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，并开始 二甲双胍，但通常需要增加二线降血糖药物。二号线的选择 降糖治疗是复杂的，因为多种可用的药物分布在几种药物上 阶级，有不同的好处和风险。新的二线抗高血糖药(钠-葡萄糖共转运体-2 抑制剂(SGLT2i)和胰升糖素样肽-1受体激动剂(GLP1))被证明可以降低糖尿病的风险 心血管疾病高危人群的心血管事件与安慰剂的比较。证据亦包括 提示这些新的药物可以降低肾脏相对保存的人患肾脏疾病的风险。 功能。与较老的药物相比，较新的药物是否对心血管和肾脏结果有好处 (成本较低)二线药物，包括二肽基肽酶-4抑制剂(DPP4)和磺脲类药物，以及是否 这些好处适用于心血管风险中等或较低的人和心血管风险较低的人。 肾功能尚不清楚。 意义/影响：研究结果将为指导抗高血糖药物的选择提供实际证据 药物按心血管危险状态、肾功能类别分类，并将提供有关不良风险的证据 事件。该提案属于几个卫生服务研究的优先事项，包括初级保健 实践(糖尿病在退伍军人中高度流行)和医疗保健信息学(使用大数据推动 照顾退伍军人)；以及研究和发展办公室的优先事项，因为我们的方法将突出退伍军人数据 作为一项国家资源，其结果将在告知护理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大规模电子健康记录和最近 因果推断和药物流行病学的方法学创新--特别是在实际应用方面。 模拟目标随机试验的世界观测数据-提供急需的证据 比较新的和旧的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数据来模拟四个- 事件中使用较新药物(SGLT2i，GLP1)和较旧药物的有效性比较的ARM随机试验 (DPP4，磺脲类)二线抗高血糖药--在二甲双胍使用者中--关于心血管 结果(目标1)、肾脏结果(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)。 方法学：对于每个特定的目标，我们将定义一个目标随机试验方案，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，我们将使用退伍军人管理局的电子病历数据来构建针对特定目标的队列，以 为相关目标模拟目标试验的规范，估计风险差异 研究对象之间的心血管疾病、肾脏疾病和不良事件。 随机化将通过基于预定义变量的治疗权重的逆概率来模拟 和高维变量选择算法。意向治疗效果的估计将使用离散的 时间生存分析和调整后的意向治疗效果将在核算损失后进行估计。 后续行动。每个方案的效果(特定治疗策略)将在考虑到非 坚持指定的治疗策略。二线之间结果风险的差异 抗高血糖药物将作为危险比和调整后的发病率报告。 实施/下一步：这项提案的结果将为临床实践指南提供参考 糖尿病的治疗。未来的研究将利用机器学习的进步来创建独特的 为每位糖尿病患者提供个性化的精准护理计划。