Objective To emulate the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial using real world data before its publication. GRADE directly compared second line glucose lowering drugs for their ability to lower glycated hemoglobin A1c (HbA1c). Design Observational study. Setting OptumLabs® Data Warehouse (OLDW), a nationwide claims database in the US, 25 January 2010 to 30 June 2019. Participants Adults with type 2 diabetes and HbA1c 6.8-8.5% while using metformin monotherapy, identified according to the GRADE trial specifications, who also used glimepiride, liraglutide, sitagliptin, or insulin glargine. Main outcome measures The primary outcome was time to HbA1c ≥7.0%. Secondary outcomes were time to HbA1c >7.5%, incident microvascular complications, incident macrovascular complications, adverse events, all cause hospital admissions, and all cause mortality. Propensity scores were estimated using the gradient boosting machine method, and inverse propensity score weighting was used to emulate randomization of the treatment groups, which were then compared using Cox proportional hazards regression. Results 8252 people were identified (19.7% of adults starting the study drugs in OLDW) who met eligibility criteria for the GRADE trial (glimepiride arm=4318, liraglutide arm=690, sitagliptin arm=2993, glargine arm=251). The glargine arm was excluded from analyses owing to small sample size. Median times to HbA1c ≥7.0% were 442 days (95% confidence interval 394 to 480 days) for glimepiride, 764 (741 to not calculable) days for liraglutide, and 427 (380 to 483) days for sitagliptin. Liraglutide was associated with lower risk of reaching HbA1c ≥7.0% compared with glimepiride (hazard ratio 0.57, 95% confidence interval 0.43 to 0.75) and sitagliptin (0.55, 0.41 to 0.73). Results were consistent for the secondary outcome of time to HbA1c >7.5%. No significant differences were observed among treatment groups for the remaining secondary outcomes. Conclusions In this emulation of the GRADE trial, liraglutide was statistically significantly more effective at maintaining glycemic control than glimepiride or sitagliptin when added to metformin monotherapy. Generating timely evidence on medical treatments using real world data as a complement to prospective trials is of value. This study was conducted using deidentified claims data from OptumLabs Data Warehouse. Raw data are not publicly available. The study protocol, code sets, and statistical analysis plan are available online.[40][1] [1]: #ref-40

中文翻译：

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使用真实世界数据模拟 GRADE 试验：回顾性比较有效性研究

目的 在 GRADE（糖尿病中的血糖降低方法：一项比较有效性研究）试验发表之前使用真实世界的数据对其进行模拟。GRADE 直接比较了二线降糖药物降低糖化血红蛋白 A1c (HbA1c) 的能力。设计观察研究。设置 OptumLabs® 数据仓库 (OLDW)，美国的全国性索赔数据库，2010 年 1 月 25 日至 2019 年 6 月 30 日。参与者患有 2 型糖尿病且 HbA1c 为 6.8-8.5%，同时使用二甲双胍单药治疗，根据 GRADE 试验规范确定，谁也使用格列美脲、利拉鲁肽、西格列汀或甘精胰岛素。主要结局指标 主要结局是达到 HbA1c ≥ 7.0% 的时间。次要结果是达到 HbA1c >7.5% 的时间、微血管并发症事件、大血管并发症事件、不良事件、全因住院，全因死亡。使用梯度提升机方法估计倾向得分，并使用逆倾向得分加权来模拟治疗组的随机化，然后使用 Cox 比例风险回归进行比较。结果 确定了 8252 人（占 OLDW 中开始研究药物的成年人的 19.7%）符合 GRADE 试验的资格标准（格列美脲组 = 4318，利拉鲁肽组 = 690，西他列汀组 = 2993，甘精胰岛素组 = 251）。由于样本量小，甘精胰岛素组被排除在分析之外。格列美脲达到 HbA1c ≥ 7.0% 的中位时间为 442 天（95% 置信区间 394 至 480 天），利拉鲁肽为 764（741 至不可计算）天，西格列汀为 427（380 至 483）天。利拉鲁肽与达到 HbA1c ≥ 7 的较低风险相关。0% 与格列美脲（风险比 0.57，95% 置信区间 0.43 至 0.75）和西格列汀（0.55，0.41 至 0.73）相比。结果与达到 HbA1c >7.5% 的次要结果一致。对于其余的次要结果，治疗组之间未观察到显着差异。结论 在这项 GRADE 试验的模拟中，利拉鲁肽与二甲双胍单药治疗相比，在维持血糖控制方面比格列美脲或西格列汀更有效，具有统计学意义。使用真实世界的数据作为对前瞻性试验的补充，及时生成关于医学治疗的证据是有价值的。这项研究是使用来自 OptumLabs 数据仓库的去识别化索赔数据进行的。原始数据不公开。研究方案、代码集和统计分析计划可在线获取。 [40][1] [1]: