Leptin for Abnormal Lipid Kinetics in HIV Lipodystrophy Syndrome
Condition: HIV Lipodystrophy
MeSH terms: HIV-Associated Lipodystrophy Syndrome; Lipodystrophy
Study type: Interventional

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.
    

Intervention name(s): Human recombinant leptin ("metreleptin"); Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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.
Other intervention name(s): metreleptin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: lipid kinetics; fat oxidation