Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study

Pamela Bowman, Åsta Sulen, Fabrizio Barbetti, Jacques Beltrand, Pernille Svalastoga, Ethel Codner, Ellen H Tessmann, Petur B Juliusson, Torild Skrivarhaug, Ewan R Pearson, Sarah E Flanagan, Tarig Babiker, Nicholas J Thomas, Maggie H Shepherd, Sian Ellard, Iwar Klimes, Magdalena Szopa, Michel Polak, Dario Iafusco, Andrew T Hattersley, Pål R Njølstad, Neonatal Diabetes International Collaborative Group, Javier Aisenberg, Ilker Akkurt, Hussein Abdul-Latif, Anees Al-Abdullah, Lubomir Barak, Joop Van Den Bergh, Anne-Marie Bertrand, Carla Bizzarri, Riccardo Bonfanti, Henri Bruel, Anthony Burrows, Francesco Cadario, Fergus J Cameron, Dennis Carson, Maryse Cartigny, Vittoria Cauvin, Helene Cave, Ali Chakera, Ravi Chetan, Giovanni Chiari, Bob Couch, Régis Coutant, Elizabeth Cummings, Adriana Dankovcikova, Liz Davis, Dorothee Deiss, Maurizio Delvecchio, Elena Faleschini, Anne-Laure Fauret, Roisin Finn, Tamsin Ford, Elisa De Franco, Bastian De Gallen, Daniela Gasperíková, Padma Guntamukkala, Vaseem Hakeem, Shinji Hasegawa, Eba H Hathout, Emmeline Heffernan, David Hill, Josephine Ho, Marie Hoarau, Reinhard Holl, Rebecca Hoddinott, Jane Houghton, Neville Howard, Natalie Hughes, Ian Hunter, Anne Kirsti Høgåsen, Helena Kuulasmaa, Sorin Ioacara, Violeta Iotova, Henrik Irgens, Alan Jaap, Kenneth Jones, Thomas Kapellen, Ellen Kaufman, Andreas Klinge, Tomasz Klupa, Ramaiyer Krishnaswamy, Tony Lafferty, Laurent LeGault, Paul Lambert, Maciej T Malecki, Olag Malievsky, Revi Mathew, Frances Mathews, Robert McVie, Ulrike Menzel, Chantale Metz, John Van Der Meulen, Gita Modgil, Dick Mul, Silvia Muther, Roos Nuboer, Susan M O'Connell, Stephen O'Riordan, Miroslav Palko, Kashyap Amratlal Patel, Roberta Pesavento, Elvira Piccinno, Janani Kumaraguru Pillai, Stephanka Pruhova, Zubin Punthakee, Ivana Rabbone, Klemens Raile, Marielisa Rincon, Danette Rose, Janine Sanchez, Susan Sandereson, Vinay Saxena, Martin Schebek, Dorothee Schmidt, Naim Shehadeh, Julian P H Shiels, Jose M C L Silva, Juraj Stanik, Tracy Tinklin, Erling Tjora, Stefano Tumini, Tiinamaija Tuomi, Akiko Uehara, Robert Van der Velde, Guido Vermeulen, Uma Visser, Paul Voorhoeve, Jan Walker, Jaques Weill, Tobias Weisner, Andrea Werner, Toni Williams, Helen Woodhead, Rønnaug Øddegård, Pamela Bowman, Åsta Sulen, Fabrizio Barbetti, Jacques Beltrand, Pernille Svalastoga, Ethel Codner, Ellen H Tessmann, Petur B Juliusson, Torild Skrivarhaug, Ewan R Pearson, Sarah E Flanagan, Tarig Babiker, Nicholas J Thomas, Maggie H Shepherd, Sian Ellard, Iwar Klimes, Magdalena Szopa, Michel Polak, Dario Iafusco, Andrew T Hattersley, Pål R Njølstad, Neonatal Diabetes International Collaborative Group, Javier Aisenberg, Ilker Akkurt, Hussein Abdul-Latif, Anees Al-Abdullah, Lubomir Barak, Joop Van Den Bergh, Anne-Marie Bertrand, Carla Bizzarri, Riccardo Bonfanti, Henri Bruel, Anthony Burrows, Francesco Cadario, Fergus J Cameron, Dennis Carson, Maryse Cartigny, Vittoria Cauvin, Helene Cave, Ali Chakera, Ravi Chetan, Giovanni Chiari, Bob Couch, Régis Coutant, Elizabeth Cummings, Adriana Dankovcikova, Liz Davis, Dorothee Deiss, Maurizio Delvecchio, Elena Faleschini, Anne-Laure Fauret, Roisin Finn, Tamsin Ford, Elisa De Franco, Bastian De Gallen, Daniela Gasperíková, Padma Guntamukkala, Vaseem Hakeem, Shinji Hasegawa, Eba H Hathout, Emmeline Heffernan, David Hill, Josephine Ho, Marie Hoarau, Reinhard Holl, Rebecca Hoddinott, Jane Houghton, Neville Howard, Natalie Hughes, Ian Hunter, Anne Kirsti Høgåsen, Helena Kuulasmaa, Sorin Ioacara, Violeta Iotova, Henrik Irgens, Alan Jaap, Kenneth Jones, Thomas Kapellen, Ellen Kaufman, Andreas Klinge, Tomasz Klupa, Ramaiyer Krishnaswamy, Tony Lafferty, Laurent LeGault, Paul Lambert, Maciej T Malecki, Olag Malievsky, Revi Mathew, Frances Mathews, Robert McVie, Ulrike Menzel, Chantale Metz, John Van Der Meulen, Gita Modgil, Dick Mul, Silvia Muther, Roos Nuboer, Susan M O'Connell, Stephen O'Riordan, Miroslav Palko, Kashyap Amratlal Patel, Roberta Pesavento, Elvira Piccinno, Janani Kumaraguru Pillai, Stephanka Pruhova, Zubin Punthakee, Ivana Rabbone, Klemens Raile, Marielisa Rincon, Danette Rose, Janine Sanchez, Susan Sandereson, Vinay Saxena, Martin Schebek, Dorothee Schmidt, Naim Shehadeh, Julian P H Shiels, Jose M C L Silva, Juraj Stanik, Tracy Tinklin, Erling Tjora, Stefano Tumini, Tiinamaija Tuomi, Akiko Uehara, Robert Van der Velde, Guido Vermeulen, Uma Visser, Paul Voorhoeve, Jan Walker, Jaques Weill, Tobias Weisner, Andrea Werner, Toni Williams, Helen Woodhead, Rønnaug Øddegård

Abstract

Background: KCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients.

Methods: In this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA1c and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817.

Findings: 90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3-10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA1c and sulfonylurea at all time points (ie, pre-transfer [for HbA1c], year 1, and most recent follow-up; n=64)-median HbA1c was 8·1% (IQR 7·2-9·2; 65·0 mmol/mol [55·2-77·1]) before transfer to sulfonylureas, 5·9% (5·4-6·5; 41·0 mmol/mol [35·5-47·5]; p<0·0001 vs pre-transfer) at 1 year, and 6·4% (5·9-7·3; 46·4 mmol/mol [41·0-56·3]; p<0·0001 vs year 1) at most recent follow-up (median 10·3 years [IQR 9·2-10·9]). In the same patients, median sulfonylurea dose at 1 year was 0·30 mg/kg per day (0·14-0·53) and at most recent follow-up visit was 0·23 mg/kg per day (0·12-0·41; p=0·03). No reports of severe hypoglycaemia were recorded in 809 patient-years of follow-up for the whole cohort (n=81). 11 (14%) patients reported mild, transient side-effects, but did not need to stop sulfonylurea therapy. Seven (9%) patients had microvascular complications; these patients had been taking insulin longer than those without complications (median age at transfer to sulfonylureas 20·5 years [IQR 10·5-24·0] vs 4·1 years [1·3-10·2]; p=0·0005). Initial improvement was noted following transfer to sulfonylureas in 18 (47%) of 38 patients with CNS features. After long-term therapy with sulfonylureas, CNS features were seen in 52 (64%) of 81 patients.

Interpretation: High-dose sulfonylurea therapy is an appropriate treatment for patients with KCNJ11 permanent neonatal diabetes from diagnosis. This therapy is safe and highly effective, maintaining excellent glycaemic control for at least 10 years.

Funding: Wellcome Trust, Diabetes UK, Royal Society, European Research Council, Norwegian Research Council, Kristian Gerhard Jebsen Foundation, Western Norway Regional Health Authority, Southern and Eastern Norway Regional Health Authority, Italian Ministry of Health, Aide aux Jeunes Diabetiques, Societe Francophone du Diabete, Ipsen, Slovak Research and Development Agency, and Research and Development Operational Programme funded by the European Regional Development Fund.

Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Cohort selection and follow-up
Figure 2
Figure 2
Sulfonylurea efficacy and metabolic control (A) Kaplan-Meier survival estimate of time to introduction of insulin in patients with sulfonylurea-treated KCNJ11 permanent neonatal diabetes. (B) Longitudinal data for HbA1c and sulfonylurea dose in 74 patients receiving sulfonylurea without daily insulin at most recent follow-up (n=70 for pre-transfer HbA1c). Missing values were imputed by assuming a linear trend between available data points, carrying the last value forward, or carrying the next value back.
Figure 3
Figure 3
Physiological studies Median incremental increase in glucose and insulin concentration above baseline in an oral glucose tolerance test and an intravenous glucose tolerance test (n=6).
Figure 4
Figure 4
CNS features Number of patients for whom CNS features were reported before and after sulfonylurea transfer, and number of patients who showed improvement of CNS features while receiving sulfonylurea therapy.

References

    1. Hattersley AT, Patel KA. Precision diabetes: learning from monogenic diabetes. Diabetologia. 2017;60:769–777.
    1. Gloyn AL, Pearson ER, Antcliff JF. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004;350:1838–1849.
    1. De Franco E, Flanagan SE, Houghton JA. The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study. Lancet. 2015;386:957–963.
    1. Sagen JV, Raeder H, Hathout E. Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes. 2004;53:2713–2718.
    1. Zung A, Glaser B, Nimri R, Zadik Z. Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2. J Clin Endocrinol Metab. 2004;89:5504–5507.
    1. Pearson ER, Flechtner I, Njølstad PR. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med. 2006;355:467–477.
    1. Tannock IF, Hickman JA. Limits to personalized cancer medicine. N Engl J Med. 2016;375:1289–1294.
    1. Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC. UKPDS 26: sulphonylurea failure in non-insulin-dependent diabetic patients over six years. Diabet Med. 1998;15:297–303.
    1. Klupa T, Skupien J, Mirkiewicz-Sieradzka B. Efficacy and safety of sulfonylurea use in permanent neonatal diabetes due to KCNJ11 gene mutations: 34-month median follow-up. Diabetes Technol Ther. 2010;12:387–391.
    1. Vendramini MF, Gurgel LC, Moisés RS. Long-term response to sulfonylurea in a patient with diabetes due to mutation in the KCNJ11 gene. Arq Bras Endocrinol Metabol. 2010;54:682–684.
    1. Iafusco D, Bizzarri C, Cadario F. No beta cell desensitisation after a median of 68 months on glibenclamide therapy in patients with KCNJ11-associated permanent neonatal diabetes. Diabetologia. 2011;54:2736–2738.
    1. Gangji AS, Cukierman T, Gerstein HC, Goldsmith CH, Clase CM. A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin. Diabetes Care. 2007;30:389–394.
    1. Clark RH, McTaggart JS, Webster R. Muscle dysfunction caused by a KATP channel mutation in neonatal diabetes is neuronal in origin. Science. 2010;329:458–461.
    1. Flanagan SE, Edghill EL, Gloyn AL, Ellard S, Hattersley AT. Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype. Diabetologia. 2006;49:1190–1197.
    1. Bowman P, Broadbridge E, Knight BA. Psychiatric morbidity in children with KCNJ11 neonatal diabetes. Diabet Med. 2016;33:1387–1391.
    1. Busiah K, Drunat S, Vaivre-Douret L. Neuropsychological dysfunction and developmental defects associated with genetic changes in infants with neonatal diabetes mellitus: a prospective cohort study. Lancet Diabetes Endocrinol. 2013;1:199–207.
    1. Carmody D, Pastore AN, Landmeier KA. Patients with KCNJ11-related diabetes frequently have neuropsychological impairments compared with sibling controls. Diabet Med. 2016;33:1380–1386.
    1. Beltrand J, Elie C, Busiah K. Sulfonylurea therapy benefits neurological and psychomotor functions in patients with neonatal diabetes owing to potassium channel mutations. Diabetes Care. 2015;38:2033–2041.
    1. Lahmann C, Kramer HB, Ashcroft FM. Systemic administration of glibenclamide fails to achieve therapeutic levels in the brain and cerebrospinal fluid of rodents. PLoS One. 2015;10:e0134476.
    1. WHO . World Health Organization; Geneva: 2006. WHO Child Growth Standards. Length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age. Methods and development.
    1. Hattersley AT, Ashcroft FM. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes. 2005;54:2503–2513.
    1. Landmeier KA, Lanning M, Carmody D, Greeley SA, Msall ME. ADHD, learning difficulties and sleep disturbances associated with KCNJ11-related neonatal diabetes. Pediatr Diabetes. 2016;18:518–523.
    1. NICE British National Formulary. Glibenclamide.
    1. Ly TT, Maahs DM, Rewers A, Dunger D, Oduwole A, Jones TW. ISPAD Clinical Practice Consensus Guidelines 2014. Assessment and management of hypoglycemia in children and adolescents with diabetes. Pediatr Diabetes. 2014;15(suppl 20):180–192.
    1. UK Prospective Diabetes Study Group UK Prospective Diabetes Study 16: overview of 6 years' therapy of type II diabetes: a progressive disease. Diabetes. 1995;44:1249–1258.
    1. DCCT Research Group Weight gain associated with intensive therapy in the diabetes control and complications trial. Diabetes Care. 1988;11:567–573.
    1. Diabetes Control and Complications Trial Research Group The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–986.
    1. Moran A, Jacobs DR, Jr, Steinberger J. Insulin resistance during puberty: results from clamp studies in 357 children. Diabetes. 1999;48:2039–2044.
    1. Hoey H, on behalf of the Hvidoere Study Group on Childhood Diabetes Psychosocial factors are associated with metabolic control in adolescents: research from the Hvidoere Study Group on Childhood Diabetes. Pediatr Diabetes. 2009;10(suppl 13):9–14.
    1. Shah RP, Spruyt K, Kragie BC, Greeley SA, Msall ME. Visuomotor performance in KCNJ11-related neonatal diabetes is impaired in children with DEND-associated mutations and may be improved by early treatment with sulfonylureas. Diabetes Care. 2012;35:2086–2088.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere