Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study.
Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study.
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DOI：
10.1016/s2213-8587(18)30106-2
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发表时间：
2018-08
期刊：
影响因子：
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通讯作者：
Neonatal Diabetes International Collaborative Group
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作者：
Bowman P;Sulen Å;Barbetti F;Beltrand J;Svalastoga P;Codner E;Tessmann EH;Juliusson PB;Skrivarhaug T;Pearson ER;Flanagan SE;Babiker T;Thomas NJ;Shepherd MH;Ellard S;Klimes I;Szopa M;Polak M;Iafusco D;Hattersley AT;Njølstad PR;Neonatal Diabetes International Collaborative Group
KCNJ11突变通过胰腺atp敏感钾通道激活导致永久性新生儿糖尿病。90%的患者成功地从胰岛素转移到口服磺脲类药物，初始血糖控制良好；然而，这种控制能否长期维持尚不清楚。约44%的2型糖尿病患者在治疗5年后出现磺脲类药物失效。因此，我们对KCNJ11永久性新生儿糖尿病患者进行了一项为期10年的多中心随访研究，以解决磺脲类药物在这些患者中的长期疗效和安全性的关键问题。在这项多中心国际队列研究中，所有在埃克塞特（英国）、罗马（意大利）、卑尔根（挪威）、巴黎（法国）和克拉科夫（波兰）五个实验室诊断为KCNJ11永久性新生儿糖尿病的患者，在2006年11月30日前从胰岛素转为口服磺脲类药物，均符合纳入条件。临床医生收集与血糖控制、磺脲剂量、严重低血糖、副作用、糖尿病并发症和生长有关的临床特征和年度数据。研究的主要结果是磺酰脲治疗失败（定义为每日胰岛素的永久性重新引入）和代谢控制（特别是糖化血红蛋白和磺酰脲剂量）。还评估了与KCNJ11永久性新生儿糖尿病相关的神经学特征。本研究已在ClinicalTrials.gov注册，注册号为NCT02624817。90名患者被确定为符合纳入条件，81名患者被纳入研究，并提供了长期（5.5年截止）结局数据。整个队列的中位随访时间为10.2年（IQR为9.3 - 10.8）。在最近的随访中（2012年12月1日至2016年10月4日），81名参与者中有75名（93%）仍然单独使用磺脲类药物治疗。我们在所有时间点（即转移前[HbA1c]，第1年和最近随访；n=64）对HbA1c和磺脲类药物的患者保持了良好的血糖控制-转移到磺脲类药物前的中位HbA1c为8.1% (IQR为7.2 - 9.2;65.0 mmol/mol[55.2 - 77.1])， 1年的中位HbA1c为5.9% （5.4 - 6 . 5;41.0 mmol/mol [35.5 - 47.5]; p< 0.0001与转移前相比），6.4% (5.9 - 7.3;46.4 mmol/mol [41.0 - 56.3])；在最近的随访中（中位10.3年[IQR 9.2 - 10.9]）， p< 0.0001（与第1年相比）。在同一患者中，1年时磺脲类药物的中位剂量为0.30 mg/kg /天（0.14 - 0.53），最近一次随访时为0.23 mg/kg /天（0.12 - 0.41;p= 0.03）。在整个队列（n=81） 809患者年的随访中，没有记录到严重低血糖的报告。11例（14%）患者报告轻微、短暂的副作用，但不需要停止磺脲类药物治疗。7例（9%）患者有微血管并发症；这些患者使用胰岛素的时间比无并发症的患者更长（转入磺脲类药物时的中位年龄为20.5年[IQR 10.5 - 24.0] vs 4.1年[IQR 1.3 - 10.2]; p= 0.0005）。38例具有中枢神经系统特征的患者中有18例（47%）转移到磺脲类药物后出现初步改善。经磺脲类药物长期治疗后，81例患者中有52例（64%）出现中枢神经系统特征。从诊断为KCNJ11型新生儿永久性糖尿病开始，大剂量磺脲类药物是合适的治疗方法。该疗法安全有效，可维持良好的血糖控制至少10年。威康信托基金、英国糖尿病协会、皇家学会、欧洲研究理事会、挪威研究理事会、克里斯蒂安·格哈德·捷成基金会、西挪威地区卫生局、南挪威和东挪威地区卫生局、意大利卫生部、青年糖尿病援助机构、法语糖尿病协会、Ipsen、斯洛伐克研究与发展署以及由欧洲区域发展基金资助的研究与发展业务方案。
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. 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. 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. 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. 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.