0.024, 0.009]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MFV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.49695% CI: [-0.019, 0.01]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MFV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.18795% CI: [-0.031, 0.007]ANCOVA
Secondary
Change in Metabolic Insulin Sensitivity. Glucose Infusion Rate Normalized to Steady-State Insulin (GIR).
The glucose infusion rate (mg/kg/min) divided by steady-state insulin (uU/mL) during a 120 minute euglycemic-hyperinsulinemic clamp provides an index of metabolic insulin sensitivity. Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome.
Time frame: 0 and 16 weeks
Population: Analysis includes only individuals that had both pre and post data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LoEx With Placebo | Change in Metabolic Insulin Sensitivity. Glucose Infusion Rate Normalized to Steady-State Insulin (GIR). | 0.0012 (mg/kg/min)/(uU/mL) |
| HiEx With Placebo | Change in Metabolic Insulin Sensitivity. Glucose Infusion Rate Normalized to Steady-State Insulin (GIR). | 0.011 (mg/kg/min)/(uU/mL) |
| LoEx With Metformin | Change in Metabolic Insulin Sensitivity. Glucose Infusion Rate Normalized to Steady-State Insulin (GIR). | 0.0086 (mg/kg/min)/(uU/mL) |
| HiEx With Metformin | Change in Metabolic Insulin Sensitivity. Glucose Infusion Rate Normalized to Steady-State Insulin (GIR). | 0.0053 (mg/kg/min)/(uU/mL) |
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention GIR, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.37395% CI: [-0.0093, 0.024]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention GIR, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.19895% CI: [-0.0055, 0.025]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention GIR, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.62295% CI: [-0.0129, 0.0211]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention GIR, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.66695% CI: [-0.0136, 0.0088]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention GIR, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.63495% CI: [-0.0169, 0.0104]ANCOVA
Comparison: Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention GIR, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1).p-value: 0.33695% CI: [-0.0174, 0.0062]ANCOVA