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：
10619451
负责人：
LAWRENCE S PHILLIPS
金额：
$ 30.06万
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/10619451
关键词：
Acceleration Adherence Adult Apoptosis Beta Cell Blinded Blood Glucose Blood Glucose Self-Monitoring Body Weight decreased Caring Cell physiology Clinical Complications of Diabetes Mellitus Continuous Glucose Monitor 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 Care Randomized Retinal Diseases Risk Running Testing Time Translating Work cell dedifferentiation cost cost effective cost effectiveness diabetes prevention program dosage excitotoxicity glargine glucagon-like peptide 1 improved lifestyle intervention mortality novel preservation prevent progression risk 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.

我们将检验以下假设：2 型糖尿病 (DM) 中典型的高血糖恶化会导致与常规护理相比，通过保持血糖正常来减少。高血糖的进展是由 β 细胞功能丧失介导的，可通过以下方法缓解：使葡萄糖正常化，减少导致β细胞去分化和凋亡的“兴奋毒性”。研究表明，当生活方式改变或 Rx 减少从 PreDM 到 DM 的进展时，治疗后没有“追赶” 结束 – 累积 DM 仍然低于对照，与自然的变化一致无论机制如何，达到正常血糖水平都是有益的：在糖尿病预防中。计划 (DPP)，仅一次达到正常血糖水平的 PreDM 受试者，DPP 中的 DM 减少 56% 结果研究 (DPPOS) – 生活方式改变、二甲双胍和对照组相似。这项研究很新颖，但该方法很容易转化为实践：1）以正常为目标葡萄糖，而不是测试 Rx 或机制 2) 在自然史早期开始，允许使用 Rx。 3）针对早期 DM 而不是 PreDM，使用 FDA 批准的 Rx。 4) 使用加速逐步强化 Rx 来通过强化 Rx 保持血糖正常。目的：评估效应大小、β 细胞功能、视网膜病变、肾病、CGM 和成本效益。方法：我们将研究 126 名成人，其中 1/3 分为 3 组早期 DM（A1c 6.0-6.9%，无 Rx；A1c 6.0-6.9%）服用二甲双胍；A1c 7.0-7.4%，服用二甲双胍 2 周磨合后[建立对二甲双胍的耐受性（如果没有）。已经在上面了），并坚持自我监测血糖（SMBG）]，所有受试者都将有生活方式每 3 个月更换一次 HbA1c 和连续血糖监测 (CGM)，并按 1:1 进行随机分配；强化 Rx：如果 SMBG 水平 > 目标（餐前 <100 mg/dl，餐后 <130 mg/dl，总共 7 次测试/周），则添加 Rx 每次服用二甲双胍的最大耐受剂量 (MTD) ≥4 周后，每周至少 3 次，连续 2 周（如果基线时未使用）+ TZD 吡格列酮 + GLP-1 RA 索马鲁肽 + SGLT2 恩格列净 + 甘精胰岛素 U300 胰岛素；或对照 Rx：按照相同顺序，每 3 个月基于 A1c：二甲双胍（如果≥7.0%），其他 Rx（如果≥7.5%）。结果：在 2.5 年的时间里，加上 3 个月的清除期，我们将量化 i) 效应大小 – 差异强化 Rx 与对照组的 HbA1c 对比；以及 (ii) β 细胞功能，主要使用 3 小时 OGTT，建模如下在 RISE 中，因为清洗后强化 Rx 与对照的趋势可能表明 β 细胞功能是否可能我们还将探讨（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 天的 CGM 是否可以替代 SMBG 来确定需要添加另一种处方（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：一项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效益，包括减少糖尿病并发症、死亡率和费用。