Search in:

Expert Review of Clinical Pharmacology Volume 9, 2016 - Issue 1

Submit an article Journal homepage

413

Views

CrossRef citations to date

Altmetric

Drug Profiles

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

Cristina Adelia MeehanDiabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health, Bethesda, MD, USACorrespondence[email protected]

Elaine CochranDiabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

Andrea KassaiDiabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

Rebecca J. BrownDiabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

Phillip GordenDiabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

Pages 59-68 | Published online: 14 Oct 2015

Cite this article
https://doi.org/10.1586/17512433.2016.1096772
CrossMark

Full Article
Figures & data
References
Citations
Metrics
Reprints & Permissions

References

Garg A. Clinical review#: lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab. 2011;96(11):3313–3325.
PubMed Web of Science ®Google Scholar

*Clincal review of the heterogenous group of diseases termed the lipodystrophies. This review explores both genetic and acquired disorders characterized by selective loss of body fat and predisposition to insulin resistance.

Garg A. Acquired and inherited lipodystrophies. N Engl J Med. 2004;350(12):1220–1234.
PubMed Web of Science ®Google Scholar
Wachslicht-Rodbard H, et al. Heterogeneity of the insulin-receptor interaction in lipoatropic diabetes. J Clin Endocrinol Metab. 1981;52(3):416–425.
PubMed Web of Science ®Google Scholar
Agarwal AK, et al. Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol Metab. 2003;88(10):4840–4847.
PubMed Web of Science ®Google Scholar
Speckman RA, et al. Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C. Am J Hum Genet. 2000;66(4):1192–1198.
PubMed Web of Science ®Google Scholar
Payne F, et al. Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease. Proc Natl Acad Sci U S A. 2014;111(24):8901–8906.
PubMed Web of Science ®Google Scholar
Javor ED, et al. Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology. 2005;41(4):753–760.
PubMed Web of Science ®Google Scholar
Safar Zadeh E, et al. The liver diseases of lipodystrophy: the long-term effect of leptin treatment. J Hepatol. 2013;59(1):131–137.
PubMed Web of Science ®Google Scholar
Arioglu E, et al. Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes. Ann Intern Med. 2000;133(4):263–274.
PubMed Web of Science ®Google Scholar
Zhang Y, et al. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425–432.
PubMed Web of Science ®Google Scholar
Coleman DL. A historical perspective on leptin. Nat Med. 2010;16(10):1097–1099.
PubMed Web of Science ®Google Scholar
Bluher S, Mantzoros CS. Leptin in humans: lessons from translational research. Am J Clin Nutr. 2009;89(3):991S–997S.
PubMed Web of Science ®Google Scholar
Frederich RC, et al. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med. 1995;1(12):1311–1314.
PubMed Web of Science ®Google Scholar
Ahima RS, et al. Role of leptin in the neuroendocrine response to fasting. Nature. 1996;382(6588):250–252.
PubMed Web of Science ®Google Scholar
Minocci A, et al. Leptin plasma concentrations are dependent on body fat distribution in obese patients. Int J Obes Relat Metab Disord. 2000;24(9):1139–1144.
PubMed Web of Science ®Google Scholar
Moon HS, et al. Leptin’s role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals. Endocr Rev. 2013;34(3):377–412.
PubMed Web of Science ®Google Scholar
Gorden P, et al. Is there a human model for the ‘metabolic syndrome’ with a defined aetiology? Diabetologia. 2010;53(7):1534–1536.
PubMed Web of Science ®Google Scholar
Heymsfield SB, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA. 1999;282(16):1568–1575.
PubMed Web of Science ®Google Scholar

*Clinical trial demonstrating the lack of effectiveness of metreleptin therapy in obese individuals with high endogenous circulating leptin.

Farooqi IS, et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest. 2002;110(8):1093–1103.
PubMed Web of Science ®Google Scholar
Paz-Filho G, Delibasi T, Erol HK, et al. Congenital leptin deficiency and thyroid function. Thyroid Res. 2009;2(1):11.
PubMedGoogle Scholar
Oral EA, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346(8):570–578.
PubMed Web of Science ®Google Scholar

*Clinical trial of nine female patients with lipodystrophy demonstrating the efficacy of metreleptin therapy to ameliorate metabolic complications such as insulin resistance, hypertriglyceridemia, and hyperglycemia.

Javor ED, et al. Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes. 2005;54(7):1994–2002.
PubMed Web of Science ®Google Scholar
Chong AY, et al. Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia. 2010;53(1):27–35.
PubMed Web of Science ®Google Scholar
Diker-Cohen T, et al. Partial and generalized lipodystrophy: comparison of baseline characteristics and response to metreleptin. J Clin Endocrinol Metab. 2015;100(5):1802–1810.
PubMed Web of Science ®Google Scholar

*Study demonstrates the baseline characteristics of patients with generalized forms of lipodystrophy versus partial forms of lipodystrophy and their respective responses to metreleptin therapy.

Rodriguez AJ, et al. 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. Arq Bras Endocrinol Metabol. 2014;58(8):783–797.
PubMed Web of Science ®Google Scholar
McDuffie JR, et al. Effects of exogenous leptin on satiety and satiation in patients with lipodystrophy and leptin insufficiency. J Clin Endocrinol Metab. 2004;89(9):4258–4263.
PubMed Web of Science ®Google Scholar
Moran SA, et al. Changes in body composition in patients with severe lipodystrophy after leptin replacement therapy. Metabolism. 2004;53(4):513–519.
PubMed Web of Science ®Google Scholar
Petersen KF, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest. 2002;109(10):1345–1350.
PubMed Web of Science ®Google Scholar

*Study that shows that chronic leptin treatment improves insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipodystrophic patients. Improved insulin action was associated with marked reduction in hepatic and muscle triglyceride content.

Lungu AO, et al. Insulin resistance is a sufficient basis for hyperandrogenism in lipodystrophic women with polycystic ovarian syndrome. J Clin Endocrinol Metab. 2012;97(2):563–567.
PubMed Web of Science ®Google Scholar
Joseph J, et al. Lipid regulation in lipodystrophy versus the obesity-associated metabolic syndrome: the dissociation of HDL-C and triglycerides. J Clin Endocrinol Metab. 2014;99(9):E1676–80.
Google Scholar
Javor ED, et al. Proteinuric nephropathy in acquired and congenital generalized lipodystrophy: baseline characteristics and course during recombinant leptin therapy. J Clin Endocrinol Metab. 2004;89(7):3199–3207.
PubMed Web of Science ®Google Scholar
Musso C, et al. Spectrum of renal diseases associated with extreme forms of insulin resistance. Clin J Am Soc Nephrol. 2006;1(4):616–622.
PubMed Web of Science ®Google Scholar
Ebihara K, et al. Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy. J Clin Endocrinol Metab. 2007;92(2):532–541.
PubMed Web of Science ®Google Scholar

*Clinical study showing the efficacy of metreleptin therapy of seven Japanese patients with generalized lipodystrophy, two acquired and five congenital, treated with metreleptin.

Ebihara K, Masuzaki H, Nakao K. Long-term leptin-replacement therapy for lipoatrophic diabetes. N Engl J Med. 2004;351(6):615–616.
PubMed Web of Science ®Google Scholar
Maguire M, et al. Pregnancy in a woman with congenital generalized lipodystrophy: leptin’s vital role in reproduction. Obstet Gynecol. 2012;119(2 Pt 2):452–455.
PubMed Web of Science ®Google Scholar
Brown RJ, et al. Lymphoma in acquired generalized lipodystrophy. Leuk Lymphoma. 2015;1–6. PMD 25864863.
PubMedGoogle Scholar
Strong AL, et al. Leptin produced by obese adipose stromal/stem cells enhances proliferation and metastasis of estrogen receptor positive breast cancers. Breast Cancer Res. 2015;17:112.
PubMed Web of Science ®Google Scholar
Shimomura I, et al. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature. 1999;401(6748):73–76.
PubMed Web of Science ®Google Scholar

*This was the first demonstration of the efficacy of metreleptin therapy to improve metabolic features in a lipodystrophic mouse model.

Simonds SE, et al. Leptin mediates the increase in blood pressure associated with obesity. Cell. 2014;159(6):1404–1416.
PubMed Web of Science ®Google Scholar
Brown RJ, Meehan CA, Gorden P. Leptin does not mediate hypertension associated with human obesity. Cell. 2015;162:465–466.
Web of Science ®Google Scholar
Reitman ML. Leptin in the liver: a toxic or beneficial mix? Cell Metab. 2012;16(1):1–2.
PubMed Web of Science ®Google Scholar
Imajo K, et al. Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptin-mediated signaling. Cell Metab. 2012;16(1):44–54.
PubMed Web of Science ®Google Scholar
Oral EA, et al. Leptin replacement therapy modulates circulating lymphocyte subsets and cytokine responsiveness in severe lipodystrophy. J Clin Endocrinol Metab. 2006;91(2):621–628.
PubMed Web of Science ®Google Scholar
Christensen JD, et al. Bone mineral content in patients with congenital generalized lipodystrophy is unaffected by metreleptin replacement therapy. J Clin Endocrinol Metab. 2014;99(8):E1493–500.
Google Scholar
Farooqi IS, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 1999;341(12):879–884.
PubMed Web of Science ®Google Scholar

*First demonstration that a hypo-leptinemic state characterized by extreme obesity responds by significant weight reduction to metreleptin therapy.

Paz-Filho G, Mastronardi CA, Licinio J. Leptin treatment: facts and expectations. Metabolism. 2015;64(1):146–156.
PubMed Web of Science ®Google Scholar
Brown RJ, Cochran E, Gorden P. Metreleptin improves blood glucose in patients with insulin receptor mutations. J Clin Endocrinol Metab. 2013;98(11):E1749–E1756.
Google Scholar
Tsoukas MA, Farr OM, Mantzoros CS. Leptin in congenital and HIV-associated lipodystrophy. Metabolism. 2015;64(1):47–59.
PubMed Web of Science ®Google Scholar
Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhea and anorexia nervosa. Lancet. 2005;366(9479):74–85.
PubMed Web of Science ®Google Scholar
Wang MY, et al. Leptin therapy in insulin-deficient type I diabetes. Proc Natl Acad Sci U S A. 2010;107(11):4813–4819.
PubMed Web of Science ®Google Scholar
Gaudet D, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371(23):2200–2206.
PubMed Web of Science ®Google Scholar

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Order Reprints Request Corporate Permissions

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

Request Academic Permissions

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.

Share icon
Back to Top

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.

People also read
Recommended articles
Cited by

To cite this article:

Reference style: APA Chicago Harvard

Citation copied to clipboard

Reference styles above use APA (6th edition), Chicago (16th edition) & Harvard (10th edition)

Download citation

Download a citation file in RIS format that can be imported by citation management software including EndNote, ProCite, RefWorks and Reference Manager.

Choose format: RIS BibTex RefWorks Direct Export

Choose options: Citation Citation & abstract Citation & references

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

References

*Clincal review of the heterogenous group of diseases termed the lipodystrophies. This review explores both genetic and acquired disorders characterized by selective loss of body fat and predisposition to insulin resistance.

*Clinical trial demonstrating the lack of effectiveness of metreleptin therapy in obese individuals with high endogenous circulating leptin.

*Clinical trial of nine female patients with lipodystrophy demonstrating the efficacy of metreleptin therapy to ameliorate metabolic complications such as insulin resistance, hypertriglyceridemia, and hyperglycemia.

*Study demonstrates the baseline characteristics of patients with generalized forms of lipodystrophy versus partial forms of lipodystrophy and their respective responses to metreleptin therapy.

*Study that shows that chronic leptin treatment improves insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipodystrophic patients. Improved insulin action was associated with marked reduction in hepatic and muscle triglyceride content.

*Clinical study showing the efficacy of metreleptin therapy of seven Japanese patients with generalized lipodystrophy, two acquired and five congenital, treated with metreleptin.

*This was the first demonstration of the efficacy of metreleptin therapy to improve metabolic features in a lipodystrophic mouse model.

*First demonstration that a hypo-leptinemic state characterized by extreme obesity responds by significant weight reduction to metreleptin therapy.

Information for

Open access

Opportunities

Help and information

Your download is now in progress and you may close this window

Login or register to access this feature

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

References

*Clincal review of the heterogenous group of diseases termed the lipodystrophies. This review explores both genetic and acquired disorders characterized by selective loss of body fat and predisposition to insulin resistance.

*Clinical trial demonstrating the lack of effectiveness of metreleptin therapy in obese individuals with high endogenous circulating leptin.

*Clinical trial of nine female patients with lipodystrophy demonstrating the efficacy of metreleptin therapy to ameliorate metabolic complications such as insulin resistance, hypertriglyceridemia, and hyperglycemia.

*Study demonstrates the baseline characteristics of patients with generalized forms of lipodystrophy versus partial forms of lipodystrophy and their respective responses to metreleptin therapy.

*Study that shows that chronic leptin treatment improves insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipodystrophic patients. Improved insulin action was associated with marked reduction in hepatic and muscle triglyceride content.

*Clinical study showing the efficacy of metreleptin therapy of seven Japanese patients with generalized lipodystrophy, two acquired and five congenital, treated with metreleptin.

*This was the first demonstration of the efficacy of metreleptin therapy to improve metabolic features in a lipodystrophic mouse model.

*First demonstration that a hypo-leptinemic state characterized by extreme obesity responds by significant weight reduction to metreleptin therapy.

Reprints and Corporate Permissions

Academic Permissions

Related research

To cite this article:

Download citation

Information for

Open access

Opportunities

Help and information

Keep up to date