Comparative Effectiveness and Safety of Newer and Older Antihyperglycemic Medications

新旧抗高血糖药物的有效性和安全性比较

• 批准号: 10334530
• 负责人: Ziyad Al-Aly
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10334530
• 关键词: Accounting; Acute Renal Failure with Renal Papillary Necrosis; Address; Adverse event; Affect; Age; Agonist; Albumins; Albuminuria; Algorithms; Benefits and Risks; Big Data; Bladder; Body mass index; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular system; Caring; Categories; Cessation of life; Characteristics; Chronic Kidney Failure; Clinical Practice Guideline; Complex; Computerized Medical Record; Creatinine; Data; Diabetes Mellitus; Diabetic Ketoacidosis; Diagnosis; Dipeptidyl Peptidases; Disease Outcome; Disease Progression; Effectiveness; Electronic Health Record; Eligibility Determination; End stage renal failure; Event; Fracture; Future; GLP-I receptor; Glomerular Filtration Rate; Glucose; Health Services Research; Healthcare; Heart Diseases; Heart failure; Hospitalization; Hypertension; Hypoglycemia; Hypoglycemic Agents; Incidence; Individual; Informatics; Intention; Kidney; Kidney Diseases; Knowledge; Life Style; Lower Extremity; Machine Learning; Metformin; Methodology; Methods; Myocardial Infarction; New Agents; Outcome; Outcome Assessment; Patients; Persons; Pharmaceutical Preparations; Pharmacoepidemiology; Placebos; Population; Probability; Protocols documentation; Race; Randomized; Randomized, Controlled Trials; Reducing Agents; Renal function; Reporting; Research Priority; Resources; Risk; Risk Assessment; Risk Estimate; Risk Reduction; Safety; Sodium; Specific qualifier value; Stroke; Subgroup; Sulfonylurea Compounds; Survival Analysis; Time; United States Department of Veterans Affairs; Urinary tract infection; Urine; Veterans; Work; acute pancreatitis; adverse event risk; arm; cardiovascular disorder risk; cardiovascular risk factor; clinical practice; cohort; comparative; comparative effectiveness; comparative effectiveness trial; comparative safety; cost; diabetes mellitus therapy; diabetes risk; discrete time; falls; follow-up; hazard; heart disease risk; high dimensionality; high risk; high risk population; inhibitor; innovation; kidney preservation; limb amputation; mortality; novel therapeutics; personalized care; primary care practice; randomized trial; randomized, clinical trials; research and development; symporter; treatment guidelines; treatment strategy; venous thromboembolism

Background: People diagnosed with diabetes are initially advised on lifestyle changes and started on metformin, but often require the addition of 2nd line antihyperglycemic medications. The choice of 2nd line antihyperglycemic therapy is complex because the multiple available drugs, distributed across several drug classes, have different benefits and risks. Newer 2nd line antihyperglycemics (sodium-glucose co-transporter-2 inhibitor (SGLT2i), and glucagon-like peptide-1 receptor agonist (GLP1)) have been shown to reduce risk of cardiovascular events compared to placebo in individuals at high risk of cardiovascular disease. Evidence also suggests that these newer agents may reduce risk of kidney disease in people with relatively preserved kidney function. Whether the newer agents offer benefits in cardiovascular and kidney outcomes compared to older (less costly) 2nd line agents including dipeptidyl peptidase-4 inhibitors (DPP4) and sulfonylureas, and whether these benefits extend to individuals with intermediate or low cardiovascular risk and people with reduced kidney function is not known. Significance/Impact: Results will provide real-world evidence to guide the selection of antihyperglycemic agents by cardiovascular risk status, kidney function category, and will provide evidence on the risk of adverse events. The proposal falls under several Health Services Research priorities including Primary Care Practice (diabetes is highly prevalent in veterans) and Health Care Informatics (using big data to advance care of veterans); and Office of Research & Development priorities as our approach will highlight VA data as a national resource and the results will have direct and substantial real-world impact in informing care. Innovation: The proposal will leverage the power of the VA’s large-scale electronic health records and recent methodologic innovations in causal inference and pharmacoepidemiology — specifically in the use of real- world observational data to emulate a target randomized trial — to provide much needed evidence of the comparative effectiveness and safety of newer vs. older antihyperglycemic agents. Specific Aims: To use observational healthcare data from the Department of Veterans Affairs to emulate four- arm randomized trials of the comparative effectiveness of incident use of newer (SGLT2i, GLP1) and older (DPP4, sulfonylureas) 2nd line antihyperglycemics—among metformin users—on cardiovascular outcomes (aim 1), kidney outcomes (aim 2), and evaluate the risk of adverse events associated with these drug classes (aim 3). Methodologies: For each specific aim we will define a target randomized trial protocol, including eligibility criteria, treatment assignment, treatment initiation, treatment strategy follow-up, outcome assessment, and analytic plan. We then will use electronic medical record data from the VA to construct aim-specific cohorts to emulate the specifications of the target trial for the related aim, estimating the differences in risk of cardiovascular disease, kidney disease, and adverse events between the studied antihyperglycemics. Randomization will be emulated by inverse probability of treatment weighting based on predefined variables and a high dimensional variable selection algorithm. Intention-to-treat effects will be estimated using discrete time survival analyses, and adjusted intention-to-treat-effects will be estimated after accounting for loss to follow-up. Per-protocol effects (of a specified treatment strategy) will be estimated after accounting for non- adherence to assigned treatment strategies. Differences in risk of outcomes between the second-line antihyperglycemics will be reported as hazard ratios and adjusted incidence rates. Implementation/Next Steps: The results from this proposal will inform clinical practice guidelines for the treatment of diabetes. Future studies will leverage advances in machine learning to create unique individualized precision care plans for each person with diabetes.

背景：被诊断为糖尿病的人最初被建议改变生活方式， 二甲双胍，但通常需要添加二线降糖药物。二线的选择 抗高血糖治疗是复杂的，因为多种可用的药物，分布在几种药物中， 有不同的利益和风险。新型二线降糖药（钠-葡萄糖协同转运蛋白-2 抑制剂（SGLT 2 i）和胰高血糖素样肽-1受体激动剂（GLP 1））已显示可降低 与安慰剂相比，在心血管疾病高风险个体中心血管事件的发生率。证据还 表明这些新的药物可能会降低相对保留肾脏的人患肾脏疾病的风险 功能较新的药物与较旧的药物相比是否在心血管和肾脏结局方面提供益处 (less昂贵的）二线药物，包括二肽基肽酶-4抑制剂（DPP 4）和磺酰脲类药物，以及是否 这些益处延伸到具有中等或低心血管风险的个体以及具有降低的 肾功能尚不清楚。 意义/影响：结果将提供真实世界的证据，以指导抗高血糖药物的选择 根据心血管风险状态、肾功能分类，将提供关于不良反应风险的证据。 事件该提案福尔斯几个卫生服务研究优先事项，包括初级保健 实践（糖尿病在退伍军人中非常普遍）和医疗保健信息学（使用大数据推进 护理退伍军人）;和研究与发展办公室的优先事项，因为我们的方法将突出VA数据 作为一种国家资源，其结果将在为护理提供信息方面产生直接和实质性的现实影响。 创新：该提案将利用退伍军人管理局的大规模电子健康记录的力量， 因果推理和药物流行病学的方法创新-特别是在使用真实的- 世界观察数据，以模拟目标随机试验-提供急需的证据， 比较新型与老式降糖药的有效性和安全性。 具体目标：使用退伍军人事务部的观察性医疗保健数据来模拟四个- 比较新型（SGLT 2 i，GLP 1）和旧型的意外使用有效性的随机对照试验 (DPP4磺脲类）二线降糖药-二甲双胍使用者-心血管 结果（目的1），肾脏结果（目的2），并评估与这些相关的不良事件的风险 毒品类别（目标3）。 方法学：对于每个特定目标，我们将定义一个目标随机试验方案，包括合格性 标准、治疗分配、治疗开始、治疗策略随访、结局评估，以及 分析计划。然后，我们将使用VA的电子病历数据来构建特定目标的队列， 为相关目的模拟目标试验的规格，估计 心血管疾病、肾脏疾病和所研究的降糖药之间的不良事件。 随机化将通过基于预定义变量的治疗权重的逆概率进行模拟 和高维变量选择算法。意向治疗效应将使用离散的 时间生存分析和调整后的意向治疗效果将在考虑损失后进行估计， 随访将在考虑非治疗后估计符合方案效应（特定治疗策略）。 坚持指定的治疗策略。二线治疗之间结局风险的差异 抗高血糖药将报告为风险比和校正的发生率。 实施/后续步骤：本提案的结果将为临床实践指南提供信息， 糖尿病的治疗未来的研究将利用机器学习的进步， 为每个糖尿病患者提供个性化的精准护理计划。