Type 2 Diabetes
Conditions
Keywords
diabetes, exercise, cardiovascular, heart, insulin sensitivity
Brief summary
People who are overweight or who have type 2 diabetes mellitus (T2DM) have higher levels of certain fats in their blood. The blood vessels and heart of most of these individuals do not work normally and people with T2DM also have an impaired ability to perform exercise. The purpose of this study is to use the free fatty acid lowering drug, acipimox, to temporarily decrease the level of fat in the bloodstream of people with T2DM and observe the physiological changes to blood vessel function and exercise capacity and insulin sensitivity. This will help the investigators to understand ways of improving blood vessel function and the ability to exercise effectively in people who are overweight or have T2DM.
Interventions
DRUGAcipimox
Subjects will take acipimox 250mg (randomized and double-blinded) by mouth four times a day for six days prior to the visit and one dose the morning of study visit.
DRUGPlacebo
Subjects will take a placebo pill 250mg (randomized and double-blinded) by mouth four times a day for six days prior to the visit and one dose the morning of study visit.
Sponsors
US Department of Veterans Affairs
Pfizer
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Sedentary adults not participating in a regular exercise program (≤ one bout of scheduled exercise per week) * Subjects must have Type 2 Diabetes * Subjects must be otherwise healthy * Ages of 30-60 years * BMI of 25-39 and stable weight for 3 months prior to the start of the study * Diabetes controlled by diet +/- insulin secretagogues (sulfonylureas or glinides), metformin, or glucose absorption blockers (acarbose). * Total glycosylated hemoglobin levels (HbA1C) ≤9% (fair control) on current therapy.
Exclusion criteria
* Any comorbid condition which could limit exercise performance including Chronic Obstructive Pulmonary Disease (COPD) or asthma * Concurrent enrollment in an interventional study. * Any tobacco use either current or within the last year * Clinically evident distal symmetrical neuropathy, determined by evaluation of symptoms (numbness, paresthesia) and signs (elicited by vibration, pinprick, light touch, ankle jerks), will be excluded. * Autonomic dysfunction (\>20 mm fall in upright BP without a change in heart rate) will be excluded. * Evidence of ischemic heart disease by history or abnormal resting or exercise electrocardiogram (EKG) (\> 1 mm ST segment depression) on screening exercise test. * Angina or any other cardiovascular, pulmonary or musculoskeletal symptoms * Presence of systolic blood pressure \>190 at rest or \>250 with exercise or diastolic pressure \>95 at rest or \>105 with exercise * Proteinuria (urine protein \>200 mg/dl) or a creatinine \> 2 mg/dl, suggestive of severe renal disease * Proliferative retinopathy * Insulin, incretin, or glitazone treatment * Niacin treatment * History of peptic ulcers * A history of hereditary angioedema * C1 esterase deficiency * Women who are pregnant or breastfeeding * Use of fibrate drugs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: VO2 Kinetics | 7 to 9 days | Evaluate the impact of these effects of NEFA-lowering VO2 kinetics as measured by tau2, the time required for VO2 to reach 67% of peak during submaximal exercise. |
| Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: Peak VO2 | 7 to 9 days | Evaluate the impact of these effects of NEFA-lowering on exercise capacity measured as peak VO2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: Power Output at Anaerobic Threshold and at Peak Exercise | 7 to 9 days | Evaluate the impact of these effects of NEFA-lowering on exercise parameters, including VO2 kinetics, peak VO2, peak heart rate, peak power output. |
| Evaluating the Effect of Acipimox on Insulin Sensitivity and Cardiovascular Function: Inflammation | 7 to 9 days | effect of lowering of endogenous non-essential fatty acids (NEFA) in diabetic adults on inflammation (hsCRP) |
| Insulin Sensitivity | 7 to 9 days | Test the hypothesis that lowering of endogenous non-essential fatty acids (NEFA) in diabetic adults will improve insulin sensitivity measured as glucose disposal by hyperinsulinemic euglycemic clamp. Unit of measure is mg/kg of lean body mass/min/microIU of insulin/ml. The unit of measure reflects the rate at which glucose needs to be infused to maintain a normal blood sugar in the setting of a given serum insulin level from an insulin infusion. As such, a higher number means more glucose was needed and indicates greater sensitivity to insulin. |
| Evaluating the Effect of Acipimox on Insulin Sensitivity and Cardiovascular Function: Cardiac Function | 7 to 9 days | Test the hypothesis that lowering of endogenous non-essential fatty acids (NEFA) in diabetic adults will improve cardiac function: echo measurement of resting ejection fraction |
| Triglycerides | 7 to 9 days | — |
| Evaluating the Effect of Acipimox on Insulin Sensitivity and Cardiovascular Function: Endothelial Function | 7 to 9 days | Test the hypothesis that lowering of endogenous non-essential fatty acids (NEFA) in diabetic adults will improve endothelial function measured by flow mediated dilation of the brachial artery. |
| Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: Peak Heart Rate | 7 to 9 days | Evaluate the impact of these effects of NEFA-lowering on exercise parameters, including VO2 kinetics, peak VO2, peak heart rate, peak power output. |
Countries
United States
Participant flow
Pre-assignment details
6 participants screen failed prior to starting the study.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Acipimox, then Placebo Subjects will take acipimox 250mg (random order crossover and double-blinded) by mouth four times a day for six days prior to the visit and one dose the morning of study visit, followed by Placebo pill 250 mg by mouth four times a day for six days prior to the visit and one dose the morning of study visit
Placebo, then Acipimox Subjects will take a placebo pill 250mg (random order crossover and double-blinded) by mouth four times a day for six days prior to the visit and one dose the morning of study visit, followed by acipimox pill 250 mg by mouth four times a day for six days prior to the visit and one dose the morning of study visit | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Region of Enrollment United States | 7 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 7 |
| other Total, other adverse events | 0 / 7 | 0 / 7 |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 |
Outcome results
Primary
Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: Peak VO2
Evaluate the impact of these effects of NEFA-lowering on exercise capacity measured as peak VO2.
Time frame: 7 to 9 days
Population: This measure was originally entered as a secondary outcome in error. A registered component of this outcome measure, peak exercise cardiac function, was not collected. This is consistent with the protocol. One participant's data could not be collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acipimox | Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: Peak VO2 | 19.7 ml/kg/min | Standard Deviation 3.1 |
| Placebo | Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: Peak VO2 | 18.2 ml/kg/min | Standard Deviation 2.6 |
Primary
Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: VO2 Kinetics
Evaluate the impact of these effects of NEFA-lowering VO2 kinetics as measured by tau2, the time required for VO2 to reach 67% of peak during submaximal exercise.
Time frame: 7 to 9 days
Population: This measure was originally entered as a secondary outcome in error. A registered component of this outcome measure, peak exercise cardiac function, was not collected. This is consistent with the protocol. One participant's data could not be collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acipimox | Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: VO2 Kinetics | 51.4 seconds | Standard Deviation 16.9 |
| Placebo | Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: VO2 Kinetics | 53.3 seconds | Standard Deviation 11.8 |
Secondary
Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: Peak Heart Rate
Evaluate the impact of these effects of NEFA-lowering on exercise parameters, including VO2 kinetics, peak VO2, peak heart rate, peak power output.
Time frame: 7 to 9 days
Population: A registered component of this outcome measure, peak exercise cardiac function, was not collected. This is consistent with the protocol. One participant's data could not be collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acipimox | Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: Peak Heart Rate | 148 beats/minute | Standard Deviation 11 |
| Placebo | Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: Peak Heart Rate | 149 beats/minute | Standard Deviation 11 |
Secondary
Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: Power Output at Anaerobic Threshold and at Peak Exercise
Evaluate the impact of these effects of NEFA-lowering on exercise parameters, including VO2 kinetics, peak VO2, peak heart rate, peak power output.
Time frame: 7 to 9 days
Population: A registered component of this outcome measure, peak exercise cardiac function, was not collected. This is consistent with the protocol. One participant's data could not be collected.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acipimox | Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: Power Output at Anaerobic Threshold and at Peak Exercise | power output at AT | 75.8 Watts | Standard Deviation 22.9 |
| Acipimox | Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: Power Output at Anaerobic Threshold and at Peak Exercise | Power output at peak | 138 Watts | Standard Deviation 40 |
| Placebo | Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: Power Output at Anaerobic Threshold and at Peak Exercise | power output at AT | 65.7 Watts | Standard Deviation 26.3 |
| Placebo | Evaluate the Impact of Acipimox on Exercise Parameters in People With Type 2 Diabetes: Power Output at Anaerobic Threshold and at Peak Exercise | Power output at peak | 129 Watts | Standard Deviation 40 |
Secondary
Evaluating the Effect of Acipimox on Insulin Sensitivity and Cardiovascular Function: Cardiac Function
Test the hypothesis that lowering of endogenous non-essential fatty acids (NEFA) in diabetic adults will improve cardiac function: echo measurement of resting ejection fraction
Time frame: 7 to 9 days
Population: This outcome measure was originally registered as a primary outcome in error.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acipimox | Evaluating the Effect of Acipimox on Insulin Sensitivity and Cardiovascular Function: Cardiac Function | 71.4 percent | Standard Deviation 5.4 |
| Placebo | Evaluating the Effect of Acipimox on Insulin Sensitivity and Cardiovascular Function: Cardiac Function | 69.9 percent | Standard Deviation 4.6 |
Secondary
Evaluating the Effect of Acipimox on Insulin Sensitivity and Cardiovascular Function: Endothelial Function
Test the hypothesis that lowering of endogenous non-essential fatty acids (NEFA) in diabetic adults will improve endothelial function measured by flow mediated dilation of the brachial artery.
Time frame: 7 to 9 days
Population: This outcome measure was originally registered as a primary outcome in error.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acipimox | Evaluating the Effect of Acipimox on Insulin Sensitivity and Cardiovascular Function: Endothelial Function | 4.9 % change | Standard Deviation 3.4 |
| Placebo | Evaluating the Effect of Acipimox on Insulin Sensitivity and Cardiovascular Function: Endothelial Function | 5.3 % change | Standard Deviation 3.9 |
Secondary
Evaluating the Effect of Acipimox on Insulin Sensitivity and Cardiovascular Function: Inflammation
effect of lowering of endogenous non-essential fatty acids (NEFA) in diabetic adults on inflammation (hsCRP)
Time frame: 7 to 9 days
Population: This outcome measure was originally registered as a primary outcome in error. One participant's data could not be collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acipimox | Evaluating the Effect of Acipimox on Insulin Sensitivity and Cardiovascular Function: Inflammation | 3.4 mg/L | Standard Deviation 1.6 |
| Placebo | Evaluating the Effect of Acipimox on Insulin Sensitivity and Cardiovascular Function: Inflammation | 4.3 mg/L | Standard Deviation 4.8 |
Secondary
Insulin Sensitivity
Test the hypothesis that lowering of endogenous non-essential fatty acids (NEFA) in diabetic adults will improve insulin sensitivity measured as glucose disposal by hyperinsulinemic euglycemic clamp. Unit of measure is mg/kg of lean body mass/min/microIU of insulin/ml. The unit of measure reflects the rate at which glucose needs to be infused to maintain a normal blood sugar in the setting of a given serum insulin level from an insulin infusion. As such, a higher number means more glucose was needed and indicates greater sensitivity to insulin.
Time frame: 7 to 9 days
Population: This outcome measure was originally registered as a primary outcome in error. One participant's data could not be collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acipimox | Insulin Sensitivity | 6.00 mg/kg LBM/min/micro IU insulin/ml | Standard Deviation 1.52 |
| Placebo | Insulin Sensitivity | 6.04 mg/kg LBM/min/micro IU insulin/ml | Standard Deviation 0.69 |
Secondary
Triglycerides
Time frame: 7 to 9 days
Population: One participant's data could not be collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acipimox | Triglycerides | 99 mg/dl | Standard Deviation 33 |
| Placebo | Triglycerides | 134 mg/dl | Standard Deviation 43 |