Case Study Illuminates Metreleptin’s Possible Role in Improving Lipid and Glycemic Profiles

Researchers in Japan have detailed a case report in which a young woman who survived childhood cancer was treated with metreleptin supplementation to improve her acquired incomplete lipodystrophy and published their findings in the Journal of the Endocrine Society.

The researchers, led by Ayako Nagayama, MD, and Kenji Ashida, MD, PhD, (Nomura Laboratory) of Kurume University School of Medicine in Fukuoka, Japan, point out that childhood cancer survivors (CCSs) often impaired glucose tolerance and hypertriglyceridemia as later complications of the total-body irradiation they had as children to treat their cancers. “These patients typically do not have a history of obesity, and they exhibit high-grade insulin resistance, fatty liver, and high mortality from cardiovascular disease,” the authors write. “Therefore, such cases are considered to be acquired incomplete lipodystrophy, which is thought to be associated with total-body irradiation and hematopoietic stem cell transplantation.”

Metreleptin, a recombinant leptin analog, is indicated for treating the complications of leptin deficiency in patients with generalized lipodystrophy, but the administration of metreleptin as a supplement in patients with incomplete lipodystrophy has not been reported. That is until these authors treated a female patient with acquired incomplete lipodystrophy, likely caused by total-body irradiation and allogeneic stem-cell transplantation for lymphocytic leukemia.

According to Ashida, metreleptin supplementation might reduce the risks of cardiovascular events in patients with lipodystrophy. Ashida says that The British Childhood Cancer Survivor Study revealed that, in this patient population, the most common non-neoplastic causes of death were circulatory diseases, which included myocardial infarction, congestive heart failure, and cerebral infarction (Fidler MM, et al. BMJ. 2016;354:i4351). Relative to the general population, childhood cancer survivors have a 3.8-fold higher risk of circulatory disease-related mortality. Moreover, survivors of hematological cancers have elevated risks of metabolic disorders and circulatory disease-related mortality (Fidler MM, et al. BMJ. 2016;354:i4351). “Therefore, we are pleased to indicate that metreleptin supplementation may help reduce the risk of cardiovascular events and improve the quality of life for CCS with incomplete lipodystrophy,” Ashida says. 

The patient in this case presented to the hospital with diabetes and hypertriglyceridemia at 24 years of age. When she was three, she was diagnosed with acute lymphocytic leukemia. Three years later, she underwent total-body irradiation and allogeneic stem cell transplantation to treat her cancer, which worked, but then at 11 years old, she was diagnosed with the hypertriglyceridemia and diabetes mellitus.

When the authors administered metreleptin (initially 0.04 mg/kg daily for one week, then 0.08 mg/kg daily subcutaneous injections), it immediately regulated her appetite and reduced her food intake, and at one month, the patient revealed remarkable improvements in her serum lipid profile and vitality. “She also exhibited reductions in her VLDL cholesterol and intermediate-density lipoprotein (IDL) cholesterol levels, with an increase in LDL cholesterol levels,” the authors write. “After 6 months, insulin sensitivity in the skeletal muscle had improved, based on a glucose infusion rate of 3.8 mg/kg/min, and her blood glucose was controlled without insulin. The patient is actively working to maintain satisfactory glucose and lipid metabolism.”

“Metreleptin supplementation improved her serum triglyceride and lipoprotein profiles, with reductions in the VLDL and IDL cholesterol fractions.”

“We report a case of young childhood cancer survivor woman complicated with acquired incomplete lipodystrophy,” Ashida says. “Her lipoprotein profile was changed by one month metreleptin administration. In addition, improvement of the peripheral glucose sensitivity was disclosed after 6 month-initiation by the glucose cramp method. We intended to indicate the leptin which secreted from adipose tissues regulate serum and ectopic organ, including liver and skeletal muscles, lipid contents.”

The authors provide three plausible explanations for how leptin supplementation improved this patient’s lipid and glycemic profiles, and indeed in future patients: high serum triglyceride levels might indicate reduced leptin activity, similar to generalized lipodystrophy; leptin may activate residual brown adipose tissue via the central nervous system, which could promote LPL activity and plasma triglyceride clearance; and leptin activity may be reduced in atrophic fat tissue after radiation therapy, as systemic irradiation therapy can induce abnormalities in adipose tissue differentiation from mesenchymal stem cells.

“In conclusion, we encountered a patient with acquired incomplete lipodystrophy that was likely related to total-body irradiation,” the authors write. “Metreleptin supplementation improved her serum triglyceride and lipoprotein profiles, with reductions in the VLDL and IDL cholesterol fractions. Furthermore, metreleptin supplementation ameliorated the disturbed insulin sensitivity. These findings suggest that metreleptin supplementation may be a useful alternative therapy for improving metabolic disorders in CCSs.”

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