Comparative Safety of Non-Insulin Agents in Pregnant Women with Pregestational Diabetes

非胰岛素药物治疗妊娠期糖尿病孕妇的安全性比较

• 批准号: 10620228
• 负责人: Sonia Hernandez-Diaz
• 金额: $ 56.22万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620228
• 关键词: Adherence; Adjuvant; Admission activity; Adverse event; American; Antidiabetic Drugs; Benefits and Risks; Calibration; Cardiovascular system; Central Nervous System; Cesarean section; Characteristics; Clinical; Clinical Trials; Computerized Medical Record; Confidence Intervals; Congenital Abnormality; Data; Databases; Defect; Diabetes Mellitus; Diagnosis; Diet; Discipline of obstetrics; Dose; Drug Exposure; Dystocia; Ensure; Equilibrium; Exclusion; Exercise; Exposure to; Fetal safety; First Pregnancy Trimester; General Population; Glucose; Glycosylated hemoglobin A; Guidelines; Gynecology; Health; Healthcare; Hyperbilirubinemia; Hypoglycemia; Induced Labor; Infant; Injections; Insulin; Laboratories; Late pregnancy; Life; Linear Models; Link; Medicaid; Metformin; Neonatal Hypoglycemia; New Agents; Non-Insulin-Dependent Diabetes Mellitus; Observational Study; Oral; Organogenesis; Outcome; Outpatients; Patients; Pattern; Pharmaceutical Preparations; Pharmacy facility; Planned Pregnancy; Polyhydramnios; Population; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnancy in Diabetics; Pregnant Women; Premature Birth; Procedures; Randomized, Controlled Trials; Recommendation; Records; Relative Risks; Research; Research Design; Research Personnel; Respiratory distress; Risk; Safety; Sample Size; Severities; Shoulder; Small for Gestational Age Infant; Stratification; Sulfonylurea Compounds; Surveys; Testing; Therapeutic; Time; Time trend; United States; United States Food and Drug Administration; Woman; Work; active comparator; adverse outcome; adverse pregnancy outcome; blood glucose regulation; clinical practice; cohort; college; comparative; comparative safety; comparison group; diabetes control; diabetic; early pregnancy; evidence base; fetal; glycemic control; health care service utilization; improved; innovation; malformation; maternal risk; maternal safety; medical complication; neonatal outcome; novel; population based; pregnant; prenatal; subcutaneous; treatment guidelines; treatment strategy; unintended pregnancy

In the general population, non-insulin agents have gained wide acceptance for the treatment of type 2 diabetes, given their efficacy and tolerability when compared to subcutaneous insulin injections. One of the most common medical complications in pregnancy is pre-gestational diabetes and its management currently focuses on achieving glucose control with diet, exercise and, if needed, insulin treatment. Both the American Diabetes Association and the College of Obstetrics and Gynecology recommend to women planning pregnancy and for those who are pregnant that oral antidiabetic agents be substituted with insulin therapy until further data regarding safety become available. However, pregnant women are commonly exposed to these agents because 1) guidelines are not universally followed, 2) some women refuse to use insulin, and 3) 50% of pregnancies are unplanned and if a woman is already using an oral agent there is no time to switch to insulin before organogenesis. Furthermore, in pregnancy, oral agents have potential benefits with respect to patient acceptability and adherence, and therefore improved glycemic control and pregnancy outcomes. Even for those patients for whom oral antidiabetic agents alone are inadequate to achieve glycemic control, they can be used to reduce insulin dose. Since randomized controlled trials in pregnancy with sufficient sample size to define the safety of these agents robustly are not realistic, we need timely information based on carefully conducted observational studies. Until then, the lack of information will continue to be a critical barrier to their use in pregnancy. Our primary objective is to quantify the risk of maternal and fetal adverse events associated with specific non-insulin antidiabetic therapies during pregnancy in comparison to insulin alone and metformin alone. We have established a cohort of 3 million pregnancies linked to infants with longitudinal information on prescriptions and clinical conditions within two population-based healthcare databases: the Medicaid Analytic eXtract (MAX) and Truven Health MarketScan (Truven). This study will identify cohorts of over 18,000 (MAX) and 15,000 (Truven) women with pre-gestational type 2 diabetes who delivered in 2000-2018. Drug exposure will be determined based on pharmacy dispensing records, and outcomes will be based on in- and outpatient diagnoses and procedures, using validated definitions. To control for diabetes severity and other confounders, we will (i) restrict the population to women with type 2 diabetes; (ii) use an active reference group; (iii) use propensity score stratification to balance aspects of diabetes severity; and (iv) use a novel propensity score calibration approach to further adjust by incorporating data on glycemic control from subsamples with either laboratory records or linked electronic medical records. Data from nationally-representative surveys will be used to ensure generalizability to the US population. Generalized linear models will estimate relative risks and their 95% confidence intervals. Sensitivity analyses will be conducted to test the robustness of the findings. Prior work by the investigators and pilot data support the feasibility of the proposed study.

在一般人群中，非胰岛素药物已获得2型糖尿病治疗的广泛接受， 鉴于与皮下胰岛素注射相比，它们的功效和耐受性。最常见的 怀孕的医疗并发症是妊娠前糖尿病，目前的管理重点是 通过饮食，运动以及需要（如果需要）胰岛素治疗来控制葡萄糖。两种美国糖尿病 协会和妇产科学院向计划怀孕的妇女建议 那些怀孕的人用胰岛素治疗代替口服抗糖尿病药物直到进一步数据 关于安全可用。但是，孕妇通常会接触到这些药物，因为 1）不普遍遵守指南，2）一些妇女拒绝使用胰岛素，3）50％的怀孕是 计划外，如果女人已经在使用口服剂，则没有时间切换到胰岛素 器官发生。此外，在怀孕中，口服剂在患者方面有潜在的好处 可接受性和依从性，因此改善了血糖控制和妊娠结局。即使是那些 单独口服抗糖尿病药物的患者无法实现血糖控制，可以使用它们 减少胰岛素剂量。由于怀孕中的随机对照试验具有足够的样本量来定义 这些代理的安全性不现实，我们需要根据精心进行的及时信息 观察性研究。在此之前，缺乏信息将继续是其使用的关键障碍 怀孕。我们的主要目的是量化与孕产妇和胎儿不良事件相关的风险 与单独的胰岛素和单独的二甲双胍相比，特定的非胰岛素抗糖尿病疗法。 我们已经建立了与婴儿有关的300万怀孕的队列 两个基于人群的医疗保健数据库中的处方和临床状况：医疗补助分析 提取物（Max）和Truven Health MarketScan（Truven）。这项研究将确定超过18,000（最大）的人群 和15,000名（Truven）妇女在2000 - 2018年分娩的2型妊娠2型糖尿病。药物暴露 将根据药房分配记录确定，结果将基于内门诊和门诊 使用经过验证的定义进行诊断和过程。为了控制糖尿病的严重程度和其他混杂因素， 我们将（i）将人口限制为2型糖尿病的女性； （ii）使用一个主动参考组； （iii）使用 倾向评分分层以平衡糖尿病严重程度的各个方面； （iv）使用新颖的倾向分数 校准方法通过合并来自子样本的血糖控制的数据，以进一步调整 实验室记录或链接的电子病历。将使用来自全国代表性调查的数据 确保对美国人口的普遍性。广义线性模型将估计相对风险及其 95％置信区间。将进行灵敏度分析以测试发现的鲁棒性。先前的工作 研究人员和试点数据支持拟议研究的可行性。