Long-term effectiveness and safety of metreleptin in the treatment of patients with partial lipodystrophy
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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.
KeywordsDiabetes 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.
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 was obtained from all patients or their legal guardians.
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