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：诊断患有糖尿病的人最初被建议改变生活方式，并开始 二甲双胍，但通常需要添加二线抗高血糖药物。 2号线的选择 抗高血糖治疗很复杂，因为多种可用药物分布在多种药物中 类别，有不同的好处和风险。较新的二线抗高血糖药（钠-葡萄糖协同转运蛋白-2 抑制剂（SGLT2i）和胰高血糖素样肽-1受体激动剂（GLP1））已被证明可以降低风险 与安慰剂相比，心血管疾病高风险个体的心血管事件。证据还 表明这些新药物可能会降低肾脏相对保存完好的人患肾脏疾病的风险 功能。与旧药物相比，新药物是否对心血管和肾脏结局有益 （成本较低）二线药物，包括二肽基肽酶 4 抑制剂 (DPP4) 和磺酰脲类药物，以及是否 这些益处延伸至心血管风险中度或低度的个人以及心血管风险较低的人 肾功能未知。 意义/影响：结果将提供真实世界的证据来指导抗高血糖药物的选择 药物的心血管风险状况、肾功能类别，并将提供不良风险的证据 事件。该提案属于多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（利用大数据推进 照顾退伍军人）；和研发办公室的优先事项，因为我们的方法将突出 VA 数据 作为国家资源，其结果将对现实世界的护理信息产生直接和重大的影响。 创新：该提案将利用 VA 大规模电子健康记录和最近的技术的力量 因果推理和药物流行病学方面的方法创新——特别是在使用真实的 世界观察数据来模拟目标随机试验——提供急需的证据 新旧抗高血糖药物的有效性和安全性比较。 具体目标：使用退伍军人事务部的观察医疗数据来模拟四个- 随机试验，比较新版本（SGLT2i、GLP1）和旧版本的事件使用的有效性 （DPP4，磺酰脲类）二线抗高血糖药（二甲双胍使用者中）对心血管的影响 结局（目标 1）、肾脏结局（目标 2），并评估与这些相关的不良事件的风险 药物类别（目标 3）。 方法：对于每个具体目标，我们将定义目标随机试验方案，包括资格 标准、治疗分配、治疗开始、治疗策略随访、结果评估和 分析计划。然后，我们将使用 VA 的电子病历数据构建特定目标的队列，以 模拟相关目标的目标试验的规范，估计风险差异 心血管疾病、肾脏疾病以及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加权的逆概率来模拟 和高维变量选择算法。将使用离散的方法来估计意向治疗效果 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 后续行动。 （特定治疗策略的）每个方案的效果将在考虑非因素后进行估计 遵守指定的治疗策略。二线治疗之间结果风险的差异 抗高血糖药物将报告为风险比和调整后的发病率。 实施/后续步骤：该提案的结果将为临床实践指南提供信息 治疗糖尿病。未来的研究将利用机器学习的进步来创造独特的 为每个糖尿病患者制定个性化的精准护理计划。