TREATMENT OPTIONS FOR TYPE 2 DIABETES IN ADOLESCENTS AND YOUTH (TODAY)

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在过去的十年里，儿童2型糖尿病的发病率急剧上升。起病越早，病程越长，这些儿童的医疗费用就越高；他们的并发症也可能比中年确诊的患者更多。对于儿童2型糖尿病维持正常血糖和预防并发症的最佳治疗方法，发表的经验很少。这项试验将确定3种治疗方法中哪一种在维持血糖控制方面最有效。虽然试验的时间不足以评估这三组患者的并发症是否有显著差异，但将测量与并发症相关的替代标记物(例如，血脂、C反应蛋白、微量蛋白尿)。 这是一项前瞻性、部分双盲、随机的临床试验，有3个治疗分支：单独使用二甲双胍，二甲双胍加强化生活方式治疗(行为矫正计划)。主要终点是连续6个月或6个月以上定义为血红蛋白A1c或=8%的失败时间。在2-6个月的跑步期间，受试者每隔1-4周就会出现一次。在随机抽样后，第一年每2个月看一次受试者，随后几年每3个月看一次。此外，生活方式组的受试者将在前6个月每周见一次PAL(体力活动和营养主管)，在后6个月每2周见一次，此后每月见一次。终点测量将在随机、6个月、24个月和研究结束时进行。 接受二甲双胍和罗格列酮联合治疗的患者，与单用二甲双胍的患者相比，他们的初步治疗失败的时间更晚。失败的定义是血红蛋白A1C8%持续6个月。 接受二甲双胍加密集生活方式改变的患者将比单用二甲双胍治疗的患者失败得晚。 具体目标 今天试验的主要目标是比较基于血糖控制的三种治疗方案的及时疗效和治疗失败情况。次要目的是：比较和评估三种治疗方法的安全性；比较三种治疗方法在β细胞功能和胰岛素抵抗、身体成分、营养、体力活动和有氧健身、心血管危险因素、微血管并发症、生活质量和心理结果等方面对T2 DM病理生理学的影响；评估个人和家庭行为对治疗反应的影响；比较三种治疗方法的相对成本效益。 2型糖尿病(T2 DM)在世界各地的许多民族以及不同社会和经济背景的人中急剧增加。在过去的十年里，患有2型糖尿病的儿童和青年人数的增加被贴上了“流行病”的标签。在20世纪90年代S之前，大多数儿科中心很少有T2 DM患者。到1994年，T2 DM患者占城市儿童糖尿病新发病例的16%，到1999年，因地理位置不同，T2 DM新发病例的百分比范围在8%-45%之间，并且在少数民族人群中占多数。 儿童和青少年的T2 DM，就像成人一样，是由于胰岛素抵抗和相对的β细胞疾病的组合。似乎有许多遗传和环境风险因素导致胰岛素抵抗和有限的β细胞储备。儿童2型糖尿病的流行与超重或有超重风险的儿童数量的增加和青少年体力活动模式的减少是一致的。T2 DM与青春期的开始、T2 DM阳性家族史以及代谢综合征的元素，如黑棘皮病和多囊卵巢综合征(PCOS)有很强的相关性。 尽管儿童人群中T2 DM的病例数量急剧增加，但还没有发表大规模的研究来调查这些疾病在儿童和青年中的病理生理学、治疗和并发症。与T2 DM相关的长期并发症和成本使此类研究势在必行。1997至2002年间，糖尿病在直接医疗费用中的估计费用从440亿美元增加到920亿美元，总费用从980亿美元增加到1320亿美元。绝大多数资金都花在了这种疾病的长期并发症上。由于长期的微血管和心血管并发症与糖尿病病程和血糖控制有关，可以推测，越来越多的儿童和青年被诊断为T2 DM，如果得不到有效的治疗，可能会在接下来的几十年里极大地增加这种疾病的经济负担。 之所以选择这项研究的药物疗法，包括单独使用二甲双胍和二甲双胍与罗格列酮联合使用，是因为二甲双胍在儿科得到批准，而且从理论上讲，这两种药物都可以改善胰岛素敏感性。没有选择更多的代理人，因为可供招募的患者估计数量不会支持有三个以上武器的试验。由于T2 DM在儿童和青年中的流行相对较新，关于在儿童T2 DM患者中使用生活方式改变来改善胰岛素敏感性和血糖控制、导致体重损失或影响其他预后指标，如血脂异常和高血压，几乎没有可控证据。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The incidence of type 2 diabetes in children has increased dramatically in the past decade. With earlier onset and thus longer duration of disease these children will have increased health care costs; they may also have more complications than someone diagnosed in middle age. There is little published experience on the best treatment to maintain normal glycemia and prevent complications in children with type 2 diabetes. This trial will determine which of 3 treatments is most effective in maintaining glycemic control. Although the trial will not be long enough to assess if there is a significant difference in complications between these 3 arms, surrogate markers associated with complications will be measured (e.g., lipid profile, C-reactive protein, microalbuminuria). This is a prospective, partially double-blinded, randomized clinical trial with 3 treatment arms: metformin alone, metformin plus intensive lifestyle treatment (behavior modification program). The primary endpoint is time to failure defined as hemoglobin A1c or =8% for 6 or more consecutive months. Subjects will be seen every 1 to 4 weeks during the 2-6 months of the runnin. After randomization, subjects will be seen every 2 months in the first year and every 3 months in subsequent years. In addition, subjects in the lifestyle arm will meet with a PAL (physical activity and nutrition leader) once a week for the first 6 months, every 2 weeks in the 2nd 6 months and monthly thereafter. Endpoint measurements will be done at randomization, 6 months, 24 months and end of study. Patients treated with metformin plus rosiglitizone will fail their primary therapy later than those on metformin alone. Failure is defined as Hemoglobin A1c8% for 6 months. Patients treated with metformin plus intensive lifestyle modification will fail later than those on metformin alone. SPECIFIC AIMS The primary objective of the TODAY trial is to compare the efficacy of the three treatment arms on time to treatment failure based on glycemic control. The secondary aims are to: compare and evaluate the safety of the three treatment arms; compae the effects of the three treatments on the pathophysiology of T2DM with regards to beta cell function and insulin resistance, body composition, nutrition, physical activity and aerobic fitness, cardiovascular risk factors, microvascular complications, quality of life, and psychological outcomes; evaluate the influence of individual and family behaviors on treatment response; and compare the relative cost effectiveness of the three treatment arms. Type 2 Diabetes Mellitus (T2DM) has dramatically increased throughout the world in many ethnic groups and among people with diverse social and economic backgrounds. Over the last decade, the increase in the number of children and youth with T2DM has been labeled an "epidemic". Before the 1990's, it was rare for most pediatric centers to have patients with T2DM. By 1994, T2DM patients represented up to 16% of new cases of diabetes in children in urban areas, and by 1999, depending on geographic location, the range of percent of new cases due to T2DM was between 8-45% and disprpoortionately represented in minority populations. T2DM in children and youth, as in adults, is due to the combination of insulin resistance and relative beta cell ailure. It appears that there are a host of genetic and environmental risk factors for insulin resistance and limited beta cell reserve. The epidemic of pediatricT2DM is coincident with the rise in the number of children who are overweight or at risk for overweight and with a decrease in the physical activity pattern of youth. There has been a strong association between T2DM and the onset of puberty, a positive family history of T2DM, and elelements of the metabolic syndrome such as acanthosis nigricans and polycystic ovarian syndrome (PCOS). Despite the dramatic increase in the number of cases of T2DM in pediatric populations, there have been no published large-scale studies investigating the pathophysiology, treatment, and complications of these disorders in children and youth. The long-term complications and costs associated with T2DM make such studies imperative. Between 1997 and 2002, the estimated cost of diabetes with regard to direct medical cost increased from $44 billion to $92 billion, and the total cost icnreased from $98 billion to $132 billion. The vast majority of monies are spent on the long-term complications of this disorder. Since the long-term microvascular and cardiovascular complications relate to duration of diabetes and to control of glycemia, it could be hypothesized that the increasing number of children and youth diagnosed with T2DM, if not effectively treated, could dramatically add to the economic burden of this disease over the ensuing decades. The pharmacologic therapies for this study, which include using metformin alone and metformin in combination with rosiglitazone, were chosen because metformin is approved in pediatrics and because theoretically both of these agents improve insulin sensitivity. Additional agents were not chosen because the estimated number of patients available for recruitment would not support a trial with more than three arms. As the epidemic of T2DM in children and youth is relatively recent, there is little controlled evidence regarding the use of lifestyle modification to improve insulin sensitivity and glycemic control, induce wieght loss, or affect other outcome measures, such as dyslipideia and hypertension, in pediatric patients with T2DM.