Brief Title
Leptin for Abnormal Lipid Kinetics in HIV Lipodystrophy Syndrome
Official Title
The Effect of Leptin Therapy on Abnormal Lipid Kinetics in Subjects With HIV Lipodystrophy Syndrome
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.
Study Type
Interventional
Primary Outcome
Rate of Total Lipolysis
Secondary Outcome
Rates of Fatty Acid Oxidation
Condition
HIV Lipodystrophy
Intervention
Human recombinant leptin ("metreleptin") Study Arms / Comparison Groups
human recombinant leptin (metreleptin)
Description: Each subject received 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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
17
Start Date
February 2003
Completion Date
October 2011
Primary Completion Date
June 2011
Eligibility Criteria
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 exclusion criteria. Other drugs excluded are growth
hormone (if used without evidence of growth hormone deficiency), Megace and
testosterone (if used without evidence of hypogonadism).
Gender
Male
Ages
18 Years - 64 Years
Accepts Healthy Volunteers
No
Contacts
Ashok Balasubramanyam, MD, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT01511016
Organization ID
H-13372
Responsible Party
Principal Investigator
Study Sponsor
Baylor College of Medicine
Study Sponsor
Ashok Balasubramanyam, MD, Principal Investigator, Baylor College of Medicine
Verification Date
December 2015