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Post hoc analysis of a randomized, double-blind, prospective trial evaluating a CXCR1/2 inhibitor in new-onset type 1 diabetes: endo-metabolic features at baseline identify a subgroup of responders

AIM: In a recent randomized, multicenter trial (NCT02814838) a short-term anti-inflammatory treatment with ladarixin (LDX; an inhibitor of the CXCR1/2 chemokine receptors) did not show benefit on preserving residual beta cell function in new-onset type 1 diabetes. We present a post hoc analysis of t...

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Autores principales: Sordi, Valeria, Monti, Paolo, Lampasona, Vito, Melzi, Raffaella, Pellegrini, Silvia, Keymeulen, Bart, Gillard, Pieter, Linn, Thomas, Bosi, Emanuele, Rose, Ludger, Pozzilli, Paolo, Giorgino, Francesco, Cossu, Efisio, Piemonti, Lorenzo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10319139/
https://www.ncbi.nlm.nih.gov/pubmed/37409229
http://dx.doi.org/10.3389/fendo.2023.1175640
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author Sordi, Valeria
Monti, Paolo
Lampasona, Vito
Melzi, Raffaella
Pellegrini, Silvia
Keymeulen, Bart
Gillard, Pieter
Linn, Thomas
Bosi, Emanuele
Rose, Ludger
Pozzilli, Paolo
Giorgino, Francesco
Cossu, Efisio
Piemonti, Lorenzo
author_facet Sordi, Valeria
Monti, Paolo
Lampasona, Vito
Melzi, Raffaella
Pellegrini, Silvia
Keymeulen, Bart
Gillard, Pieter
Linn, Thomas
Bosi, Emanuele
Rose, Ludger
Pozzilli, Paolo
Giorgino, Francesco
Cossu, Efisio
Piemonti, Lorenzo
author_sort Sordi, Valeria
collection PubMed
description AIM: In a recent randomized, multicenter trial (NCT02814838) a short-term anti-inflammatory treatment with ladarixin (LDX; an inhibitor of the CXCR1/2 chemokine receptors) did not show benefit on preserving residual beta cell function in new-onset type 1 diabetes. We present a post hoc analysis of trial patients in the predefined subgroup analysis developed according to baseline daily insulin requirement (DIR) tertiles. METHOD: A double-blind, randomized (2:1), placebo-controlled study was conducted in 45 men and 31 women (aged 18–46 years) within 100 days of the first insulin administration. Patients received LDX (400 mg twice daily) for three cycles of 14 days on/14 days off, or placebo. The primary endpoint was the area under the curve for C-peptide [AUC (0–120 min)] in response to a 2-h mixed meal tolerance test (MMTT) at week 13 ± 1. Seventy-five patients completed the week 13 MMTT and were divided into three groups according to the DIR tertiles: lower, ≤ 0.23U/kg/die (n = 25); middle, 0.24–0.40 U/kg/die (n = 24); upper, ≥ 0.41 U/kg/die (n = 26). RESULTS: When considering the patients in the upper tertile (HIGH-DIR), C-peptide AUC (0–120 min) at 13 weeks was higher in the LDX group (n = 16) than in the placebo (n = 10) group [difference: 0.72 nmol/L (95% CI 0.9–1.34), p = 0.027]. This difference reduced over time (0.71 nmol/L at 26 weeks, p = 0.04; 0.42 nmol/L at 52 weeks, p = 0.29), while it has never been significant at any time in patients in the lower and/or middle tertile (LOW-DIR). We characterized at baseline the HIGH-DIR and found that endo-metabolic (HOMA-B, adiponectin, and glucagon-to-C-peptide ratio) and immunologic (chemokine (C-C motif) ligand 2 (CCL2)/monocyte chemoattractant protein 1 (MCP1) and Vascular Endothelial Growth Factor (VEGF)) features distinguished this group from LOW-DIR. CONCLUSION: While LDX did not prevent the progressive loss of beta-cell function in the majority of treated subjects, the post hoc analysis suggests that it could work in subjects with HIGH-DIR at baseline. As we found differences in endo-metabolic and immunologic parameters within this subgroup, this generates the hypothesis that the interactions between host factors and drug action can contribute to its efficacy. Further research is needed to evaluate this hypothesis.
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spelling pubmed-103191392023-07-05 Post hoc analysis of a randomized, double-blind, prospective trial evaluating a CXCR1/2 inhibitor in new-onset type 1 diabetes: endo-metabolic features at baseline identify a subgroup of responders Sordi, Valeria Monti, Paolo Lampasona, Vito Melzi, Raffaella Pellegrini, Silvia Keymeulen, Bart Gillard, Pieter Linn, Thomas Bosi, Emanuele Rose, Ludger Pozzilli, Paolo Giorgino, Francesco Cossu, Efisio Piemonti, Lorenzo Front Endocrinol (Lausanne) Endocrinology AIM: In a recent randomized, multicenter trial (NCT02814838) a short-term anti-inflammatory treatment with ladarixin (LDX; an inhibitor of the CXCR1/2 chemokine receptors) did not show benefit on preserving residual beta cell function in new-onset type 1 diabetes. We present a post hoc analysis of trial patients in the predefined subgroup analysis developed according to baseline daily insulin requirement (DIR) tertiles. METHOD: A double-blind, randomized (2:1), placebo-controlled study was conducted in 45 men and 31 women (aged 18–46 years) within 100 days of the first insulin administration. Patients received LDX (400 mg twice daily) for three cycles of 14 days on/14 days off, or placebo. The primary endpoint was the area under the curve for C-peptide [AUC (0–120 min)] in response to a 2-h mixed meal tolerance test (MMTT) at week 13 ± 1. Seventy-five patients completed the week 13 MMTT and were divided into three groups according to the DIR tertiles: lower, ≤ 0.23U/kg/die (n = 25); middle, 0.24–0.40 U/kg/die (n = 24); upper, ≥ 0.41 U/kg/die (n = 26). RESULTS: When considering the patients in the upper tertile (HIGH-DIR), C-peptide AUC (0–120 min) at 13 weeks was higher in the LDX group (n = 16) than in the placebo (n = 10) group [difference: 0.72 nmol/L (95% CI 0.9–1.34), p = 0.027]. This difference reduced over time (0.71 nmol/L at 26 weeks, p = 0.04; 0.42 nmol/L at 52 weeks, p = 0.29), while it has never been significant at any time in patients in the lower and/or middle tertile (LOW-DIR). We characterized at baseline the HIGH-DIR and found that endo-metabolic (HOMA-B, adiponectin, and glucagon-to-C-peptide ratio) and immunologic (chemokine (C-C motif) ligand 2 (CCL2)/monocyte chemoattractant protein 1 (MCP1) and Vascular Endothelial Growth Factor (VEGF)) features distinguished this group from LOW-DIR. CONCLUSION: While LDX did not prevent the progressive loss of beta-cell function in the majority of treated subjects, the post hoc analysis suggests that it could work in subjects with HIGH-DIR at baseline. As we found differences in endo-metabolic and immunologic parameters within this subgroup, this generates the hypothesis that the interactions between host factors and drug action can contribute to its efficacy. Further research is needed to evaluate this hypothesis. Frontiers Media S.A. 2023-06-20 /pmc/articles/PMC10319139/ /pubmed/37409229 http://dx.doi.org/10.3389/fendo.2023.1175640 Text en Copyright © 2023 Sordi, Monti, Lampasona, Melzi, Pellegrini, Keymeulen, Gillard, Linn, Bosi, Rose, Pozzilli, Giorgino, Cossu and Piemonti https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Sordi, Valeria
Monti, Paolo
Lampasona, Vito
Melzi, Raffaella
Pellegrini, Silvia
Keymeulen, Bart
Gillard, Pieter
Linn, Thomas
Bosi, Emanuele
Rose, Ludger
Pozzilli, Paolo
Giorgino, Francesco
Cossu, Efisio
Piemonti, Lorenzo
Post hoc analysis of a randomized, double-blind, prospective trial evaluating a CXCR1/2 inhibitor in new-onset type 1 diabetes: endo-metabolic features at baseline identify a subgroup of responders
title Post hoc analysis of a randomized, double-blind, prospective trial evaluating a CXCR1/2 inhibitor in new-onset type 1 diabetes: endo-metabolic features at baseline identify a subgroup of responders
title_full Post hoc analysis of a randomized, double-blind, prospective trial evaluating a CXCR1/2 inhibitor in new-onset type 1 diabetes: endo-metabolic features at baseline identify a subgroup of responders
title_fullStr Post hoc analysis of a randomized, double-blind, prospective trial evaluating a CXCR1/2 inhibitor in new-onset type 1 diabetes: endo-metabolic features at baseline identify a subgroup of responders
title_full_unstemmed Post hoc analysis of a randomized, double-blind, prospective trial evaluating a CXCR1/2 inhibitor in new-onset type 1 diabetes: endo-metabolic features at baseline identify a subgroup of responders
title_short Post hoc analysis of a randomized, double-blind, prospective trial evaluating a CXCR1/2 inhibitor in new-onset type 1 diabetes: endo-metabolic features at baseline identify a subgroup of responders
title_sort post hoc analysis of a randomized, double-blind, prospective trial evaluating a cxcr1/2 inhibitor in new-onset type 1 diabetes: endo-metabolic features at baseline identify a subgroup of responders
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10319139/
https://www.ncbi.nlm.nih.gov/pubmed/37409229
http://dx.doi.org/10.3389/fendo.2023.1175640
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