Anti-interleukin-21 antibody and liraglutide for the preservation of β-cell function in adults with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled, phase 2 trial.
Autor: | von Herrath M; Novo Nordisk A/S, Søborg, Denmark., Bain SC; Swansea University Medical School, Swansea, UK., Bode B; Atlanta Diabetes Associates, Atlanta, GA, USA; Emory University School of Medicine, Atlanta, GA, USA., Clausen JO; Novo Nordisk A/S, Søborg, Denmark., Coppieters K; Novo Nordisk A/S, Måløv, Denmark., Gaysina L; Kazan Federal University, Kazan, Russia., Gumprecht J; Medical University of Silesia, Katowice, Poland., Hansen TK; Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark., Mathieu C; Clinical and Experimental Endocrinology, UZ Gasthuisberg, University of Leuven, Leuven, Belgium., Morales C; Endocrinology and Nutrition Department, Virgen Macarena Hospital, Seville, Spain., Mosenzon O; Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Centre, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel., Segel S; Novo Nordisk A/S, Aalborg, Denmark., Tsoukas G; Department of Medicine, McGill University, Montreal, QC, Canada., Pieber TR; Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. Electronic address: thomas.pieber@medunigraz.at. |
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Jazyk: | angličtina |
Zdroj: | The lancet. Diabetes & endocrinology [Lancet Diabetes Endocrinol] 2021 Apr; Vol. 9 (4), pp. 212-224. Date of Electronic Publication: 2021 Mar 01. |
DOI: | 10.1016/S2213-8587(21)00019-X |
Abstrakt: | Background: Type 1 diabetes is characterised by progressive loss of functional β-cell mass, necessitating insulin treatment. We aimed to investigate the hypothesis that combining anti-interleukin (IL)-21 antibody (for low-grade and transient immunomodulation) with liraglutide (to improve β-cell function) could enable β-cell survival with a reduced risk of complications compared with traditional immunomodulation. Methods: This randomised, parallel-group, placebo-controlled, double-dummy, double-blind, phase 2 trial was done at 94 sites (university hospitals and medical centres) in 17 countries. Eligible participants were adults aged 18-45 years with recently diagnosed type 1 diabetes and residual β-cell function. Individuals with unstable type 1 diabetes (defined by an episode of severe diabetic ketoacidosis within 2 weeks of enrolment) or active or latent chronic infections were excluded. Participants were randomly assigned (1:1:1:1), with stratification by baseline stimulated peak C-peptide concentration (mixed-meal tolerance test [MMTT]), to the combination of anti-IL-21 and liraglutide, anti-IL-21 alone, liraglutide alone, or placebo, all as an adjunct to insulin. Investigators, participants, and funder personnel were masked throughout the treatment period. The primary outcome was the change in MMTT-stimulated C-peptide concentration at week 54 (end of treatment) relative to baseline, measured via the area under the concentration-time curve (AUC) over a 4 h period for the full analysis set (intention-to-treat population consisting of all participants who were randomly assigned). After treatment cessation, participants were followed up for an additional 26-week off-treatment observation period. This trial is registered with ClinicalTrials.gov, NCT02443155. Findings: Between Nov 10, 2015, and Feb 27, 2019, 553 adults were assessed for eligibility, of whom 308 were randomly assigned to receive either anti-IL-21 plus liraglutide, anti-IL-21, liraglutide, or placebo (77 assigned to each group). Compared with placebo (ratio to baseline 0·61, 39% decrease), the decrease in MMTT-stimulated C-peptide concentration from baseline to week 54 was significantly smaller with combination treatment (0·90, 10% decrease; estimated treatment ratio 1·48, 95% CI 1·16-1·89; p=0·0017), but not with anti-IL-21 alone (1·23, 0·97-1·57; p=0·093) or liraglutide alone (1·12, 0·87-1·42; p=0·38). Despite greater insulin use in the placebo group, the decrease in HbA Interpretation: The combination of anti-IL-21 and liraglutide could preserve β-cell function in recently diagnosed type 1 diabetes. The efficacy of this combination appears to be similar to that seen in trials of other disease-modifying interventions in type 1 diabetes, but with a seemingly better safety profile. Efficacy and safety should be further evaluated in a phase 3 trial programme. Funding: Novo Nordisk. (Copyright © 2021 Elsevier Ltd. All rights reserved.) |
Databáze: | MEDLINE |
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