A Clinical Trial to Prevent New Onset Diabetes After Transplantation

描述（申请人提供）：同种异体肾移植后，胰腺β细胞群受到四种反调节代谢因素的无情惩罚，即：(1)糖异生手术相关的应激；(2)外源性糖皮质激素诱导外周胰岛素抵抗和肝脏糖异生；(3)钙调磷酸酶抑制剂（环孢素或他克莫司）直接损伤β细胞；(4)慢性尿毒症相关性厌食症消除后继发的膳食热量负荷增加。由于这种代谢参与，45-80%的新肾移植受者（KTRs）将表现出持续的可逆性高血糖，30%将维持慢性糖耐受性受损，15-20%将在移植后第一年末死于移植后新发糖尿病（NODAT）。NODAT是一种2型糖尿病，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风险增加、较高的医疗保健利用率和明显较差的肾移植和患者生存率相关。由于钙调磷酸酶抑制剂是肾移植的主要免疫抑制药物，因此NODAT的不良决定因素在很大程度上是不可避免的，70-80%的KTRs最初采用高剂量皮质类固醇治疗，然后采用低剂量维持治疗，改善饮食摄入是肾移植的一个期望益处。有证据表明，在2型糖尿病发展早期，持续高血糖诱导的糖毒性状态导致胰腺β细胞功能持续下降。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，在普通人群中诱导新诊断的2型糖尿病缓解方面显示出希望。我们假设，在肾移植后立即出现糖代谢异常的非糖尿病ktr患者早期使用胰岛素治疗，可以在随后的随访中停止抗糖尿病治疗，从而降低NODAT的发生率。我们已经完成了一项概念验证临床试验，在50例ktr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的KTRs人群中进行一项安全性和有效性的开放标签、块随机临床试验，以验证早期NPH胰岛素治疗方案将NODAT发生率从15%降低到10%，而实验组和对照组之间可检测到低血糖的风险没有显著差异的主要假设。在使用O'Brien-Fleming方法进行一次中期分析后，180ktr的样本量有90%的能力检测移植后1年发生NODAT的风险降低30%。该研究将在密歇根大学卫生系统（n=90）和维也纳医科大学“总医院”（n=90）进行。参与者将在24个月的时间内入组，随机分组后至少随访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.