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

我们将检验以下假设：2型糖尿病（DM）中典型的高血糖恶化将 与常规护理相比，通过保持葡萄糖正常来降低血糖。 高血糖症的进展是由β细胞功能丧失介导的，这将通过以下方式缓解： 使葡萄糖正常化，减少导致β细胞去分化和凋亡的"兴奋性毒性"。在多个 研究中，当生活方式改变或Rx减少从PreDM到DM的进展时， 干预结束后-累积DM仍然低于对照组，与自然DM的变化一致。 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 在DPP计划中，仅一次达到正常血糖水平的PreDM受试者的DM减少了56%。 结果研究（DPPOS）-生活方式改变、二甲双胍和对照组相似。 这项研究将是新颖的，但方法将很容易转化为实践：1）目标是正常的 葡萄糖，而不是测试Rx或机制。2)在自然史早期开始，允许使用Rx 低血糖的风险很低3)针对早期DM而非PreDM，使用已获FDA批准的Rx 对于DM。4)使用加速阶梯强化处方，以保持血糖正常。 目的：评估效应量、β细胞功能、视网膜病变、肾病、CGM和成本效益。 方法：126例成人，分为3组，每组各占1/3（A1c 6.0 - 6.9%，无Rx; A1c 6.0 - 6.9% 二甲双胍; A1c 7.0 - 7.4%，二甲双胍）。2周导入期后[以确定对二甲双胍的耐受性（如果不耐受 已经使用），并坚持自我血糖监测（SMBG）]，所有受试者将接受生活方式 变更支持;每3个月进行一次HbA1c和动态血糖监测（CGM）;并以1：1的比例随机分配至 强化Rx：如果SMBG水平>目标（餐前<100 mg/dl，餐后<130 mg/dl，每周共7次检测），则添加Rx， 每种Rx：二甲双胍最大耐受剂量（MTD）≥ 4周后，每周至少3次，连续2周 (if基线时未使用）+TZD吡格列酮+GLP-1 RA Semaglutide + SGLT 2恩格列净+甘精胰岛素U300 胰岛素;或对照Rx：以相同顺序，基于A1c每3个月一次：如果≥ 7.0%，则为二甲双胍，如果≥ 7.5%，则为其他Rx。 结果：超过2.5年，加上3个月的洗脱期，我们将定量i）效应量- 强化Rx组与对照组的HbA1c;（ii）β细胞功能，主要使用3小时OGTT，建模为 在RISE中，由于洗脱后强化Rx vs.对照的趋势可能表明β细胞功能是否可能 维持下去我们还将探讨（iii）视网膜病变（通过眼底照片的盲法分级）;（iv）肾病 （微量白蛋白尿和eGFR）;（v）14天CGM是否可以替代SMBG以确定 需要增加另一种处方（因为CGM可能更容易在初级保健中使用），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 葡萄糖应该产生长期益处，包括降低糖尿病并发症、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.