New advances in the treatment of generalized lipodystrophy: role of metreleptin

Abstract

Recombinant methionyl human leptin or metreleptin is a synthetic leptin analog that has been trialed in patients with leptin-deficient conditions, such as leptin deficiency due to mutations in the leptin gene, hypothalamic amenorrhea, and lipodystrophy syndromes. These syndromes are characterized by partial or complete absence of adipose tissue and hormones derived from adipose tissue, most importantly leptin. Patients deficient in leptin exhibit a number of severe metabolic abnormalities such as hyperglycemia, hypertriglyceridemia, and hepatic steatosis, which can progress to diabetes mellitus, acute pancreatitis, and hepatic cirrhosis, respectively. For the management of these abnormalities, multiple therapies are usually required, and advanced stages may be progressively difficult to treat. Following many successful trials, the US Food and Drug Administration approved metreleptin for the treatment of non-HIV-related forms of generalized lipodystrophy. Leptin replacement therapy with metreleptin has, in many cases, reversed these metabolic complications, with improvements in glucose-insulin-lipid homeostasis, and regression of fatty liver disease. Besides being effective, a daily subcutaneous administration of metreleptin is generally safe, but the causal association between metreleptin and immune complications (such as lymphoma) is still unclear. Moreover, further investigation is needed to elucidate mechanisms by which metreleptin leads to the development of anti-leptin antibodies. Herein, we review clinical aspects of generalized lipodystrophy and the pharmacological profile of metreleptin. Further, we examine studies that assessed the safety and efficacy of metreleptin, and outline some clinical perspectives on the drug.

Metreleptin treatment for congenital generalized lipodystrophy type 4 (CGL4): a case report

“…Generalized lipodystrophies develop due to the absence of leptin, and antibodies to metreleptin, an exogenous leptin, may be produced because it is easily recognized as a foreign protein in vivo or may have high antigenicity. Approximately 15–32% of patients with lipodystrophy develop a hypersensitive reaction to metreleptin (14), and up to 95% of patients develop anti-metreleptin antibodies (10). However, anti-metreleptin antibodies generally appear within 4–6 mo and then their production decreases with continued therapy, and clinical deterioration has only been observed in 4 out of 134 lipodystrophies (15).…”

“…Therefore, the strategy of treating lipodystrophies is to improve insulin resistance and hypertriglyceridemia. Metreleptin, a synthetic analog of human leptin, is an effective treatment for lipodystrophies because it improves serum levels of glucose and triglycerides and decreases levels of glycosylated hemoglobin (HbA 1C ) (10). However, there are no reports of the use of metreleptin treatments for CGL4 because CGL4 is a rare disease.…”

Multifocal lipoatrophy secondary to insulin injection in a patient with type 2 diabetes, hepatitis B virus infection, and liver cirrhosis

“…2,6,7 Furthermore, liver diseases, including virus hepatitis, liver cirrhosis, and fatty liver, can also be associated with partial or generalized acquired lipoatrophy. [8][9][10][11] In the patient reported herein, we do not know whether the pathogenesis of the lipoatrophy was related to the HBV infection or liver cirrhosis. To determine this, further clinical characterization and laboratory work will be required.…”

Cardiac Manifestations of Congenital Generalized Lipodystrophy

“…Marked elevations in triglyceride and insulin levels with low HDL cholesterol levels have been well documented to be associated with increased atherosclerosis, and people with CGL fit this metabolic profile ( 28 ). In addition, fatty liver, which is frequently associated with lipodystrophy, is also known to be associated with an increased risk for cardiovascular disease (CVD) ( 29 ).…”