Cardiovascular Disease, HIV Infections, HIV Lipodystrophy, Insulin Resistance, The Metabolic Syndrome
Conditions
Keywords
HIV/AIDS, Heart disease, Diabetes, Cardiovascular disease risk, Dyslipidemia, Visceral adiposity, treatment experienced
Brief summary
We hypothesize that the hearts of HIV+ people with The Metabolic Syndrome use and oxidize fats and sugars inappropriately, and that this may impair the heart's ability to pump blood. We hypothesize that exercise training or pioglitazone (Actos) will improve fat and sugar metabolism in the hearts of HIV+ people with The Metabolic Syndrome. This study will advance our understanding of cardiovascular disease in HIV+ people, and will test the efficacy of exercise training and pioglitazone for improving insulin resistance, heart metabolism and heart function in this at risk population.
Detailed description
We hypothesize that myocardial free fatty acid and glucose utilization and oxidation rates are dysregulated in HIV+ people with The Metabolic Syndrome in comparison to HIV+ people without The Metabolic Syndrome, and in comparison to HIV-seronegative people with and without The Metabolic Syndrome. We hypothesize that dysregulated myocardial fatty acid and glucose metabolism is associated with impaired heart function (diastolic dysfunction) in HIV+ people with The Metabolic Syndrome. We will use myocardial positron emission tomography, radioactive isotope tracers of palmitate and glucose, and echocardiography to evaluate myocardial metabolism and function. HIV+ people with The Metabolic Syndrome will receive 16wks of exercise training or pioglitazone (Actos), and we will evaluate their potential beneficial effects on myocardial metabolism and function.
Interventions
DRUGPioglitazone
30mg/day for 16 weeks
BEHAVIORALExercise Training
Cardiorespiratory and resistance exercise training 3days/wk for 16 weeks
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
28 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
All participants both with and without metabolic syndrome: 1. 28-50 years old. 2. Plasma HIV RNA less than 5,000 copies/mL for previous 3 months OR CD4 count greater than 100 cells/µL for previous 3 months. 3. Stable for at least the past 3 months on any HAART regimen. 4. Normal blood chemistries for at least 1 month prior to enrollment: platelet count \>50,000/mm3, absolute neutrophil count \>750/mm3, liver transaminases \<2.5x the upper limit of normal (ULN), creatinine \<1.3x ULN, albumin \>30g/L, creatine kinase \<5.9x ULN. Menstruating women must have a negative urine beta-HCG pregnancy test within 14 days prior to study. To control for potential metabolic effects of alterations in female hormones during the menstrual cycle, all menstruating women will be studied during the follicular phase (serum 17beta-estradiol \<165 pg/mL).
Exclusion criteria
1. Frank obesity (BMI \>35kg/m2). 2. Chronic hepatitis B infection (HB surface antigen positive). Active hepatitis C infection (detectable Hep C RNA). Those who have cleared hepatitis B or C infection are eligible. 3. Diabetes \[fasting glucose \>125 mg/dL, or fasting insulin \>45 µU/mL, or 2-hr glucose \>200mg/dL\]. 4. Medications or agents that regulate glucose metabolism (e.g., insulin-sensitizers, insulin-secretagogues). Lipid lowering agents that regulate lipid metabolism (i.e. fibrate, statin). 5. Gestational diabetes, pregnancy, or nursing mothers. 6. Serum triglycerides ≥ 500 mg/dL. 7. Hypogonadism \[total testosterone \<200ng/dL (men) or \<15ng/dL (women)\]; thyroid disorder \[TSH \<0.2 or \>12µIU/mL\]; hypercortisolemia \[morning cortisol \>22µg/dL\]. Replacement testosterone or thyroid hormones to normalize abnormal levels is acceptable, as long as treatment and blood levels have been stable for at least 3 months. 8. Use of human growth hormone (hGH) or GH-secretagogues (GH-releasing hormone-peptides) within the previous 3 months. 9. History of serious cardiovascular disease; MI, angina pectoris, heart failure, congenital heart disease, coronary artery disease, coronary artery bypass graft, stroke. Bundle branch block is exclusionary because it limits the interpretability of the resting/exercise ECG. Cardiovascular or physical contraindications to maximal exercise testing on a cycle ergometer. 10. Uncontrolled hypertension (\>140/90 mmHg). Certain antihypertensive medications will be permitted (diuretics, ACE inhibitors) as long as the medication, dose, and blood pressure have been stable for at least 3 months. 11. Well-trained athletes (defined as \>3 exercise training exposures/week; \>30min regimented exercise/exposure maintained for at least the prior 4 weeks). 12. History of or active substance abuse (eg, alcoholism, cocaine, heroin, crack, methamphetamine, phencyclidine). 13. Active secondary infection. Any significant change in chronic suppressive therapy for an opportunistic infection during 1 month prior to enrollment. 14. New serious systemic infection during the 3 weeks prior to enrollment. 15. History of hyperlactatemia or lactic acidosis, esp. with rapid weight loss. 16. Debilitating-painful myopathy or neuropathy that requires 'assistance' to conduct normal activities of daily living (dressing, hygiene, preparing meals, operating a vehicle). These might affect peripheral substrate metabolism. 17. Chronic renal insufficiency/failure or other comorbid conditions (eg. cancer, COPD) that alter metabolism. 18. Pancreatitis, celiac disease, or cirrhosis. 19. Inadequate macronutrient or energy intake, or malabsorptive disorder. 20. Dementia or any condition that would prevent voluntary informed consent or compliance. 21. Other compounds or blinded investigational new drugs that might affect metabolism or confound data interpretation (eg. RU486, interleukin therapy, or cytokine-receptor antagonist). 22. Oral glucocorticoid or corticosteroid use within previous 3 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Myocardial Glucose Utilization Rate | Weeks 0 and 16 | Radio-tracer (11C-glucose) and positron emission tomography quantification of myocardial glucose utilization rate. The rate at which glucose exits the blood, enters the muscle cells in the left ventricle, and is metabolized (ATP generation, glycolysis, glycogenolysis, or lactate production). Total glucose utilization rate in the left ventricle of the heart. |
| Myocardial Glucose Utilization Rate Per Unit Insulin | Weeks 0 and 16 | Radio-tracer (11C-glucose) and positron emission tomography quantification of myocardial glucose utilization rate per unit of plasma insulin. Total glucose utilization rate in the left ventricle of the heart expressed per unit of the circulating plasma insulin concentration. |
| Myocardial Fatty Acid Utilization Rate | Weeks 0 and 16 | Radio-tracer (11C-palmitate) and positron emission tomography quantification of myocardial fatty acid utilization rate. The rate at which palmitate exits the blood, enters the muscle cells in the left ventricle, and is metabolized (oxidation, re-esterification). |
| Myocardial Fatty Acid Oxidation Rate | Weeks 0 and 16 | Radio-tracer (11C-palmitate) and positron emission tomography quantification of myocardial fatty acid oxidation rate. |
| Myocardial Fatty Acid Esterification | Weeks 0 and 16 | Radio-tracer (11C-palmitate) and positron emission tomography quantification of myocardial fatty acid esterification as a % of total fatty acid extraction |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Myocardial Contractile Function During Diastole | Weeks 0 and 16 | Echocardiographic quantification of (E/A) early to late diastolic filling velocity. Aria transfer blood to the ventricles in 2 steps: 1. blood collected in the atria falls into the ventricles when the atrioventricular valves opens. In the left heart, the velocity at which the blood moves during this initial action is called the early or E filling velocity. 2. residual blood in the atria, is emptied during diastole by atrial contraction. The velocity of the blood during atrial contraction is the A (for atrial) filling velocity. These are expressed as a ratio (E/A). If A exceeds E velocity (ratio \<1.0) this is a clinical marker of diastolic dysfunction. This can occur when the left ventricular wall becomes so stiff as to impair proper filling, which can lead to diastolic heart failure. |
| Myocardial Contractile Function During Systole | Weeks 0 and 16 | Echocardiographic quantification of E' wall velocity during systole averaged at the lateral wall and septum |
| Fasting Lipids and Lipoproteins | Week 0 and 16 | fasting serum triglycerides, LDL-, and HDL-cholesterol concentrations |
| Fasting Glucose Insulin and HOMA | Week 0 and 16 | fasting plasma glucose, insulin concentrations and HOMA-insulin resistance |
Countries
United States
Participant flow
Recruitment details
Twenty four participants were enrolled from the AIDS Clinical Trials Unit and Infectious Diseases Clinics at Washington University School of Medicine in St. Louis, Missouri, USA. This was a prospective, two-group, random assignment study.
Pre-assignment details
Exclusion criteria: medications or dietary supplements that affect metabolism (β-blocker, β-agonist, Ca2+ channel blocker, corticosteroid), neuromuscular disorder that affects metabolism or ability to exercise, consumed \>3 alcohol drinks/wk, active Hep C or B, recreational-anabolic -appetite stimulant drugs, regular physical exercise.
Participants by arm
| Arm | Count |
|---|---|
| Pioglitazone Pioglitazone (Actos, 30mg/day for 16 weeks) | 12 |
| Exercise Training Cardiorespiratory and resistance exercise training 3days/wk for 16 weeks | 12 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 4 |
Baseline characteristics
| Characteristic | Exercise Training | Pioglitazone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 12 Participants | 24 Participants |
| Age Continuous | 41 years STANDARD_DEVIATION 6 | 42 years STANDARD_DEVIATION 7 | 42 years STANDARD_DEVIATION 6 |
| Region of Enrollment United States | 12 participants | 12 participants | 24 participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 12 Participants | 9 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 12 | 0 / 8 |
| serious Total, serious adverse events | 0 / 12 | 0 / 8 |
Outcome results
Primary
Myocardial Fatty Acid Esterification
Radio-tracer (11C-palmitate) and positron emission tomography quantification of myocardial fatty acid esterification as a % of total fatty acid extraction
Time frame: Weeks 0 and 16
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pioglitazone | Myocardial Fatty Acid Esterification | Week 0 | 7 (% of total fatty acid extraction) | Standard Error 7 |
| Pioglitazone | Myocardial Fatty Acid Esterification | Week 16 | 4 (% of total fatty acid extraction) | Standard Error 5 |
| Exercise Training | Myocardial Fatty Acid Esterification | Week 0 | 4 (% of total fatty acid extraction) | Standard Error 3 |
| Exercise Training | Myocardial Fatty Acid Esterification | Week 16 | 7 (% of total fatty acid extraction) | Standard Error 5 |
Primary
Myocardial Fatty Acid Oxidation Rate
Radio-tracer (11C-palmitate) and positron emission tomography quantification of myocardial fatty acid oxidation rate.
Time frame: Weeks 0 and 16
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pioglitazone | Myocardial Fatty Acid Oxidation Rate | Week 0 | 92.4 (nmol palmitate/g heart muscle/min | Standard Error 27.5 |
| Pioglitazone | Myocardial Fatty Acid Oxidation Rate | Week 16 | 110.1 (nmol palmitate/g heart muscle/min | Standard Error 31.7 |
| Exercise Training | Myocardial Fatty Acid Oxidation Rate | Week 0 | 106.3 (nmol palmitate/g heart muscle/min | Standard Error 49.6 |
| Exercise Training | Myocardial Fatty Acid Oxidation Rate | Week 16 | 97.5 (nmol palmitate/g heart muscle/min | Standard Error 36.6 |
Primary
Myocardial Fatty Acid Utilization Rate
Radio-tracer (11C-palmitate) and positron emission tomography quantification of myocardial fatty acid utilization rate. The rate at which palmitate exits the blood, enters the muscle cells in the left ventricle, and is metabolized (oxidation, re-esterification).
Time frame: Weeks 0 and 16
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pioglitazone | Myocardial Fatty Acid Utilization Rate | Week 16 | 129.3 (nmol palmitate/g heart muscle/min | Standard Error 34.5 |
| Pioglitazone | Myocardial Fatty Acid Utilization Rate | Week 0 | 119.3 (nmol palmitate/g heart muscle/min | Standard Error 39.8 |
| Exercise Training | Myocardial Fatty Acid Utilization Rate | Week 0 | 119.8 (nmol palmitate/g heart muscle/min | Standard Error 48.7 |
| Exercise Training | Myocardial Fatty Acid Utilization Rate | Week 16 | 130.4 (nmol palmitate/g heart muscle/min | Standard Error 55.2 |
Primary
Myocardial Glucose Utilization Rate
Radio-tracer (11C-glucose) and positron emission tomography quantification of myocardial glucose utilization rate. The rate at which glucose exits the blood, enters the muscle cells in the left ventricle, and is metabolized (ATP generation, glycolysis, glycogenolysis, or lactate production). Total glucose utilization rate in the left ventricle of the heart.
Time frame: Weeks 0 and 16
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pioglitazone | Myocardial Glucose Utilization Rate | Week 0 | 109.6 (nmol glucose/g heart muscle/min | Standard Error 70.5 |
| Pioglitazone | Myocardial Glucose Utilization Rate | Week 16 | 109.1 (nmol glucose/g heart muscle/min | Standard Error 55.2 |
| Exercise Training | Myocardial Glucose Utilization Rate | Week 0 | 106.7 (nmol glucose/g heart muscle/min | Standard Error 69 |
| Exercise Training | Myocardial Glucose Utilization Rate | Week 16 | 87.2 (nmol glucose/g heart muscle/min | Standard Error 97.4 |
Primary
Myocardial Glucose Utilization Rate Per Unit Insulin
Radio-tracer (11C-glucose) and positron emission tomography quantification of myocardial glucose utilization rate per unit of plasma insulin. Total glucose utilization rate in the left ventricle of the heart expressed per unit of the circulating plasma insulin concentration.
Time frame: Weeks 0 and 16
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pioglitazone | Myocardial Glucose Utilization Rate Per Unit Insulin | Week 0 | 14.9 (nmol glucose/g heart muscle/min/µU insu | Standard Error 22.1 |
| Pioglitazone | Myocardial Glucose Utilization Rate Per Unit Insulin | Week 16 | 15.7 (nmol glucose/g heart muscle/min/µU insu | Standard Error 12.4 |
| Exercise Training | Myocardial Glucose Utilization Rate Per Unit Insulin | Week 0 | 11.9 (nmol glucose/g heart muscle/min/µU insu | Standard Error 11 |
| Exercise Training | Myocardial Glucose Utilization Rate Per Unit Insulin | Week 16 | 21.7 (nmol glucose/g heart muscle/min/µU insu | Standard Error 40.8 |
Secondary
Fasting Glucose Insulin and HOMA
fasting plasma glucose, insulin concentrations and HOMA-insulin resistance
Time frame: Week 0 and 16
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pioglitazone | Fasting Glucose Insulin and HOMA | glucose (mg/dL) wk 0 | 102 mg/dL µU/mL | Standard Error 15 |
| Pioglitazone | Fasting Glucose Insulin and HOMA | glucose wk 16 | 95.3 mg/dL µU/mL | Standard Error 13 |
| Pioglitazone | Fasting Glucose Insulin and HOMA | insulin (µU/mL) wk 0 | 20.5 mg/dL µU/mL | Standard Error 25.7 |
| Pioglitazone | Fasting Glucose Insulin and HOMA | insulin wk 16 | 11.4 mg/dL µU/mL | Standard Error 9.6 |
| Pioglitazone | Fasting Glucose Insulin and HOMA | HOMA-IR wk 0 | 6.1 mg/dL µU/mL | Standard Error 10.4 |
| Pioglitazone | Fasting Glucose Insulin and HOMA | HOMA-IR wk 16 | 2.8 mg/dL µU/mL | Standard Error 2.7 |
| Exercise Training | Fasting Glucose Insulin and HOMA | HOMA-IR wk 0 | 3.3 mg/dL µU/mL | Standard Error 1.7 |
| Exercise Training | Fasting Glucose Insulin and HOMA | glucose (mg/dL) wk 0 | 91.9 mg/dL µU/mL | Standard Error 9.5 |
| Exercise Training | Fasting Glucose Insulin and HOMA | insulin wk 16 | 11.8 mg/dL µU/mL | Standard Error 7.6 |
| Exercise Training | Fasting Glucose Insulin and HOMA | glucose wk 16 | 86.8 mg/dL µU/mL | Standard Error 8.2 |
| Exercise Training | Fasting Glucose Insulin and HOMA | HOMA-IR wk 16 | 2.6 mg/dL µU/mL | Standard Error 1.6 |
| Exercise Training | Fasting Glucose Insulin and HOMA | insulin (µU/mL) wk 0 | 14.8 mg/dL µU/mL | Standard Error 8.4 |
Secondary
Fasting Lipids and Lipoproteins
fasting serum triglycerides, LDL-, and HDL-cholesterol concentrations
Time frame: Week 0 and 16
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pioglitazone | Fasting Lipids and Lipoproteins | triglycerides wk 0 | 199 mg/dL | Standard Error 119 |
| Pioglitazone | Fasting Lipids and Lipoproteins | triglycerides wk 16 | 182 mg/dL | Standard Error 91 |
| Pioglitazone | Fasting Lipids and Lipoproteins | LDL-cholesterol wk 0 | 115 mg/dL | Standard Error 36 |
| Pioglitazone | Fasting Lipids and Lipoproteins | LDL-cholesterol wk 16 | 97 mg/dL | Standard Error 17 |
| Pioglitazone | Fasting Lipids and Lipoproteins | HDL-cholesterol wk 0 | 38.9 mg/dL | Standard Error 11 |
| Pioglitazone | Fasting Lipids and Lipoproteins | HDL-cholesterol wk 16 | 38.8 mg/dL | Standard Error 12.4 |
| Exercise Training | Fasting Lipids and Lipoproteins | HDL-cholesterol wk 0 | 38.1 mg/dL | Standard Error 8.4 |
| Exercise Training | Fasting Lipids and Lipoproteins | triglycerides wk 0 | 185 mg/dL | Standard Error 58 |
| Exercise Training | Fasting Lipids and Lipoproteins | LDL-cholesterol wk 16 | 90 mg/dL | Standard Error 24 |
| Exercise Training | Fasting Lipids and Lipoproteins | triglycerides wk 16 | 159 mg/dL | Standard Error 33 |
| Exercise Training | Fasting Lipids and Lipoproteins | HDL-cholesterol wk 16 | 39.8 mg/dL | Standard Error 21.8 |
| Exercise Training | Fasting Lipids and Lipoproteins | LDL-cholesterol wk 0 | 112 mg/dL | Standard Error 26 |
Secondary
Myocardial Contractile Function During Diastole
Echocardiographic quantification of (E/A) early to late diastolic filling velocity. Aria transfer blood to the ventricles in 2 steps: 1. blood collected in the atria falls into the ventricles when the atrioventricular valves opens. In the left heart, the velocity at which the blood moves during this initial action is called the early or E filling velocity. 2. residual blood in the atria, is emptied during diastole by atrial contraction. The velocity of the blood during atrial contraction is the A (for atrial) filling velocity. These are expressed as a ratio (E/A). If A exceeds E velocity (ratio \<1.0) this is a clinical marker of diastolic dysfunction. This can occur when the left ventricular wall becomes so stiff as to impair proper filling, which can lead to diastolic heart failure.
Time frame: Weeks 0 and 16
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pioglitazone | Myocardial Contractile Function During Diastole | Week 0 | 1.4 ratio | Standard Error 0.6 |
| Pioglitazone | Myocardial Contractile Function During Diastole | Week 16 | 1.4 ratio | Standard Error 0.5 |
| Exercise Training | Myocardial Contractile Function During Diastole | Week 0 | 1.4 ratio | Standard Error 0.3 |
| Exercise Training | Myocardial Contractile Function During Diastole | Week 16 | 1.5 ratio | Standard Error 0.2 |
Secondary
Myocardial Contractile Function During Systole
Echocardiographic quantification of E' wall velocity during systole averaged at the lateral wall and septum
Time frame: Weeks 0 and 16
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pioglitazone | Myocardial Contractile Function During Systole | Week 0 | 12.7 cm/sec | Standard Error 1.8 |
| Pioglitazone | Myocardial Contractile Function During Systole | Week 16 | 12.8 cm/sec | Standard Error 1.6 |
| Exercise Training | Myocardial Contractile Function During Systole | Week 0 | 13.1 cm/sec | Standard Error 2.4 |
| Exercise Training | Myocardial Contractile Function During Systole | Week 16 | 13.6 cm/sec | Standard Error 0.4 |