Metreleptin for metabolic disorders associated with generalized or partial lipodystrophy

Abstract

Lipodystrophy is a group of acquired and inherited disorders characterized by selective loss of adipose tissue. Despite wide genotypic and phenotypic variety, many patients with lipodystrophy have similar metabolic complications including insulin resistance, diabetes mellitus, hypertriglyceridemia and hepatic steatosis. Often, these metabolic abnormalities are severe and difficult to treat with conventional glucose and lipid-lowering therapies. Lack of adipose tissue also results in marked hypoleptinemia, and there has recently been much interest in using leptin-replacement therapy to treat the metabolic complications of lipodystrophy. Administration of metreleptin, the human recombinant leptin analogue, has been shown in prospective, open-label studies to improve glucose control, dyslipidemia and steatohepatitis. This article summarizes the current evidence for the safety and efficacy of leptin-replacement therapy in patients with lipodystrophy.

Drug targeting of leptin resistance

“…Further, leptin has been used in lipodystrophic animals or patients, where low leptin levels were associated with hyperphagia and increase of fat storage in the liver and skeletal muscle, and finally to type II diabetes and metabolic disorders [115,116]. Leptin or metreleptin (the recombinant methionyl form of the human hormone) administration is able to improve glucose homeostasis and plasma lipid profile, and reduce steatosis in metabolic disorders associated with lipodystrophy or human virus-associated immunodeficiency [117,118]. In 2014, the U.S. Food and Drug Administration approved metreleptin, for injection, as replacement therapy to treat the complications of leptin deficiency, in addition to diet, in patients with congenital or acquired generalized lipodystrophy.…”

Leptin replacement therapy for the treatment of non-HAART associated lipodystrophy syndromes: a meta-analysis into the effects of leptin on metabolic and hepatic endpoints

“…Numerous animal models have shown that exogenous supplementation of leptin, in order to achieve physiological levels of the hormone, is effective in restoring normal glycemic control, normal serum lipid profile and liver function (10,11). In humans, leptin replacement therapy (LRT) with recombinant methionyl human leptin (r-metHuLeptin, metreleptin) has been evaluated by several clinical trials (12), and has been recently approved by the FDA for the treatment of patients with generalized lipodystrophy (13). Administered as a subcutaneous injection once or twice daily, metreleptin reverses the metabolic abnormalities that are seen in LS, leading to significant improvements in overall health (14)(15)(16).…”

Metreleptin in lipodystrophy: a profile of its use

“…Metreleptin is a protein of ≈ 16 kDa that differs from endogenous human leptin by having an amino-terminal methionine residue [5]. Being an analogue of human leptin [3,5], metreleptin binds to and activates the leptin receptor, thus mimicking the physiological effects of endogenous leptin [8]. Metreleptin improves metabolic abnormalities associated with LD, including glycaemic control, hypertriglyceridaemia and insulin sensitivity [5,9].…”

“…generalized LD) or only in specific areas (i.e. partial LD) [1], with abnormal accumulation of fat in unaffected regions often evident [3]. Fat tissue plays a key role in lipid metabolism and glucose homeostasis [4], and its loss in LD interferes with hunger/satiety signals (commonly leading to hyperphagia), resulting in inappropriate lipid storage in muscle, the liver and other organs [1,2].…”

“…These limitations and the knowledge that serum levels of leptin (an adipose tissue-secreted hormone with effects such as appetite suppression, promotion of hepatic lipolysis and glucose usage in skeletal muscle, and inhibition of insulin secretion [5,7]) tend to be low in patients with LD [2], prompted investigation of leptin replacement therapy as a potential treatment option [6]. Metreleptin [Myalepta ® (EU); Myalept ® (USA)] is a recombinant analogue of human leptin [3,5] this change correlating with a reduction in low-density lipoprotein cholesterol [18].…”