Endogenous Leptin Concentrations Poorly Predict Metreleptin Response in Patients With Partial Lipodystrophy

Rasimcan Meral; Noemi Malandrino; Mary Walter; Adam H Neidert; Ranganath Muniyappa; Elif Arioglu Oral; Rebecca J Brown

doi:10.1210/clinem/dgab760

Endogenous Leptin Concentrations Poorly Predict Metreleptin Response in Patients With Partial Lipodystrophy

J Clin Endocrinol Metab. 2022 Mar 24;107(4):e1739-e1751. doi: 10.1210/clinem/dgab760.

Authors

Rasimcan Meral^{1

2

3

4}, Noemi Malandrino¹, Mary Walter⁵, Adam H Neidert², Ranganath Muniyappa¹, Elif Arioglu Oral², Rebecca J Brown¹

Affiliations

¹ Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD, USA.
² Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
³ Department of Medical Biology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
⁴ Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
⁵ Clinical Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

Abstract

Context: Leptin replacement with metreleptin improves glycemia and hypertriglyceridemia in severely hypoleptinemic patients with generalized lipodystrophy (GLD), but its effects are variable in partially leptin-deficient patients with partial lipodystrophy (PLD).

Objective: Compare 3 leptin assays (Study I); identify diagnostic performance of leptin assays to detect responders to metreleptin for each assay (Study II).

Design: Study I: cross-sectional analysis of average bias between leptin assays. Study II: retrospective analysis of diagnostic accuracy of potential leptin cut points to detect clinical responders to metreleptin.

Setting: National Institutes of Health; University of Michigan.

Participants and interventions: Study I: Metreleptin-naïve patients with lipodystrophy (GLD, n = 33, PLD, n = 67) and healthy volunteers (n = 239). Study II: GLD (n = 66) and PLD (n = 84) patients treated with metreleptin for 12 months.

Outcome measures: Leptin concentrations by Millipore radioimmunoassay (RIA), Millipore enzyme-linked immunosorbent assay (MELISA), and R&D Systems enzyme-linked immunosorbent assay (RDELISA). Response to metreleptin therapy was defined as either reduction ≥1.0% in A1c or ≥30% in serum triglycerides.

Results: RDELISA measured 3.0 ± 9.5 ng/mL higher than RIA; MELISA measured 11.0 ± 17.8 and 14.0 ±19.2 less than RIA and RDELISA, respectively. Leptin by RIA, MELISA, and RDELISA modestly predicted metreleptin response in GLD + PLD [receiver operating characteristic (ROC) area under the curve (AUC) 0.74, 0.69, and 0.71, respectively; P < 0.01 for all] with lower predictive power in PLD (ROC AUC 0.63, 0.61 and 0.65, respectively; P > 0.05 for all). The only reproducible cut point identified on sensitivity analyses was RIA leptin 7.2 ng/mL (sensitivity 56%; specificity 78%).

Conclusions: Three common leptin assays are not interchangeable, and a reliable cut point to select responders to metreleptin was not identified.

Trial registration: ClinicalTrials.gov NCT00001987 NCT00025883 NCT01778556 NCT00428987 NCT00677313 NCT01679197.

Keywords: ELISA; RIA; assay; cut point; leptin; lipodystrophy; metreleptin.

Published by Oxford University Press on behalf of the Endocrine Society 2021.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Cross-Sectional Studies
Humans
Leptin* / analogs & derivatives
Lipodystrophy* / chemically induced
Lipodystrophy* / drug therapy
Retrospective Studies

Substances

Leptin
metreleptin

Supplementary concepts

Lipodystrophy, Partial, Acquired

Associated data