Leptin for Abnormal Lipid Kinetics in HIV Lipodystrophy Syndrome

NCT ID: NCT01511016

Last Updated: 2016-01-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 17 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-02-28
• Study Completion Date: 2011-10-31

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.

Conditions

HIV Lipodystrophy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

human recombinant leptin (metreleptin)

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.

Group Type: EXPERIMENTAL

Human recombinant leptin ("metreleptin")

Intervention Type: DRUG

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 injection

Each subject received 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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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.

Interventions

Human 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.

Intervention Type: DRUG

Placebo

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.

Intervention Type: DRUG

Other Intervention Names

metreleptin

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 64 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Baylor College of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Ashok Balasubramanyam

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ashok Balasubramanyam, MD

Role: PRINCIPAL_INVESTIGATOR

Baylor College of Medicine

Locations

Baylor College of Medicine

Houston, Texas, United States

Countries

United States

References

Sekhar RV, Jahoor F, Iyer D, Guthikonda A, Paranilam J, Elhaj F, Coraza I, Balasubramanyam A. Leptin replacement therapy does not improve the abnormal lipid kinetics of hypoleptinemic patients with HIV-associated lipodystrophy syndrome. Metabolism. 2012 Oct;61(10):1395-403. doi: 10.1016/j.metabol.2012.03.013. Epub 2012 Apr 28.

Reference Type: RESULT

PMID: 22542724 (View on PubMed)

Other Identifiers

H-13372

Identifier Type: -

Identifier Source: org_study_id