A Clinical Trial to Prevent New Onset Diabetes After Transplantation

描述(申请人提供)：异基因肾移植后立即，胰腺β细胞团受到四个反调节代谢因素的无情惩罚，即：(1)糖异生手术相关的应激反应；(2)外源性糖皮质激素诱导的外周胰岛素抵抗和肝脏糖异生；(3)钙调神经磷酸酶抑制剂(环孢素A或他克莫司)对胰岛β细胞的直接损伤；(4)由于慢性尿毒症相关厌食的消除而导致的饮食热量负荷增加。由于这种代谢参与，到移植后第一年结束时，45-80%的新肾移植受者(KTRs)将表现出持续的可逆性高血糖，30%将保持慢性受损的葡萄糖耐受，15%-20%将死于移植后新发糖尿病(NODAT)。NODAT是一种2型糖尿病，高达30%的肾移植受者在移植后第三年存活。NODAT与移植后心血管事件的风险增加、更高的医疗保健利用率以及显著劣质的肾移植和患者存活率相关。NODAT的危险因素在很大程度上是不可避免的，因为钙调神经磷酸酶抑制剂是肾移植的主要免疫抑制药物，70%-80%的KTRs最初接受大剂量皮质类固醇治疗，然后进行低剂量维持治疗，改善饮食摄入量是肾移植的理想益处。有证据表明，在2型糖尿病发展的早期阶段，持续高血糖引起的糖毒性状态会导致胰岛β细胞功能的持续下降。最近，通过积极降低高血糖和早期开始胰岛素治疗来保护β细胞，在诱导普通人群中新诊断的2型糖尿病缓解方面显示出希望。我们推测，在肾移植后立即出现糖代谢异常的非糖尿病KDR中，早期使用胰岛素治疗将使随后的随访期间停止抗糖尿病治疗，并将减少NODAT的发生率。我们已经完成了一项概念验证临床试验，在50个KDR的移植后立即使用基础胰岛素。12个月时NODAT的患病率降低了65%。我们现在建议在不同人群的KDR中进行一项安全有效的开放标签、区组随机临床试验，以检验主要假设，即早期使用NPH胰岛素方案将使NODAT的发生率从15%降至10%，而试验组和对照组之间可检测到的低血糖风险没有显著差异。在用O‘Brien-Fleming方法保护一项中期分析后，180 KTRs的样本量有90%的能力在移植后一年检测到NODAT的风险降低30%。这项研究将在密歇根大学卫生系统(n=90)和维也纳医科大学综合医院(n=90)进行。参与者将在24个月的时间内登记，随机化后的最低随访时间为24个月。

DESCRIPTION (provided by applicant): Immediately following allogeneic kidney transplantation, the pancreatic beta-cell mass is relentlessly punished by four counterregulatory metabolic factors namely: (1) gluconeogenic surgery-related stress; (2) exogenous glucocortocoid-induced peripheral insulin resistance and hepatic gluconeogenesis; (3) direct beta-cell injury by the calcineurin inhibitor (cyclosporine or tacrolimus) and; (4) increased dietary caloric load secondary to the abrogation of chronic uremia-related anorexia. Consequent to this metabolic engagement, 45-80% of new kidney transplant recipients (KTRs) will manifest persistent reversible hyperglycemia, 30% will maintain chronic impaired glucose intolerance and 15-20% will succumb to new onset diabetes after transplantation (NODAT) by the end of the first post transplant year. NODAT is a form type 2 diabetes mellitus that afflicts up to 30% of kidney transplant recipients who survive through the third post transplant year. NODAT is associated with increased risk for post transplant cardiovascular events, higher health care utilization and dramatically inferior kidney graft and patient survival. The offending determinants of NODAT are largely unavoidable because calcineurin inhibitors are the mainstay immunosuppressive drug for kidney transplantation, 70-80% of KTRs are treated initially high dose corticosteroid followed by low dose maintenance therapy and improved dietary intake is a desired benefit of kidney transplantation. Evidence shows that the state of glucotoxicity induced by persistent hyperglycemia causes continuous decline in pancreatic beta-cell function during the early period of development of type 2 diabetes mellitus. More recently, protection of beta-cells by aggressive lowering of hyperglycemia with early initiation of insulin therapy has shown promise in inducing remission of newly diagnosed type 2 diabetes mellitus in the general population. We posit that early use of insulin therapy in previously non-diabetic KTRs who exhibit abnormal glucose metabolism immediately after kidney transplantation will enable the discontinuation of anti-diabetic therapy during the subsequent follow-up and will result in a reduced incidence of NODAT. We have completed a proof-of-concept clinical trial, using basal insulin during the immediate post-transplant period in 50 KTRs. The prevalence of NODAT at 12 months was reduced by 65%. We now propose to conduct a safety and efficacy open-label, block-randomized clinical trial in a diverse population of KTRs to test the primary hypothesis that an early NPH insulin regimen will reduce the incidence of NODAT from 15% to 10% without a significant difference in the risk of detectable hypoglycemia between the experimental and the control arms of the study. A sample size of 180 KTRs has a 90% power to detect a 30% risk reduction for NODAT at one-year post transplantation after protecting one interim analysis with the O'Brien-Fleming method. The study would be conducted at the University of Michigan Health System (n=90) and the Medical University of Vienna 'General Hospital' (n=90). Participants will be enrolled over a 24 months period with a minimum follow-up of 24 months post randomization.