, Volume 64, Issue 3, pp 500–511 | Cite as

Long-term effectiveness and safety of metreleptin in the treatment of patients with partial lipodystrophy

  • Elif A. OralEmail author
  • Phillip Gorden
  • Elaine Cochran
  • David Araújo-Vilar
  • David B. Savage
  • Alison Long
  • Gregory Fine
  • Taylor Salinardi
  • Rebecca J. Brown
Original Article



To evaluate the effects of metreleptin in patients with partial lipodystrophy (PL).


Patients aged ≥ 6 months with PL, circulating leptin < 12.0 ng/mL, and diabetes mellitus, insulin resistance, or hypertriglyceridemia received metreleptin doses (once or twice daily) titrated to a mean of 0.124 mg/kg/day. Changes from baseline to month 12 in glycated hemoglobin (HbA1c) and fasting serum triglycerides (TGs; co-primary endpoints), fasting plasma glucose (FPG), and liver volume were evaluated. Additional assessments included the proportions of patients achieving target decreases in HbA1c or fasting TGs at month 12, long-term treatment effects, and treatment-emergent adverse events (TEAEs).


Significant (p < 0.05) reductions in HbA1c (−0.6%), fasting TGs (−20.8%), FPG (−1.2 mmol/L), and liver volume (−13.4%) were observed in the overall PL population at month 12. In a subgroup of patients with baseline HbA1c ≥ 6.5% or TGs ≥ 5.65 mmol/L, significant (p < 0.05) reductions were seen in HbA1c (−0.9%), fasting TGs (−37.4%), FPG (−1.9 mmol/L), and liver volume (−12.4%). In this subgroup, 67.9% of patients had a ≥ 1% decrease in HbA1c or ≥ 30% decrease in fasting TGs, and 42.9% had a ≥ 2% decrease in HbA1c or ≥ 40% decrease in fasting TGs. Long-term treatment in this subgroup led to significant (p < 0.05) reductions at months 12, 24, and 36 in HbA1c, fasting TGs, and FPG. Metreleptin was well tolerated with no unexpected safety signals. The most common TEAEs were abdominal pain, hypoglycemia, and nausea.


In patients with PL, treatment with metreleptin was well tolerated and resulted in improvements in glycemic control, hypertriglyceridemia, and liver volume.


Diabetes mellitus Leptin Lipodystrophy Metreleptin Partial lipodystrophy 



All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this paper and take responsibility for the integrity of the work as a whole. Aegerion provided funding for medical writing and editing support in the development of this article; Jennifer L. Giel, PhD, and Raewyn M. Poole, MSc, of inScience Communications, Springer Healthcare (Philadelphia, PA, USA), on the basis of input from authors, wrote the first draft and revised subsequent drafts of the manuscript, and David Boffa, on behalf of, and Adrienne Schreiber of inScience Communications, Springer Healthcare (Philadelphia, PA, USA) copyedited and styled the manuscript per journal requirements. Aegerion Pharmaceuticals reviewed the manuscript drafts and provided feedback to the authors. The authors had full editorial control of the manuscript and provided their final approval of all content. Jean-Karl Sirois provided statistical analyses on behalf of Veristat LLC (Montreal, Canada), which was funded by Aegerion Pharmaceuticals, Inc. The authors acknowledge the services of the Clinical Core Laboratory of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health for measurement of leptin levels; this work was not funded by Aegerion Pharmaceuticals.


This work was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases. E.A.O. is partially supported by UM Lipodystrophy Fund gifted by the Sopha family and White Point Foundation of Turkey. D.B.S. is supported by the Wellcome Trust (WT 107064), the MRC Metabolic Disease Unit (MRC_MC_UU_12012.1), and The National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and NIHR Rare Disease Translational Research Collaboration.

Compliance with ethical standards

Conflict of interest

E.A.O. has served as a consultant to Aegerion Pharmaceuticals, Akcea Therapeutics, AstraZeneca, Regeneron Therapeutics, and Thera Therapeutics; has received grant support from Aegerion Pharmaceuticals, Akcea Therapeutics, AstraZeneca, Gemphire Therapeutics, GIDynamics, and Ionis Pharmaceuticals; and has received nonmaterial support from Aegerion Pharmaceuticals and Boehringer Ingelheim. D.A.V. and D.B.S. have served as consultants to Aegerion Pharmaceuticals. A.L. and T.S. are former employees and G.F. is a current employee of Aegerion Pharmaceuticals. E.C., P.G., and R.B. report no conflicts of interest.

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice and was approved by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases institutional review boards.

Informed consent

Informed consent was obtained from all patients or their legal guardians.

Supplementary material

12020_2019_1862_MOESM1_ESM.docx (21 kb)
Supplementary information


  1. 1.
    R.J. Brown, D. Araujo-Vilar, P.T. Cheung, D. Dunger, A. Garg, M. Jack, L. Mungai, E.A. Oral, N. Patni, K.I. Rother, J. von Schnurbein, E. Sorkina, T. Stanley, C. Vigouroux, M. Wabitsch, R. Williams, T. Yorifuji, The diagnosis and management of lipodystrophy syndromes: a multi-society practice guideline. J. Clin. Endocrinol. Metab. 101(12), 4500–4511 (2016). CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Y. Handelsman, E.A. Oral, Z.T. Bloomgarden, R.J. Brown, J.L. Chan, D. Einhorn, A.J. Garber, A. Garg, W.T. Garvey, G. Grunberger, R.R. Henry, N. Lavin, C.D. Tapiador, C. Weyer, The clinical approach to the detection of lipodystrophy – an AACE consensus statement. Endocr. Pract. 19(1), 107–116 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    A. Garg, Acquired and inherited lipodystrophies. New. Engl. J. Med. 350(12), 1220–1234 (2004). CrossRefPubMedGoogle Scholar
  4. 4.
    D. Araújo-Vilar, F. Santini, Diagnosis and treatment of lipodystrophy: a step-by-step approach. J. Endocrinol. Invest., [e-pub ahead of print] (2018).
  5. 5.
    C. Guillín-Amarelle, S. Sánchez-Iglesias, A. Castro-Pais, L. Rodriguez-Cañete, L. Ordóñez-Mayán, M. Pazos, B. González-Méndez, S. Rodríguez-García, F.F. Casanueva, A. Fernández-Marmiesse, D. Araújo-Vilar, Type 1 familial partial lipodystrophy: understanding the Kobberling syndrome. Endocrine 54(2), 411–421 (2016). CrossRefPubMedGoogle Scholar
  6. 6.
    B. Akinci, H. Onay, T. Demir, S. Savas-Erdeve, R. Gen, I.Y. Simsir, F.E. Keskin, M.S. Erturk, A.K. Uzum, G.F. Yaylali, N.K. Ozdemir, T. Atik, S. Ozen, B.S. Yurekli, T. Apaydin, C. Altay, G. Akinci, L. Demir, A. Comlekci, M. Secil, E.A. Oral, Clinical presentations, metabolic abnormalities and end-organ complications in patients with familial partial lipodystrophy. Metab. Clin. Exp. 72, 109–119 (2017). CrossRefPubMedGoogle Scholar
  7. 7.
    A. Garg, Clinical review#: Lipodystrophies: genetic and acquired body fat disorders. J. Clin. Endocrinol. Metab. 96(11), 3313–3325 (2011). CrossRefPubMedGoogle Scholar
  8. 8.
    A. Garg, Gender differences in the prevalence of metabolic complications in familial partial lipodystrophy (Dunnigan variety). J. Clin. Endocrinol. Metab. 85(5), 1776–1782 (2000). CrossRefPubMedGoogle Scholar
  9. 9.
    C. Saponaro, M. Gaggini, F. Carli, A. Gastaldelli, The subtle balance between lipolysis and lipogenesis: a critical point in metabolic homeostasis. Nutrients 7(11), 9453–9474 (2015). CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    N. Patni, A. Garg, Congenital generalized lipodystrophies—new insights into metabolic dysfunction. Nat. Rev. Endocrinol. 11(9), 522–534 (2015). CrossRefPubMedGoogle Scholar
  11. 11.
    C.A. Meehan, E. Cochran, A. Kassai, R.J. Brown, P. Gorden, Metreleptin for injection to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy. Exp. Rev. Clin. Pharmacol. 9(1), 59–68 (2016). CrossRefGoogle Scholar
  12. 12.
    E.A. Oral, Lipoatrophic diabetes and other related syndromes. Rev. Endocr. Metab. Dis. 4(1), 61–77 (2003)CrossRefGoogle Scholar
  13. 13.
    T. Diker-Cohen, E. Cochran, P. Gorden, R.J. Brown, Partial and generalized lipodystrophy: comparison of baseline characteristics and response to metreleptin. J. Clin. Endocrinol. Metab. 100(5), 1802–1810 (2015). CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    B. Akinci, F.D. Koseoglu, H. Onay, S. Yavuz, C. Altay, I.Y. Simsir, S. Ozisik, L. Demir, M. Korkut, N. Yilmaz, S. Ozen, G. Akinci, T. Atik, M. Calan, M. Secil, A. Comlekci, T. Demir, Acquired partial lipodystrophy is associated with increased risk for developing metabolic abnormalities. Metab. Clin. Exp. 64(9), 1086–1095 (2015). CrossRefPubMedGoogle Scholar
  15. 15.
    Myalept [Package Insert]. (Aegerion Pharmaceuticals, Inc., Cambridge, 2015)
  16. 16.
    Myalepta; Summary of Product Characteristics. (2018). Accessed 14 Jan 14 2019
  17. 17.
    J.L. Chan, K. Lutz, E. Cochran, W. Huang, Y. Peters, C. Weyer, P. Gorden, Clinical effects of long-term metreleptin treatment in patients with lipodystrophy. Endocr. Pract. 17(6), 922–932 (2011). CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    A.Y. Chong, B.C. Lupsa, E.K. Cochran, P. Gorden, Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia 53(1), 27–35 (2010). CrossRefPubMedGoogle Scholar
  19. 19.
    J.D. Christensen, A.O. Lungu, E. Cochran, M.T. Collins, R.I. Gafni, J.C. Reynolds, K.I. Rother, P. Gorden, R.J. Brown, Bone mineral content in patients with congenital generalized lipodystrophy is unaffected by metreleptin replacement therapy. J. Clin. Endocrinol. Metab. 99(8), E1493–E1500 (2014). CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    J. Joseph, R.D. Shamburek, E.K. Cochran, P. Gorden, R.J. Brown, Lipid regulation in lipodystrophy versus the obesity-associated metabolic syndrome: the dissociation of HDL-C and triglycerides. J. Clin. Endocrinol. Metab. 99(9), E1676–E1680 (2014). CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    F. Kamran, K.I. Rother, E. Cochran, E. Safar Zadeh, P. Gorden, R.J. Brown, Consequences of stopping and restarting leptin in an adolescent with lipodystrophy. Horm. Res. Paediatr. 78(5-6), 320–325 (2012). CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    R. Muniyappa, B.S. Abel, A. Asthana, M.F. Walter, E.K. Cochran, A.T. Remaley, M.C. Skarulis, P. Gorden, R.J. Brown, Metreleptin therapy lowers plasma angiopoietin-like protein 3 in patients with generalized lipodystrophy. J. Clin. Lipidol. 11(2), 543–550 (2017). CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    R.J. Brown, E.A. Oral, E. Cochran, D. Araujo-Vilar, D.B. Savage, A. Long, G. Fine, T. Salinardi, P. Gorden, Long-term effectiveness and safety of metreleptin in the treatment of patients with generalized lipodystrophy. Endocrine 60(3), 479–489 (2018). CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    E.A. Oral, V. Simha, E. Ruiz, A. Andewelt, A. Premkumar, P. Snell, A.J. Wagner, A.M. DePaoli, M.L. Reitman, S.I. Taylor, P. Gorden, A. Garg, Leptin-replacement therapy for lipodystrophy. New. Engl. J. Med. 346(8), 570–578 (2002). CrossRefPubMedGoogle Scholar
  25. 25.
    C. Vatier, S. Fetita, P. Boudou, C. Tchankou, L. Deville, J. Riveline, J. Young, L. Mathivon, F. Travert, D. Morin, J. Cahen, O. Lascols, F. Andreelli, Y. Reznik, E. Mongeois, I. Madelaine, M. Vantyghem, J. Gautier, C. Vigouroux, One-year metreleptin improves insulin secretion in patients with diabetes linked to genetic lipodystrophic syndromes. Diabetes Obes. Metab. 18(7), 693–697 (2016). CrossRefPubMedGoogle Scholar
  26. 26.
    V. Simha, L. Subramanyam, L. Szczepaniak, C. Quittner, B. Adams-Huet, P. Snell, A. Garg, Comparison of efficacy and safety of leptin replacement therapy in moderately and severely hypoleptinemic patients with familial partial lipodystrophy of the Dunnigan variety. J. Clin. Endocrinol. Metab. 97(3), 785–792 (2012). CrossRefPubMedGoogle Scholar
  27. 27.
    N. Ajluni, M. Dar, J. Xu, A.H. Neidert, E.A. Oral, Efficacy and safety of metreleptin in patients with partial lipodystrophy: lessons from an expanded access program. J. Diabetes Metab. 7(3), 659 (2016). CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    A. Garg, National Organization for Rare Disorders (NORD): Familial partial lipodystrophy. (2015). Accessed 4 Oct 2017
  29. 29.
    E. Chiquette, E.A. Oral, A. Garg, D. Araujo-Vilar, P. Dhankhar, Estimating the prevalence of generalized and partial lipodystrophy: findings and challenges. Diabetes Metab. Syndr. Obes. 10, 375–383 (2017). CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Elif A. Oral
    • 1
    Email author
  • Phillip Gorden
    • 2
  • Elaine Cochran
    • 2
  • David Araújo-Vilar
    • 3
  • David B. Savage
    • 4
  • Alison Long
    • 5
  • Gregory Fine
    • 5
  • Taylor Salinardi
    • 5
  • Rebecca J. Brown
    • 2
  1. 1.Department of Internal MedicineMichigan MedicineAnn ArborUSA
  2. 2.National Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaUSA
  3. 3.Department of MedicineUniversity of Santiago de CompostelaSantiago de CompostelaSpain
  4. 4.The University of Cambridge Metabolic Research LaboratoriesWellcome Trust-MRC Institute of Metabolic ScienceCambridgeUK
  5. 5.Aegerion PharmaceuticalsCambridgeUSA

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