An Observational Study of the Effects of Metreleptin in Young Adults With Congenital Leptin Deficiency

Congenital leptin deficiency (CLD) is a rare autosomal recessive condition caused by a mutation in the leptin gene (LEP). This mutation leads to a severe deficiency in leptin, a hormone secreted primarily by adipocytes. Leptin is also secreted by gastric mucosal cells, in response to stimuli such as food intake. Leptin has many important physiologic roles, including serving as a signal to the hypothalamus of both long-term (adipocyte) and short-term (gastric) energy storage. Individuals with CLD have hyperphagia and morbid obesity with an onset in early childhood. Hypogonadotropic hypogonadism, insulin resistance, and immune dysfunction are also often observed in patients with CLD but these features can be of varying degrees of severity.

Recombinant human leptin (metreleptin; Myalept®) was approved by the U.S. Food and Drug Administration in 2014 to treat the complications of leptin deficiency in patients with generalized lipodystrophy (GL). Commercial use of metreleptin is restricted to patients with leptin deficiency due to GL. However, ~3 dozen patients worldwide who are known to have congenital leptin deficiency (CLD) have been treated safely and successfully with metreleptin in the investigational setting for two decades. Metreleptin therapy has been shown to reduce hunger and desire to eat in leptin-deficient humans, and significant weight loss is typical.

Some questions remain regarding the pluripotent effects of metreleptin in patients with CLD. Understudied aspects of physiology in these patients include the role of leptin (independent of weight) in insulin sensitivity, hepatic steatosis, and sleep. For each of these areas, there is preliminary evidence from humans or the ob/ob (leptin-deficient) mouse model for a beneficial role of leptin, but important knowledge gaps remain.