Metreleptin for injection to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy

Abstract

The lipodystrophies represent a class of diseases characterized by leptin deficiency. Leptin deficiency is associated with a severe form of the metabolic syndrome characterized by dyslipidemia, insulin resistance, diabetes, and ovarian dysfunction. Metreleptin is the pharmaceutical derived product that has been approved by the Food and Drug Administration (FDA) to treat the severe metabolic abnormalities of the generalized forms of lipodystrophy. Herein we describe the properties of metreleptin, its use in patients, which includes the administration of the drug and how it may be acquired by medical professionals as well as its safety, tolerability, and properties. Finally, we speculate on future uses and development of metreleptin.

The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline

“…There is no age limit for initiation of metreleptin; children as young as 6 months have been treated. A dosing algorithm is provided in Supplemental Table 4 (40). Dose adjustments should be made in response to metabolic parameters and weight change, with clinical and laboratory assessment performed every 3–6 months.…”

“…Reduced food intake is at least partially responsible for many of the metabolic improvements. If excessive weight loss occurs, the dose of metreleptin should be reduced (Supplemental Table 4) (40). …”

The long road to leptin

“…In each case, leptin treatment improves one or more abnormalities generally associated with starvation. Lipodystrophy, the complete or partial absence of fat, is a heterogeneous disorder associated with leptin deficiency, a severe, sometimes intractable insulin resistance, and diabetes, as well as hyperlipidemia and nonalcoholic steatohepatitis (NASH) (41)(42)(43). Leptin is currently an approved therapy for generalized lipodystrophy and has also shown potential for the treatment of patients with partial lipodystrophy and severe metabolic abnormalities (though, at present, it is not approved for this indication) (44).…”

“…Finally, as mentioned above, in NZO mice, leptin resistance can develop because of impaired leptin transport, although little is known about the transcytotic mechanism (60). In humans, leptin is highly potent in patients with low endogenous levels, though its effects in otherwise normal lean patients have never been comprehensively studied (41)(42)(43)48). In contrast, leptin has variable effects as a monotherapy for obesity in the general population (61).…”

Renaissance of leptin for obesity therapy

“…Although only mild and transient adverse effects were reported with the combination of pramlintide and metreleptin, in 2011, Amylin Inc. decided to halt the development of this combination therapy because of potential safety issues. Whether this relates to metreleptininduced generation of antibodies with neutralising activity remains speculative, however, in the meantime, metreleptin has been approved for treating leptin deficiency in patients with congenital or acquired lipodystrophy [55][56][57].…”