Clinical Trial: Leptin for Abnormal Lipid Kinetics in HIV Lipodystrophy Syndrome

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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 Summary:

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 show
Sponsor: Baylor College of Medicine

Current Primary Outcome:

• Rate of Total Lipolysis [ Time Frame: 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 [ Time Frame: 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

Original Primary Outcome: Rates of lipolysis [ Time Frame: Change from Baseline at 2 and 4 months ]

Current Secondary Outcome:

• Rates of Fatty Acid Oxidation [ Time Frame: 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 [ Time Frame: 4 months after treatment. ]
  Fasting plasma non-HDL-cholesterol was calculated from measured total cholesterol and HDL cholesterol.
• Glucose Levels After Glucose Challenge [ Time Frame: 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. [ Time Frame: 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.

Original Secondary Outcome:

• Rates of Fatty Acid Oxidation [ Time Frame: Change from Baseline at 2 and 4 months. ]
  Rates of fatty acid oxidation will be measured in breath samples following stable isotope infusions of 13C-labeled palmitate.
• Fasting plasma lipids [ Time Frame: Change from Baseline at 2 and 4 months. ]
  Fasting plasma cholesterol, HDL-cholesterol and triglycerides will be measured.
• Glucose Levels After Glucose Challenge [ Time Frame: Change from Baseline at 2 and 4 months. ]
  An oral glucose tolerance test will be performed, with measurements of glucose at each time point.
• Insulin Levels After Oral Glucose Challenge. [ Time Frame: Change from Baseline at 2 and 4 months. ]
  An oral glucose tolerance test will be performed, with measurements of insulin at each time point

Dates:
Date Received: January 11, 2012
Date Started: February 2003
Date Completion:
Last Updated: December 21, 2015
Last Verified: December 2015