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.
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.
- INCLUSION CRITERIA:
All ethnic groups.
Males and females.
- Age greater than or equal to 6 months.
- Clinically significant lipodystrophy, identified by the study physician during the
physical examination as an absence of fat outside the range of normal variation
and/or identified as a disfiguring factor by the patient.
Circulating leptin levels less than 12.0 ng/ml in females and less than 8.0 ng/ml in males
as measured by Linco assay on a specimen obtained after an overnight fast. In children
ages 6 months 5 years, a circulating leptin level of less than 6 ng/mL will be used.
Leptin samples will be run through Millipore Laboratories, who use the Linco Assay, which
has been the assay previously used to measure leptin levels throughout this study period.
Presence of at least one of the following metabolic abnormalities:
1. Presence of diabetes as defined by the 2007 ADA criteria
1. Fasting plasma glucose greater than or equal to 126 mg/dL, or
2. 2 hour plasma glucose greater than or equal to 200 mg/dL following a 75 gram
(1.75gm/kg) oral glucose load, or
3. Diabetic symptoms with a random plasma glucose greater than or equal to 200
2. Fasting insulin greater than 30 micro units/ml.
3. Fasting hypertriglyceridemia greater than 200 mg/dL or postprandially elevated
triglycerides greater than 500 mg/dL when fasting is clinically not indicated (e.g.
-Persons with impaired decision-making capacity and who may be unable to provide
informed consent may participate in this study per the discretion of the Principal
Pregnant women, women in their reproductive years who do not use an effective method
of birth control, and women currently nursing or lactating within 6 weeks of having
Exclusions for underlying diseases likely to increase side effects or hinder
objective data collection:
- Known infectious liver disease
- Known HIV infection
- Current alcohol or substance abuse
- Psychiatric disorder impeding competence or compliance
- Active tuberculosis
- Use of anorexiogenic drugs
- Other condition(s) which in the opinion of the clinical investigators would
impede completion of the study
- Subjects who have known hypersensitivity to E. Coli derived proteins.
- Subjects with acquired lipodystrophy and a hematologic abnormality such as
neutropenia and/or lymphadenopathy