Metreleptin and generalized lipodystrophy and evolving therapeutic perspectives

Tchang, Beverly G.; Shukla, Alpana; Aronne, Louis J.

doi:10.1517/14712598.2015.1052789

Cited by 21 publications

(17 citation statements)

References 93 publications

(74 reference statements)

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“…The beneficial effects of leptin repletion on hepatic and peripheral insulin sensitivity, hepatic lipid content, and dyslipidemia in lipodystrophic and congenitally leptin-deficient states have been noted previously (22), though without the clear disassociation from changes in food intake that was achieved by Brown et al (6). The abrupt cessation of leptin in the subjects with generalized lipodystrophy may be viewed as physiologically similar to the disproportionate (to fat mass), sharp declines in circulating leptin concentrations that occur during fasting, which is a metabolic state that is largely nonresponsive to leptin (23).…”

Section: Leptin Physiology Is Metabolic Context Dependentsupporting

confidence: 58%

Physiological responses to leptin levels in lipodystrophy: a model for other hypoleptinemias?

Rosenbaum¹,

Leibel²

2018

Journal of Clinical Investigation

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Brown et al. report that two weeks of exogenous leptin administration to leptin-naive individuals with lipodystrophy resulted in increased energy expenditure and lipolysis, decreased ectopic liver fat, improved hepatic and peripheral insulin sensitivity, and attenuated dyslipidemia. Leptin withdrawal in individuals with lipodystrophy did not produce reciprocal effects on these phenotypes and resulted in significant improvements only in hepatic insulin sensitivity. This asymmetry in responses to leptin initiation and cessation is consistent with the other aspects of leptin biology that are dependent on the metabolic context in which this adipocyte-derived hormone functions.

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Section: Leptin Physiology Is Metabolic Context Dependentsupporting

confidence: 58%

Physiological responses to leptin levels in lipodystrophy: a model for other hypoleptinemias?

Rosenbaum¹,

Leibel²

2018

Journal of Clinical Investigation

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“…The identification of these secondary phenotypes of PCOS is of importance also because these patients often benefit from tailored therapies, including specific dietary management as well as insulin sensitizers, particularly thiazolidinediones (pioglitazone) (69,72), which, however, requires the presence of residual adipose depots to achieve metabolic benefit. Finally, in patients with lipodystrophy and low levels of serum leptin, administration of recombinant human leptin may be dramatically beneficial in improving glycemic control, dyslipidemia and lipid accumulation in the liver (73). To conclude, the endocrinologists who deal with PCOS should be aware of the forms of PCOS secondary to SSIR as they are not so uncommon.…”

Section: Severe Insulin-resistant Syndrome and Pcosmentioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Secondary polycystic ovary syndrome: theoretical and practical aspects

Pasquali

Diamanti-Kandarakis

Gambineri

2016

European Journal of Endocrinology

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PCOS is a clinical heterogeneous entity of female androgen excess diagnosed by exclusion of other disorders responsible for androgen excess. The concept of secondary PCOS implies that there is a primary well-defined cause leading to the PCOS phenotype with underlying androgen overproduction, regardless of the origin. In these cases, we presume the term of 'secondary PCOS' could be used. In all these conditions, the potential complete recovery of the hyperandrogenemic state as well as the remission of the PCOS phenotype should follow the removal of the cause. If accepted, these concepts could help clinicians to perform in-depth investigations of the potential factors or disorders responsible for the development of these specific forms of secondary PCOS. Additionally, this could contribute to develop further research on factors and mechanisms involved in the development of the classic and the nonclassic PCOS phenotypes. Invited author's profileRenato Pasquali is full professor of Endocrinology & Metabolism and Director of the division of Endocrinology of the S.Orsola-Malpighi Hospital, Bologna, Italy. He also heads the School of Specialization in Endocrinology and Metabolism, University Alma Mater Studiorum of Bologna, Italy. He is a member of numerous national and international scientific societies and serves on the editorial boards of international journals. His scientific interests relate to (i) the pathophysiology and treatment of the polycystic ovary syndrome; (ii) the endocrinology of obesity (sex hormones, the hypothalamic-pituitary-adrenal axis, and the endocannabinoid system).

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“…Recombinant methionyl human leptin (r-met-HuLeptin) or simply metreleptin is a 146 amino acid (~16 kDa) protein that structurally is near-identical to the human leptin protein, except with the addition of a methionyl residue on the N-terminal domain of the tertiary protein structure ( Table 1 ). 11 , 12 , 27 Its action within the body mirrors that of the naturally occurring leptin hormone. However, the additional methionyl residue increases its half-life to approximately 3.8–4.7 hours, whereas previous studies have suggested that the half-life of a slower acting pool of leptin was 71 minutes.…”

Section: Metreleptinmentioning

confidence: 99%

“…Since leptin is a cytokine with the potential to alter CYP450 expression, 30 caution is warranted when prescribing metreleptin if the patient is simultaneously receiving drugs metabolized by CYP450, or if they are receiving metreleptin and are about to start a course of drugs metabolized by CYP450 with a narrow therapeutic index, such as oral contraceptives. 27 …”

Section: Metreleptinmentioning

confidence: 99%

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

Rodríguez

Mastronardi

Paz-Filho

2015

TCRM

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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.

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Metreleptin and generalized lipodystrophy and evolving therapeutic perspectives

Cited by 21 publications

References 93 publications

Physiological responses to leptin levels in lipodystrophy: a model for other hypoleptinemias?

Physiological responses to leptin levels in lipodystrophy: a model for other hypoleptinemias?

MANAGEMENT OF ENDOCRINE DISEASE: Secondary polycystic ovary syndrome: theoretical and practical aspects

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

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