Conditions: Lipodystrophy
Keywords: Lipoatrophic Diabetes Diabetes Mellitus Hypertriglyceridemia NASH Lipodystrophy Leptin Diabetes
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 103
Healthy volunteers: no

Brief summary:
This study will evaluate the safety and effectiveness of leptin replacement therapy in patients with lipodystrophy (also called lipoatrophy). Patients have a total or partial loss of fat cells. They also lack the hormone leptin, which is produced by fat cells. The leptin deficiency usually causes high blood lipid (fat) levels and insulin resistance that may lead to diabetes. Patients may have hormone imbalances, fertility problems, large appetite, and liver disease due to fat accumulation.

Patients age greater than or equal to 6 months with significant lipodystrophy may be eligible for this study. Participants will be admitted to the NIH Clinical Center for 10 days for the following studies before beginning 12 months of leptin therapy:

* Insulin tolerance test
* Ultrasound of the liver and, if abnormalities are found, possibly liver biopsies.
* Fasting blood tests
* Resting metabolic rate
* Magnetic resonance imaging of the liver and other organs, and of muscle and fat.
* Pelvic ultrasound in women to detect ovarian cysts.
* Estimation of body fat
* Oral glucose tolerance test
* Intravenous glucose tolerance test
* Appetite level and food intake
* Hormone function tests
* Questionnaires to assess activity and mood
* 24-hour urine collections

Additional studies may include blood tests for genetic studies of lipodystrophy, a muscle biopsy to study muscle proteins involved in regulating energy expenditure before and after leptin replacement, and examination of a surgical specimen (if available) to study molecules that may be involved in energy storage and use.

When the above tests are completed, leptin therapy begins. The drug is injected under the skin twice a day for 4 months and then once a day, if feasible. The dose is increased at the 1- and 2-month visits. Follow-up visits at 1, 2, 4, 6, 8 and 12 months after therapy starts include a physical examination, blood tests and a meeting with a dietitian. At the end of 12 months, all baseline studies described above are repeated. Patients record their symptoms weekly throughout the study. Those with diabetes measure their blood glucose levels daily before each meal and at bedtime.

Detailed description:
Lipoatrophic diabetes is a syndrome characterized by insulin resistance in association with a paucity of adipose tissue. Patients with severe lipoatrophy die prematurely, typically from the complications of diabetes or liver disease. Experiments with lipoatrophic mice suggest that the insulin resistance is caused by the lack of adipose tissue. Adipose tissue normally produces leptin, a hormone that increases insulin action. For the last fourteen years, we have been studying the extent to which leptin deficiency causes diabetes in lipoatrophic patients. In fact, in our initial study we have seen nearly 60% amelioration of fasting glucose, triglycerides and free fatty acid levels and about 2% actual decreases from baseline HbA1c levels with 4 months of leptin replacement therapy. This response has continued to be sustained, as we continue to follow patients that have now received leptin replacement therapy for fourteen years.

This is an open-labeled study. The study monitors the safety and efficacy of recombinant methionyl human leptin (A-100) replacement in children and adults. We are looking at the long-term effects of leptin replacement on extended therapy. In this long-term replacement protocol, we will monitor metabolic control (e.g. glucose, insulin, and triglyceride levels) as primary outcome measures. Ancillary studies will evaluate the effect of Metreleptin on other hormonal axes, growth and development and on liver pathology.

We continue to evaluate the efficacy in a broader leptin deficient population of patients with lipodystrophy. Current inclusion criteria in patients greater than or equal to 5 years include female patients with leptin levels \< 12 ng/mL and male patients with leptin levels \< 8 ng/mL. We continue to seek patients who meet these criteria. In children ages 6 months 5 years, we will use a cut-off leptin level of 6 ng/mL in both genders.

Patients who are greater than or equal to age 5 years will be evaluated every 6 months during the first year of therapy. If no improvements are seen after 6 months of therapy, then the study medication may be increased to 150% of the predicted dose (0.09mg/kg/day for males and girls less than 10 years of age/ 0.12mg/kg/day for females 10 years of age and older) from 6 months to 1 year on therapy. If no improvements are seen after increasing to 150% of the predicted dose, then the study medication will be withdrawn. If the patient shows improvements in his/her metabolic parameters while on leptin, the patient will be invited to continue taking the study medication. The investigators will strive for all patients responding to leptin to bring their metabolic parameters into the normal range. The maximum dose of leptin that will be given is 0.24 mg/kg/day for females 10 and older, and 0.12 mg/kg/day for males and females less than 10 years of age. After the first year of treatment, the patient will be evaluated every 6 months through the second year of treatment, and then the study period will end. After two years of treatment, extending the treatment period on an annual basis will be the decision of the patient, principal investigator and Bristol-Myers Squibb (BMS)/AstraZeneca Pharmaceuticals (AZ). Leptin is supplied by BMS/AZ, and is currently only available through research studies. Neither the NIH nor BMS/AZ can guarantee that leptin will be available indefinitely and/or after the study ends. However, leptin was recently approved by the FDA on February 25, 2014, for use in patients with generalized lipodystrophy.

All patient referrals for acceptance into the protocol, are initiated by the physician/health care provider.

Arms:
arm 1: subcutaneous metreleptin injections in one to two daily doses ranging from 0.06 to 0.24 mg/kg per day.

Interventions: intervention 1: Metreleptin
Intervention descriptions: intervention 1: Drug treatment

Protocol document: