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

改变 2 型糖尿病的自然病史 — — — 变化 — 研究

基本信息

批准号：
10298826
负责人：
LAWRENCE S PHILLIPS
金额：
$ 37.95万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298826
关键词：
Adherence Adult Apoptosis Beta Cell Blinded Blood Glucose Blood Glucose Self-Monitoring Body Weight decreased Caring Cell physiology Clinical Complications of Diabetes Mellitus Control Groups Diabetes Mellitus Disease Disease remission Dropout Early Diagnosis Ensure Evaluation Eye FDA approved Fundus Glucose Glycosylated hemoglobin A Goals Hour Hyperglycemia Hypoglycemia Insulin Intervention Intervention Studies Kidney Kidney Diseases Life Style Maintenance Mediating Medical Metformin Methods Microalbuminuria Modeling Natural History Non-Insulin-Dependent Diabetes Mellitus OGTT Outcome Outcome Study Patients Pattern Pharmaceutical Preparations Pioglitazone Prediabetes syndrome Prevention Primary Health Care Randomized Retinal Diseases Risk Running Testing Time Translating Work base cell dedifferentiation cost cost effective cost effectiveness diabetes prevention program dosage excitotoxicity glargine glucagon-like peptide 1 glucose monitor improved lifestyle intervention mortality novel novel strategies preservation prevent treatment arm treatment as usual trend

项目摘要

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.

我们将测试以下假设：2型糖尿病（DM）中高血糖的典型担心会与通常的护理相比，通过保持葡萄糖正常来减少。高血糖的进展是由β细胞功能的丧失介导的，这将通过使葡萄糖归一化，从而降低了“兴奋毒性”，从而导致β细胞去分化和凋亡。在多个研究，当生活方式改变或RX降低了从PERM到DM的发展时，没有“追赶” 干预措施结束了 - 累积DM比对照组少，与自然变化一致历史。无论机制如何，达到正常葡萄糖都是有益的：预防糖尿病计划（DPP），仅达到正常葡萄糖水平的PERPM受试者，DPP中的DM降低了56％结果研究（DPPO） - 生活方式改变，二甲双胍和对照组的相似之处。这项研究将是新颖的，但是该方法将很容易转化为实践：1）正常的目标葡萄糖，而不是测试RX或机制。 2）从自然史开始，允许使用RX 低血糖症的风险非常低。 3）使用已经批准的RX目标早期DM而不是PERDM 对于DM。 4）使用RX加速加速加强，以密集的RX保持葡萄糖正常。目的：评估效果大小，β细胞功能，视网膜病，肾病，CGM和成本效益。方法：我们将研究126名成年人，每组3组的早期DM（A1C 6.0-6.9％，无RX； A1C 6.0-6.9％）中各有1/3 在二甲双胍上； A1C 7.0-7.4％，二甲双胍）。经过2周的磨合后[建立对二甲双胍的耐受性（如果不是）已经），并遵守对血糖的自我监测（SMBG）]，所有受试者都有生活方式更改支持；每3个月HBA1C和连续葡萄糖监测（CGM）；并随机分为1：1，密集的RX：如果SMBG级别为>目标（<100 mg/dl Premeal，<130 poftmeal，总计7个测试/周），则添加RX 每种RX的最大耐受剂量（MTD）≥4周后，至少3倍/周连续2周（如果不在基线处） + TZD吡格列酮 + GLP-1 RA Semaglutide + SGLT2 Empagliflozin + Grargine U300 胰岛素;或控制RX：按照相同的顺序，基于A1C每3个月：二甲双胍，如果≥7.0％，则其他RX如果≥7.5％。结果：超过2。5年，再加上3个月的冲洗，我们将定量i）效果大小 - 差异 HBA1C具有密集的RX与控件；（ii）β细胞函数，主要使用3小时的OGTT和建模为在上升中，由于洗涤后具有密集的RX与控制的趋势可能表明β细胞功能是否可能维持。我们还将探索（III）视网膜病（通过眼底照片的盲评分）；（iv）肾病（微量白蛋白尿和EGFR）；（v）是否可以将14天的CGM替换为SMBG 需要添加另一个RX（因为CGM在初级保健中更容易使用）和（VI）成本效益。影响：一项积极的研究将导致医疗实践发生变化，因为早期诊断和正常化葡萄糖应产生长期益处，包括减少糖尿病并发症，死亡率和成本。