HIV Lipodystrophy
Conditions
Keywords
lipid kinetics, fat oxidation
Brief summary
HIV lipodystrophy syndrome (HLS) is characterized by loss of fat in the arms and legs, with increase in fat in the abdomen, and abnormal blood lipid levels. Persons with HLS have high risk for cardiovascular disease and diabetes mellitus and the metabolic syndrome. The investigators have previously shown that the abnormal lipid levels and lipodystrophy in HLS are associated with defective regulation of lipid metabolic rates, specifically, accelerated lipolysis (breakdown of stored fats), and decreased fat oxidation (utilization of fats for energy). Patients with HLS also have low levels of the hormone leptin. The investigators hypothesize that treatment of these patients with leptin will improve fat oxidation and may slow the rate of lipolysis. Hence, the investigators propose to study the effect of leptin therapy on lipid metabolic rates and lipid and glucose levels in adults with HLS. The investigators will use state of the art stable isotope tracer techniques and gas chromatography mass spectrometry (GCMS) to measure lipolysis, fat oxidation, and fat re-esterification in adipose tissues and liver.
Detailed description
The HIV lipodystrophy syndrome (HLS) is characterized by peripheral fat wasting and central obesity, and hyperlipidemia (mainly hypertriglyceridemia), which results in insulin resistance. HLS patients are at high risk for cardiovascular disease, diabetes mellitus and the metabolic syndrome. The investigators have previously shown that the alterations in lipid metabolism in the so-called mixed form of HLS are due to dysregulation of lipid kinetics at two levels. First, there appears to be an acceleration in lipid kinetics, with higher total and net lipolysis despite higher intra-adipocyte re-esterification. However, the percentage of fatty acid flux being oxidized remains the same, leading to increased hepatic recycling of fatty acids to triglycerides (TG), and export of TG-rich VLDL into the circulation. Second, there is reduced clearance of chylomicron and VLDL-TG from the plasma, resulting in the striking hypertriglyceridemia associated with this syndrome. The investigators propose that these alterations in lipid kinetics account for the phenotypic changes characteristic of this syndrome: increased lipolysis would facilitate peripheral lipoatrophy, increased intra-adipocyte re-esterification (if selective in intrabdominal depots) would contribute to the central obesity, and increased hepatic re-esterification together with impaired VLDL- and chylomicron-TG clearance would lead to hypertriglyceridemia. Rational treatment of HLS should be targeted at these fundamental kinetic defects. Leptin is in many ways an ideal agent, since it increases fat oxidation, and shifts the ratio of utilization of free fatty acids derived from lipolysis towards oxidation and away from re-esterification, and decreases plasma triglyceride levels. HLS patients with lipoatrophy have low circulating levels of leptin. Moreover, leptin has been shown to be effective in correcting similar defects in fat redistribution and circulating lipids in non-HIV forms of lipodystrophy. Hence, the investigators propose to study (using a blinded, placebo-controlled, dose escalating design) the effect of leptin therapy on lipid kinetics and fat distribution in adult subjects with the lipoatrophic and mixed (peripheral lipoatrophy and central adiposity) forms of HLS. The investigators will use state of the art stable isotope tracer techniques and gas chromatography mass spectrometry (GCMS) to measure whole body lipolysis, lipid oxidation, lipid re-esterification and hepatic lipid recycling.
Interventions
DRUGHuman recombinant leptin (metreleptin)
Metreleptin was administered at a dose of 0.02 mg / kg body weight for two months, followed by a dose of 0.04 mg / kg for two more months.
DRUGPlacebo
Placebo was administered at a dose of 0.02 mg / kg body weight daily by subcutaneous injection for two months, followed by 0.04 mg / kg for two more months.
Sponsors
Baylor College of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* predominantly lipoatrophic or mixed phenotype of HIV-lipodystrophy (based on self-observation and evaluation by a study physician utilizing a visual scale; * AM fasting leptin \< 4.0 ng/ml * hypertriglyceridemia (fasting serum TG 250-1000 mg /dl). * normal biochemistry (except altered lipid and glucose profile). Patients with the American Diabetes Association diagnostic criteria for diabetes were included provided the HbA1c level was \<7.5% and they received no anti-diabetic medications for at least 3 months. * well-controlled HIV infection status evidenced by viral RNA titers \<400 copies/ml, on stable HAART.
Exclusion criteria
* acute or chronic illnesses. * use of antidiabetic medications in the previous 3 months, or of lipid-lowering drugs in the previous 6 weeks are also
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Total Lipolysis | 4 months after treatment | Rate of total lipolysis was measured in plasma samples by mass spectrometry following stable isotope infusions of labeled glycerol and palmitate |
| Rate of Net Lipolysis | 4 months after treatment | Rate of net lipolysis was measured in plasma samples by mass spectrometry following stable isotope infusions of labeled glycerol and palmitate |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rates of Fatty Acid Oxidation | 4 months after treatment | Rates of fatty acid oxidation were measured in breath samples following stable isotope infusions of 13C-labeled palmitate. |
| Fasting Plasma Non-HDL-C | 4 months after treatment. | Fasting plasma non-HDL-cholesterol was calculated from measured total cholesterol and HDL cholesterol. |
| Glucose Levels After Glucose Challenge | 4 months after treatment. | An oral glucose tolerance test was performed. This is not PD/PK in the sense that we are not studying the distribution or clearance of a drug. Rather, we are performing a standard clinical test of glucose tolerance. i.e., a test for diabetes and pre-diabetes. Although multiple time points are used in this test, the outcome is a single value, either a blood glucose level after 2 hours or an area-under-the-curve. In this study we are reporting the area-under-the-curve. |
| Insulin Levels After Oral Glucose Challenge. | 4 months after treatment. | An oral glucose tolerance test was performed to measure endogenous insulin response. This is not PD/PK in the sense that we are not studying the distribution or clearance of a drug. Rather, we are performing a clinical test of endogenous insulin response to glucose i.e., an endocrine test. Although multiple time points are used in this test, the outcome is a single value, i.e., an area-under-the-curve for insulin. |
Countries
United States
Participant flow
Recruitment details
HIV-positive subjects meeting the entry criteria were recruited from March, 2003 until November, 2010 from the clinics of Harris County Hospital District, and Legacy Community Health Center, Houston.
Pre-assignment details
If a potential study subject was already taking a lipid lowering medication at the time of screening but was otherwise eligible for the study, he/she was invited to stop the medication for 6 weeks, at the end of which the fasting triglyceride level was re-measured to gauge eligibility.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Injection Each subject will receive placebo at a dose of 0.02 mg / kg body weight daily by subcutaneous injection for two months, followed by a dose of 0.04 mg / kg for two more months.
Placebo : Placebo will administered at a dose of 0.02 mg / kg body weight daily by subcutaneous injection for two months, followed by 0.04 mg / kg for two more months. | 8 |
| Human Recombinant Leptin (Metreleptin) Each subject will receive 0.02 mg leptin / kg body weight daily by subcutaneous injection for two months, followed by 0.04 mg leptin / kg for two more months.
Human recombinant leptin (metreleptin) : Metreleptin will be administered at a dose of 0.02 mg / kg body weight for two months, followed by a dose of 0.04 mg / kg for two more months. | 9 |
| Total | 17 |
Baseline characteristics
| Characteristic | Human Recombinant Leptin (Metreleptin) | Placebo Injection | 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 | 9 Participants | 8 Participants | 17 Participants |
| Age, Continuous | 44.9 years STANDARD_DEVIATION 7.8 | 49.1 years STANDARD_DEVIATION 6.8 | 46.9 years STANDARD_DEVIATION 7.3 |
| Region of Enrollment United States | 9 participants | 8 participants | 17 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 9 Participants | 8 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 8 | 0 / 9 |
| serious Total, serious adverse events | 1 / 8 | 2 / 9 |
Outcome results
Primary
Rate of Net Lipolysis
Rate of net lipolysis was measured in plasma samples by mass spectrometry following stable isotope infusions of labeled glycerol and palmitate
Time frame: 4 months after treatment
Population: Subjects in each group were analyzed and compared after 4 months of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Injection | Rate of Net Lipolysis | 0.386 mmol FFA/kg/h | Standard Error 0.074 |
| Human Recombinant Leptin (Metreleptin) | Rate of Net Lipolysis | 0.508 mmol FFA/kg/h | Standard Error 0.106 |
Primary
Rate of Total Lipolysis
Rate of total lipolysis was measured in plasma samples by mass spectrometry following stable isotope infusions of labeled glycerol and palmitate
Time frame: 4 months after treatment
Population: Subjects in each group were analyzed and compared after 4 months of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Injection | Rate of Total Lipolysis | 0.649 mmol FFA/kg/h | Standard Error 0.073 |
| Human Recombinant Leptin (Metreleptin) | Rate of Total Lipolysis | 0.767 mmol FFA/kg/h | Standard Error 0.137 |
Secondary
Fasting Plasma Non-HDL-C
Fasting plasma non-HDL-cholesterol was calculated from measured total cholesterol and HDL cholesterol.
Time frame: 4 months after treatment.
Population: Number of subjects in each group remaining after 4 months of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Injection | Fasting Plasma Non-HDL-C | 136 mg/dL | Standard Error 9 |
| Human Recombinant Leptin (Metreleptin) | Fasting Plasma Non-HDL-C | 127 mg/dL | Standard Error 7 |
Secondary
Glucose Levels After Glucose Challenge
An oral glucose tolerance test was performed. This is not PD/PK in the sense that we are not studying the distribution or clearance of a drug. Rather, we are performing a standard clinical test of glucose tolerance. i.e., a test for diabetes and pre-diabetes. Although multiple time points are used in this test, the outcome is a single value, either a blood glucose level after 2 hours or an area-under-the-curve. In this study we are reporting the area-under-the-curve.
Time frame: 4 months after treatment.
Population: Number of subjects remaining after 4 months of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Injection | Glucose Levels After Glucose Challenge | 6268 mg/dL | Standard Error 434 |
| Human Recombinant Leptin (Metreleptin) | Glucose Levels After Glucose Challenge | 6647 mg/dL | Standard Error 514 |
Secondary
Insulin Levels After Oral Glucose Challenge.
An oral glucose tolerance test was performed to measure endogenous insulin response. This is not PD/PK in the sense that we are not studying the distribution or clearance of a drug. Rather, we are performing a clinical test of endogenous insulin response to glucose i.e., an endocrine test. Although multiple time points are used in this test, the outcome is a single value, i.e., an area-under-the-curve for insulin.
Time frame: 4 months after treatment.
Population: Number of subjects remaining after 4 months of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Injection | Insulin Levels After Oral Glucose Challenge. | 1580 microU/mL | Standard Error 954 |
| Human Recombinant Leptin (Metreleptin) | Insulin Levels After Oral Glucose Challenge. | 2868 microU/mL | Standard Error 890 |
Secondary
Rates of Fatty Acid Oxidation
Rates of fatty acid oxidation were measured in breath samples following stable isotope infusions of 13C-labeled palmitate.
Time frame: 4 months after treatment
Population: Number of subjects in each group remaining at the end of 4 months of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Injection | Rates of Fatty Acid Oxidation | 0.239 mmol FFA/kg/h | Standard Error 0.023 |
| Human Recombinant Leptin (Metreleptin) | Rates of Fatty Acid Oxidation | 0.214 mmol FFA/kg/h | Standard Error 0.04 |