Repaglinide versus insulin for newly diagnosed diabetes in patients with cystic fibrosis: a multicentre, open-label, randomised trial

CFRD Study Group

doi:10.1016/S2213-8587(17)30400-X

Repaglinide versus insulin for newly diagnosed diabetes in patients with cystic fibrosis: a multicentre, open-label, randomised trial

CFRD Study Group

Clinic of Pediatric and Adolescent Medicine

59 Citations (Scopus)

Abstract

Background: As survival among patients with cystic fibrosis has improved in recent decades, complications have become increasingly relevant. The most frequent complication is cystic-fibrosis-related diabetes. The recommended treatment is injected insulin, but some patients are treated with oral antidiabetic drugs to ease the treatment burden. We assessed the efficacy and safety of oral antidiabetic drugs. Methods: We did a multicentre, open-label, comparative, randomised trial in 49 centres in Austria, France, Germany, and Italy. Eligible patients had cystic fibrosis, were older than 10 years, and had newly diagnosed diabetes. We used a central randomisation schedule derived from a Geigy random number table to assign patients 1:1 to receive insulin or repaglinide, stratified by sex and age (10–15 years or >15 years). The primary outcome was glycaemic control assessed by mean change in HbA_1c concentration from baseline after 24 months of treatment. Differences between groups were assessed by linear models. The primary and safety analyses were done in the modified intention-to-treat population (including patients who stopped treatment early because of lack of efficacy). This trial is registered with ClinicalTrials.gov, number NCT00662714. Findings: We enrolled 34 patients in the repaglinide group and 41 in the insulin group, of whom 30 and 37, respectively, were included in the analyses. At 24 months, glycaemic control was similar in the repaglinide and insulin groups (mean change in HbA_1c concentration from baseline 0·2% [SD 0·7%], 1·7 mmol/mol [8·1 mmol/mol] with repaglinide vs −0·2% [1·3%], −2·7 mmol/mol, [14·5 mmol/mol] with insulin; mean difference between groups −0·4%, (95% CI −1·1 to 0·2 [−4·4 mmol/mol, −11·5 to 2·7], p=0·15). The most frequent adverse events were pulmonary events (43 [40%] of 107 in the repaglinide group and 60 [45%] of 133 in the insulin group), and the most frequent serious adverse events were pulmonary events leading to hospital admission (five [50%] of ten and seven [54%] of 13, respectively). Interpretation: Repaglinide for glycaemic control in patients with cystic-fibrosis-related diabetes is as efficacious and safe as insulin. Funding: Mukoviszidose eV, Vaincre la Mucoviscidose, ABCF Association, and Novo Nordisk.

Original language	English
Journal	The Lancet Diabetes and Endocrinology
Volume	6
Issue number	2
Pages (from-to)	114-121
Number of pages	8
ISSN	2213-8587
DOIs	https://doi.org/10.1016/S2213-8587(17)30400-X
Publication status	Published - 02.2018

Funding

The study was funded by Mukoviszidose eV, Vaincre la Mucoviscidose, and ABCF Association. NovoNordisk Germany provided financial support for the study and also provided the repaglinide and the human regular insulin and injection aids free of charge. Local support for study organisation was provided by Mukoviszidose Institut GmbH, Bonn, Germany and URC Necker Cochin, Paris, France. We thank all patients and the staff in all study centres for participating in this trial. We thank the members of the CFRD Study Group ( appendix ), who recruited participants and collected study data; Elisabeth Kohne, Department of Paediatrics and Adolescent Medicine, University Children's Hospital Ulm, Ulm, Germany, for performing centralised HbA 1c measurements; Katharina Fink, Institute of Epidemiology and Medical Biometry (ZIBMT), University of Ulm, Ulm, Germany, for data management and statistical analyses; and Sibylle Schmidt, Paediatric Clinic, University Medicine Rostock, Rostock, Germany, for assistance in editing the report. None of the individuals at the participating centres who contributed to the report supported the study as consultants or had financial investment in the funding sources.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

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10.1016/S2213-8587(17)30400-X

Cite this

@article{c954d85421014d378e5afdc7c921d10c,

title = "Repaglinide versus insulin for newly diagnosed diabetes in patients with cystic fibrosis: a multicentre, open-label, randomised trial",

abstract = "Background: As survival among patients with cystic fibrosis has improved in recent decades, complications have become increasingly relevant. The most frequent complication is cystic-fibrosis-related diabetes. The recommended treatment is injected insulin, but some patients are treated with oral antidiabetic drugs to ease the treatment burden. We assessed the efficacy and safety of oral antidiabetic drugs. Methods: We did a multicentre, open-label, comparative, randomised trial in 49 centres in Austria, France, Germany, and Italy. Eligible patients had cystic fibrosis, were older than 10 years, and had newly diagnosed diabetes. We used a central randomisation schedule derived from a Geigy random number table to assign patients 1:1 to receive insulin or repaglinide, stratified by sex and age (10–15 years or >15 years). The primary outcome was glycaemic control assessed by mean change in HbA1c concentration from baseline after 24 months of treatment. Differences between groups were assessed by linear models. The primary and safety analyses were done in the modified intention-to-treat population (including patients who stopped treatment early because of lack of efficacy). This trial is registered with ClinicalTrials.gov, number NCT00662714. Findings: We enrolled 34 patients in the repaglinide group and 41 in the insulin group, of whom 30 and 37, respectively, were included in the analyses. At 24 months, glycaemic control was similar in the repaglinide and insulin groups (mean change in HbA1c concentration from baseline 0·2\% [SD 0·7\%], 1·7 mmol/mol [8·1 mmol/mol] with repaglinide vs −0·2\% [1·3\%], −2·7 mmol/mol, [14·5 mmol/mol] with insulin; mean difference between groups −0·4\%, (95\% CI −1·1 to 0·2 [−4·4 mmol/mol, −11·5 to 2·7], p=0·15). The most frequent adverse events were pulmonary events (43 [40\%] of 107 in the repaglinide group and 60 [45\%] of 133 in the insulin group), and the most frequent serious adverse events were pulmonary events leading to hospital admission (five [50\%] of ten and seven [54\%] of 13, respectively). Interpretation: Repaglinide for glycaemic control in patients with cystic-fibrosis-related diabetes is as efficacious and safe as insulin. Funding: Mukoviszidose eV, Vaincre la Mucoviscidose, ABCF Association, and Novo Nordisk.",

author = "\{CFRD Study Group\} and Manfred Ballmann and Dominique Hubert and Assael, \{Baroukh M.\} and Doris Staab and Alexandra Hebestreit and Lutz Naehrlich and Tanja Nickolay and Nicole Prinz and Holl, \{Reinhard W.\} and Ute Staden and Martin Cla{\ss}en and Antje Schuster and Uwe Mellies and Posselt, \{Hans Georg\} and Matthias Wiebel and Ernst Rietschel and Martin Stern and Helmut Teschler and Christina Smaczny and Thomas K{\"o}hnlein and Vera Wienhausen-Wilke and Andreas Claa{\ss} and Thomas Biedermann and Gerd Dockter and Holger K{\"o}ster and Helge Hebestreit and Ballke, \{Ernst Hinrich\} and Heuer, \{Hans Eberhard\} and Wolfgang Kamin and Peter K{\"u}ster and R{\"u}diger Szczepanski and Keller, \{Klaus Michael\} and Horst Generlich and Bresser, \{Hans Georg\} and Matthias Kopp and Egbert Herting and Feickert, \{Hans Joachim\} and J{\"u}rgen Hautz and Birgit Schilling and Egbert Meyer and Mall, \{Marcus A.\} and Wolfram Wiebicke and Tegtmeyer, \{Friedrich Karl\} and Marguerite Honer and Helen Mosnier-Pudar and G{\'e}rard Lenoir and Robert, \{Jean Jacques\} and Laurence Kessler and Laurence Weiss and Rapha{\"e}le Nove-Josserand",

note = "Funding Information: The study was funded by Mukoviszidose eV, Vaincre la Mucoviscidose, and ABCF Association. NovoNordisk Germany provided financial support for the study and also provided the repaglinide and the human regular insulin and injection aids free of charge. Local support for study organisation was provided by Mukoviszidose Institut GmbH, Bonn, Germany and URC Necker Cochin, Paris, France. We thank all patients and the staff in all study centres for participating in this trial. We thank the members of the CFRD Study Group ( appendix ), who recruited participants and collected study data; Elisabeth Kohne, Department of Paediatrics and Adolescent Medicine, University Children's Hospital Ulm, Ulm, Germany, for performing centralised HbA 1c measurements; Katharina Fink, Institute of Epidemiology and Medical Biometry (ZIBMT), University of Ulm, Ulm, Germany, for data management and statistical analyses; and Sibylle Schmidt, Paediatric Clinic, University Medicine Rostock, Rostock, Germany, for assistance in editing the report. None of the individuals at the participating centres who contributed to the report supported the study as consultants or had financial investment in the funding sources. Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2018",

month = feb,

doi = "10.1016/S2213-8587(17)30400-X",

language = "English",

volume = "6",

pages = "114--121",

journal = "The Lancet Diabetes and Endocrinology",

issn = "2213-8587",

publisher = "Elsevier Ltd",

number = "2",

}

TY - JOUR

T1 - Repaglinide versus insulin for newly diagnosed diabetes in patients with cystic fibrosis: a multicentre, open-label, randomised trial

AU - CFRD Study Group

AU - Ballmann, Manfred

AU - Hubert, Dominique

AU - Assael, Baroukh M.

AU - Staab, Doris

AU - Hebestreit, Alexandra

AU - Naehrlich, Lutz

AU - Nickolay, Tanja

AU - Prinz, Nicole

AU - Holl, Reinhard W.

AU - Staden, Ute

AU - Claßen, Martin

AU - Schuster, Antje

AU - Mellies, Uwe

AU - Posselt, Hans Georg

AU - Wiebel, Matthias

AU - Rietschel, Ernst

AU - Stern, Martin

AU - Teschler, Helmut

AU - Smaczny, Christina

AU - Köhnlein, Thomas

AU - Wienhausen-Wilke, Vera

AU - Claaß, Andreas

AU - Biedermann, Thomas

AU - Dockter, Gerd

AU - Köster, Holger

AU - Hebestreit, Helge

AU - Ballke, Ernst Hinrich

AU - Heuer, Hans Eberhard

AU - Kamin, Wolfgang

AU - Küster, Peter

AU - Szczepanski, Rüdiger

AU - Keller, Klaus Michael

AU - Generlich, Horst

AU - Bresser, Hans Georg

AU - Kopp, Matthias

AU - Herting, Egbert

AU - Feickert, Hans Joachim

AU - Hautz, Jürgen

AU - Schilling, Birgit

AU - Meyer, Egbert

AU - Mall, Marcus A.

AU - Wiebicke, Wolfram

AU - Tegtmeyer, Friedrich Karl

AU - Honer, Marguerite

AU - Mosnier-Pudar, Helen

AU - Lenoir, Gérard

AU - Robert, Jean Jacques

AU - Kessler, Laurence

AU - Weiss, Laurence

AU - Nove-Josserand, Raphaële

N1 - Funding Information: The study was funded by Mukoviszidose eV, Vaincre la Mucoviscidose, and ABCF Association. NovoNordisk Germany provided financial support for the study and also provided the repaglinide and the human regular insulin and injection aids free of charge. Local support for study organisation was provided by Mukoviszidose Institut GmbH, Bonn, Germany and URC Necker Cochin, Paris, France. We thank all patients and the staff in all study centres for participating in this trial. We thank the members of the CFRD Study Group ( appendix ), who recruited participants and collected study data; Elisabeth Kohne, Department of Paediatrics and Adolescent Medicine, University Children's Hospital Ulm, Ulm, Germany, for performing centralised HbA 1c measurements; Katharina Fink, Institute of Epidemiology and Medical Biometry (ZIBMT), University of Ulm, Ulm, Germany, for data management and statistical analyses; and Sibylle Schmidt, Paediatric Clinic, University Medicine Rostock, Rostock, Germany, for assistance in editing the report. None of the individuals at the participating centres who contributed to the report supported the study as consultants or had financial investment in the funding sources. Publisher Copyright: © 2018 Elsevier Ltd Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2018/2

Y1 - 2018/2

N2 - Background: As survival among patients with cystic fibrosis has improved in recent decades, complications have become increasingly relevant. The most frequent complication is cystic-fibrosis-related diabetes. The recommended treatment is injected insulin, but some patients are treated with oral antidiabetic drugs to ease the treatment burden. We assessed the efficacy and safety of oral antidiabetic drugs. Methods: We did a multicentre, open-label, comparative, randomised trial in 49 centres in Austria, France, Germany, and Italy. Eligible patients had cystic fibrosis, were older than 10 years, and had newly diagnosed diabetes. We used a central randomisation schedule derived from a Geigy random number table to assign patients 1:1 to receive insulin or repaglinide, stratified by sex and age (10–15 years or >15 years). The primary outcome was glycaemic control assessed by mean change in HbA1c concentration from baseline after 24 months of treatment. Differences between groups were assessed by linear models. The primary and safety analyses were done in the modified intention-to-treat population (including patients who stopped treatment early because of lack of efficacy). This trial is registered with ClinicalTrials.gov, number NCT00662714. Findings: We enrolled 34 patients in the repaglinide group and 41 in the insulin group, of whom 30 and 37, respectively, were included in the analyses. At 24 months, glycaemic control was similar in the repaglinide and insulin groups (mean change in HbA1c concentration from baseline 0·2% [SD 0·7%], 1·7 mmol/mol [8·1 mmol/mol] with repaglinide vs −0·2% [1·3%], −2·7 mmol/mol, [14·5 mmol/mol] with insulin; mean difference between groups −0·4%, (95% CI −1·1 to 0·2 [−4·4 mmol/mol, −11·5 to 2·7], p=0·15). The most frequent adverse events were pulmonary events (43 [40%] of 107 in the repaglinide group and 60 [45%] of 133 in the insulin group), and the most frequent serious adverse events were pulmonary events leading to hospital admission (five [50%] of ten and seven [54%] of 13, respectively). Interpretation: Repaglinide for glycaemic control in patients with cystic-fibrosis-related diabetes is as efficacious and safe as insulin. Funding: Mukoviszidose eV, Vaincre la Mucoviscidose, ABCF Association, and Novo Nordisk.

AB - Background: As survival among patients with cystic fibrosis has improved in recent decades, complications have become increasingly relevant. The most frequent complication is cystic-fibrosis-related diabetes. The recommended treatment is injected insulin, but some patients are treated with oral antidiabetic drugs to ease the treatment burden. We assessed the efficacy and safety of oral antidiabetic drugs. Methods: We did a multicentre, open-label, comparative, randomised trial in 49 centres in Austria, France, Germany, and Italy. Eligible patients had cystic fibrosis, were older than 10 years, and had newly diagnosed diabetes. We used a central randomisation schedule derived from a Geigy random number table to assign patients 1:1 to receive insulin or repaglinide, stratified by sex and age (10–15 years or >15 years). The primary outcome was glycaemic control assessed by mean change in HbA1c concentration from baseline after 24 months of treatment. Differences between groups were assessed by linear models. The primary and safety analyses were done in the modified intention-to-treat population (including patients who stopped treatment early because of lack of efficacy). This trial is registered with ClinicalTrials.gov, number NCT00662714. Findings: We enrolled 34 patients in the repaglinide group and 41 in the insulin group, of whom 30 and 37, respectively, were included in the analyses. At 24 months, glycaemic control was similar in the repaglinide and insulin groups (mean change in HbA1c concentration from baseline 0·2% [SD 0·7%], 1·7 mmol/mol [8·1 mmol/mol] with repaglinide vs −0·2% [1·3%], −2·7 mmol/mol, [14·5 mmol/mol] with insulin; mean difference between groups −0·4%, (95% CI −1·1 to 0·2 [−4·4 mmol/mol, −11·5 to 2·7], p=0·15). The most frequent adverse events were pulmonary events (43 [40%] of 107 in the repaglinide group and 60 [45%] of 133 in the insulin group), and the most frequent serious adverse events were pulmonary events leading to hospital admission (five [50%] of ten and seven [54%] of 13, respectively). Interpretation: Repaglinide for glycaemic control in patients with cystic-fibrosis-related diabetes is as efficacious and safe as insulin. Funding: Mukoviszidose eV, Vaincre la Mucoviscidose, ABCF Association, and Novo Nordisk.

UR - https://www.scopus.com/pages/publications/85035345718

U2 - 10.1016/S2213-8587(17)30400-X

DO - 10.1016/S2213-8587(17)30400-X

M3 - Journal articles

C2 - 29199116

AN - SCOPUS:85035345718

SN - 2213-8587

VL - 6

SP - 114

EP - 121

JO - The Lancet Diabetes and Endocrinology

JF - The Lancet Diabetes and Endocrinology

IS - 2

ER -

Repaglinide versus insulin for newly diagnosed diabetes in patients with cystic fibrosis: a multicentre, open-label, randomised trial

Abstract

Funding

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Research Areas and Centers

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