Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients With Type 1 Diabetes: A Randomized Clinical Trial.
Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients With Type 1 Diabetes: A Randomized Clinical Trial.
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DOI：
10.1001/jama.2017.17070
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发表时间：
2017-11-21
期刊：
影响因子：
--
通讯作者：
Greenbaum CJ
中科院分区：
文献类型：
--
作者：
Writing Committee for the Type 1 Diabetes TrialNet Oral Insulin Study Group;Krischer JP;Schatz DA;Bundy B;Skyler JS;Greenbaum CJ
1型糖尿病需要重大的生活方式改变，并会增加发病率和死亡率。预防或延缓糖尿病的发生将产生重大的临床效果。目的：确定口服胰岛素是否能延缓1型糖尿病患者自身抗体阳性亲属的1型糖尿病发病。在2007年3月2日至2015年12月21日期间，加拿大、美国、澳大利亚、新西兰、英国、意大利、瑞典、芬兰和德国登记了至少有两种自身抗体的亲属，包括胰岛素自身抗体和正常的糖耐量。主要研究组(n=389)在静脉葡萄糖耐量试验中有高于阈值的第一时相胰岛素释放。第二层1中的55名患者的抗体谱与主要研究组相同，只是他们的第一时相胰岛素释放低于阈值。第二层(n=114)和第三层(n=3)具有不同的自身抗体谱和第一时相胰岛素释放阈值组合。跟踪调查一直持续到2016年12月31日。随机接受7.5 mg/d的口服胰岛素(n=283)或安慰剂(n=277)，包括主要研究组的参与者接受口服胰岛素(n=203)或安慰剂(n=186)。主要研究组的主要结果是糖尿病发生的时间。显着性基于单侧阈值0.05，报道了单侧95%的CI。在总共560名随机参与者(登记的中位数年龄8.2岁；四分位数范围[IQR]，5.7-12.1岁；170名男孩[60%]；90.7%的非西班牙裔白人；57.6%的兄弟姐妹患有1型糖尿病)中，550人完成了试验，其中包括389名参与者(中位数年龄8.4岁；245名男孩[63%])，382名(96%)在主要研究组。在主要研究组2.7年(IQR，1.5-4.6年)的中位随访期间，口服胰岛素组有58名参与者(28.5%)被诊断为糖尿病，而安慰剂组有62名(33%)被诊断为糖尿病。两组患者发生糖尿病的时间没有显著差异(风险比[HR]为0.87；95%可信区间为0-1.2；P=.21)。在第二层(n=55)，口服胰岛素组有13名参与者(48.1%)被诊断为糖尿病，而安慰剂组有19名参与者(70.3%)被诊断为糖尿病。口服胰岛素组出现糖尿病的时间显著延长(HR，0.45；95%CI，0-0.82；P=0.006)。在其他第二层的116名参与者的组间比较中，患糖尿病的比率为1.03(95%CI，0-2.11；P=.53)，而在整个队列中，560名参与者患糖尿病的比率为0.83(95%CI，0-1.07；P=.11)，两者没有显著差异。最常见的不良事件是感染(n=254)，口服胰岛素组有134例，安慰剂组有120例，但没有发生与研究相关的重大不良事件。在1型糖尿病患者自身抗体阳性的亲属中，与安慰剂相比，口服胰岛素7.5 mg/d并未延缓或阻止1型糖尿病的发展超过2.7年。这些发现不支持口服胰岛素在本研究中用于糖尿病预防。ClinicalTrials.gov标识：NCT00419562
Type 1 diabetes requires major lifestyle changes and carries increased morbidity and mortality. Prevention or delay of diabetes would have major clinical effect. To determine whether oral insulin delays onset of type 1 diabetes in autoantibody-positive relatives of patients with type 1 diabetes. Between March 2, 2007, and December 21, 2015, relatives with at least 2 autoantibodies, including insulin autoantibodies and normal glucose tolerance, were enrolled in Canada, the United States, Australia, New Zealand, the United Kingdom, Italy, Sweden, Finland, and Germany. The main study group (n = 389) had first-phase insulin release on an intravenous glucose tolerance test that was higher than the threshold. The 55 patients in the secondary stratum 1 had an identical antibody profile as the main study group except they had first-phase insulin release that was lower than the threshold. Secondary strata 2 (n = 114) and strata 3 (n = 3) had different autoantibody profiles and first-phase insulin release threshold combinations. Follow-up continued through December 31, 2016. Randomization to receive 7.5mg/d of oral insulin (n = 283) or placebo (n = 277), including participants in the main study group who received oral insulin (n = 203) or placebo (n = 186). The primary outcome was time to diabetes in the main study group. Significance was based on a 1-sided threshold of .05, and 1-sided 95% CIs are reported. Of a total of 560 randomized participants (median enrollment age, 8.2 years; interquartile range [IQR], 5.7–12.1 years; 170 boys [60%]; 90.7% white non-Hispanic; 57.6% with a sibling with type 1 diabetes), 550 completed the trial including 389 participants (median age, 8.4 years; 245 boys [63%]), 382 (96%) in the main study group. During a median follow-up of 2.7 years (IQR, 1.5–4.6 years) in the main study group, diabetes was diagnosed in 58 participants (28.5%) in the oral insulin group and 62 (33%) in the placebo group. Time to diabetes was not significantly different between the 2 groups (hazard ratio [HR], 0.87; 95% CI, 0–1.2; P = .21). In secondary stratum 1 (n = 55), diabetes was diagnosed in 13 participants (48.1%) in the oral insulin group and in 19 participants (70.3%) in the placebo group. The time to diabetes was significantly longer with oral insulin (HR, 0.45; 95%CI, 0–0.82; P = .006). The HR for time to diabetes for the between-group comparisons for the 116 participants in the other secondary stratum was 1.03 (95%CI, 0–2.11; P = .53) and for the entire cohort of 560 participants was 0.83 (95%CI, 0–1.07; P = .11), which were not significantly different. The most common adverse event was infection (n = 254), with 134 events in the oral insulin group and 120 events in the placebo group, but no significant study-related adverse events occurred. Among autoantibody-positive relatives of patients with type 1 diabetes, oral insulin at a dose of 7.5mg/d, compared with placebo, did not delay or prevent the development of type 1 diabetes over 2.7 years. These findings do not support oral insulin as used in this study for diabetes prevention. clinicaltrials.gov Identifier: NCT00419562
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糖尿病的医疗标准 - 2010年。
影响因子：
16.2
作者：
American Diabetes Association
通讯作者：
American Diabetes Association
影响因子：
168.9
作者：
Sherry, Nicole;Hagopian, William;Ludvigsson, Johnny;Jain, Sunil M.;Wahlen, Jack;Ferry, Robert J., Jr.;Bode, Bruce;Aronoff, Stephen;Holland, Christopher;Carlin, David;King, Karen L.;Wilder, Ronald L.;Pillemer, Stanley;Bonvini, Ezio;Johnson, Syd;Stein, Kathryn E.;Koenig, Scott;Herold, Kevan C.;Daifotis, Anastasia G.
通讯作者：
Daifotis, Anastasia G.
影响因子：
15.9
作者：
Herold, KC;Burton, JB;Bluestone, JA
通讯作者：
Bluestone, JA
影响因子：
7.7
作者：
Hagopian, William;Ferry, Robert J., Jr.;Ludvigsson, Johnny
通讯作者：
Ludvigsson, Johnny
影响因子：
120.7
作者：
Bonifacio, Ezio;Ziegler, Anette-G.;Achenbach, Peter
通讯作者：
Achenbach, Peter