CHANGING THE NATURAL HISTORY OF TYPE 2 DIABETES – “CHANGE” STUDY

我们将检验这一假设，即2型糖尿病(DM)典型的高血糖恶化将 与平时的护理相比，通过保持正常的血糖来减少。 高血糖的进展是由β细胞功能丧失所介导的，这种功能将被以下物质缓解 使血糖正常化，减少导致β-细胞去分化和凋亡的“兴奋性毒性”。在多个 研究发现，当生活方式改变或用药减缓了从前期糖尿病到糖尿病的进展时，在 干预结束-累积DM仍然低于对照组，与自然 历史。无论机制如何，达到正常血糖都是有益的：在糖尿病预防中 计划(DPP)，只有一次达到正常血糖水平的糖尿病前期受试者，在DPP中DM减少56% 结果研究(DPPOS)-在生活方式改变、二甲双胍和对照组中相似。 这项研究将是新颖的，但方法将很容易转化为实践：1)以正常为目标 葡萄糖，而不是测试Rx或机制。2)在自然历史早期就开始，允许使用Rx 低血糖的风险非常低。3)目标是早期DM而不是前DM，使用已获FDA批准的处方 对于DM。4)用加速阶梯强化的Rx维持正常的血糖。 目的：评估疗效大小、β细胞功能、视网膜病变、肾病、慢性粒细胞白血病和成本-效果。 方法：我们将研究126名成人，每组1/3的早期糖尿病(A1C6.0-6.9%，无Rx；A1C6.0-6.9% 关于二甲双胍；A1c 7.0-7.4%，关于二甲双胍)。经过两周的磨合[建立对二甲双胍的耐受性(如果不是 已经)，并坚持自我监测血糖(SMBG)]，所有受试者都将有生活方式 更换支持；每3个月进行一次HbA1c和持续血糖监测(CGM)；并按1：1随机分配，至 强化处方：如果SMBG水平达到目标(餐前100毫克/分升，餐后130次，每周共7次测试)，则添加处方 ≥后每周至少3次，连续2周，每个处方最大耐受量为4周：二甲双胍 (如果不在基线上)+TZD吡格列酮+GLP-1 RA半胱氨酸+SGLT2埃帕利福秦+甘精U300 胰岛素；或对照处方：按相同顺序，以A1c为基础，每3个月一次：二甲双胍如果≥为7.0%，其他处方如果≥为7.5%。 结果：在2.5年内，加上3个月的淘汰，我们将量化i)效应大小-差异 和(Ii)β细胞功能，主要使用3小时OGTT，建模为 在上升，因为洗涤后密集的Rx与控制的趋势可能表明β-细胞功能是否可能 要持续下去。我们还将探讨(Iii)视网膜病变(通过眼底照片的盲法分级)；(Iv)肾病 (V)是否可以用14天的CGM代替SMBG来确定 需要增加另一个处方(因为CGM在初级保健中可能更容易使用)，以及(Vi)成本效益。 影响：积极的研究将导致医疗实践的改变，因为早期诊断和正常化 葡萄糖应该会产生长期的好处，包括减少糖尿病并发症、死亡率和成本。

We will test the hypothesis that the typical worsening of hyperglycemia in type 2 diabetes (DM) will be reduced by keeping glucose normal compared to usual care. Progression of hyperglycemia is mediated by loss of β-cell function, which will be mitigated by normalizing glucose, reducing the “excitotoxicity” leading to β-cell dedifferentiation and apoptosis. In multiple studies, when lifestyle change or Rx reduced progression from PreDM to DM, there was no “catch-up” after the interventions ended – cumulative DM remained less than in controls, consistent with a change in the natural history. Reaching normal glucose is beneficial regardless of the mechanism: in the Diabetes Prevention Program (DPP), PreDM subjects who achieved normal glucose levels only once, had 56% less DM in the DPP Outcomes Study (DPPOS) – similar in lifestyle change, metformin, and control groups. This study will be novel, but the approach will be easy to translate into practice: 1) Aim for normal glucose, instead of testing an Rx or mechanisms. 2) Start early in the natural history, allowing use of Rx with a very low risk of hypoglycemia. 3) Target early DM instead of PreDM, using Rx already FDA approved for DM. 4) Use accelerated stepped intensification of Rx to keep glucose normal with intensive Rx. Aims: assess effect size, β-cell function, retinopathy, nephropathy, CGM, and cost-effectiveness. Methods: We will study 126 adults, 1/3 each in 3 groups of early DM (A1c 6.0-6.9%, no Rx; A1c 6.0-6.9% on metformin; A1c 7.0-7.4%, on metformin). After a 2-week run-in [to establish tolerance to metformin (if not on it already), and adherence to self monitoring of blood glucose (SMBG)], all subjects will have lifestyle change support; HbA1c and continuous glucose monitoring (CGM) every 3 months; and be randomized 1:1, to intensive Rx: adding Rx if SMBG levels are > goal (<100 mg/dl premeal, <130 postmeal, total 7 tests/week) at least 3x/week for 2 weeks in a row after ≥4 weeks of maximum tolerated dosage (MTD) of each Rx: metformin (if not on it at baseline) + TZD pioglitazone + GLP-1 RA semaglutide + SGLT2 empagliflozin + glargine U300 insulin; or control Rx: in the same order, based on A1c every 3 months: metformin if ≥7.0%, other Rx if ≥7.5%. Outcomes: Over 2.5 years, plus a 3-month washout, we will quantitate i) effect size – differences in HbA1c with intensive Rx vs. controls; and (ii) β-cell function, primarily using 3-hour OGTTs with modeling as in RISE, since trends with intensive Rx vs. controls post-washout may indicate whether β-cell function is likely to be sustained. We will also explore (iii) retinopathy (by blinded grading of fundus photos); (iv) nephropathy (microalbuminuria and eGFR); (v) whether 14 days of CGM could be substituted for SMBG in identifying the need to add another Rx (since CGM might be easier to use in primary care), and (vi) cost-effectiveness. Impact: A positive study will lead to a change in medical practice, since early diagnosis and normalizing glucose should produce longterm benefits, including reduced diabetes complications, mortality, and costs.