Objective To compare the effectiveness of three commonly prescribed oral antidiabetic drugs added to metformin for people with type 2 diabetes mellitus requiring second line treatment in routine clinical practice. Design Cohort study emulating a comparative effectiveness trial (target trial). Setting Linked primary care, hospital, and death data in England, 2015-21. Participants 75 739 adults with type 2 diabetes mellitus who initiated second line oral antidiabetic treatment with a sulfonylurea, DPP-4 inhibitor, or SGLT-2 inhibitor added to metformin. Main outcome measures Primary outcome was absolute change in glycated haemoglobin A1c (HbA1c) between baseline and one year follow-up. Secondary outcomes were change in body mass index (BMI), systolic blood pressure, and estimated glomerular filtration rate (eGFR) at one year and two years, change in HbA1c at two years, and time to ≥40% decline in eGFR, major adverse kidney event, hospital admission for heart failure, major adverse cardiovascular event (MACE), and all cause mortality. Instrumental variable analysis was used to reduce the risk of confounding due to unobserved baseline measures. Results 75 739 people initiated second line oral antidiabetic treatment with sulfonylureas (n=25 693, 33.9%), DPP-4 inhibitors (n=34 464 ,45.5%), or SGLT-2 inhibitors (n=15 582, 20.6%). SGLT-2 inhibitors were more effective than DPP-4 inhibitors or sulfonylureas in reducing mean HbA1c values between baseline and one year. After the instrumental variable analysis, the mean differences in HbA1c change between baseline and one year were −2.5 mmol/mol (95% confidence interval (CI) −3.7 to −1.3) for SGLT-2 inhibitors versus sulfonylureas and −3.2 mmol/mol (−4.6 to −1.8) for SGLT-2 inhibitors versus DPP-4 inhibitors. SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in reducing BMI and systolic blood pressure. For some secondary endpoints, evidence for SGLT-2 inhibitors being more effective was lacking—the hazard ratio for MACE, for example, was 0.99 (95% CI 0.61 to 1.62) versus sulfonylureas and 0.91 (0.51 to 1.63) versus DPP-4 inhibitors. SGLT-2 inhibitors had reduced hazards of hospital admission for heart failure compared with DPP-4 inhibitors (0.32, 0.12 to 0.90) and sulfonylureas (0.46, 0.20 to 1.05). The hazard ratio for a ≥40% decline in eGFR indicated a protective effect versus sulfonylureas (0.42, 0.22 to 0.82), with high uncertainty in the estimated hazard ratio versus DPP-4 inhibitors (0.64, 0.29 to 1.43). Conclusions This emulation study of a target trial found that SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in lowering mean HbA1c, BMI, and systolic blood pressure and in reducing the hazards of hospital admission for heart failure ( v DPP-4 inhibitors) and kidney disease progression ( v sulfonylureas), with no evidence of differences in other clinical endpoints. Owing to data sharing restrictions, the data used in this study cannot be shared directly. Researchers may, however, apply to use Clinical Practice Research Datalink (CPRD) data linked with other health datasets. Further instructions are available on the CPRD website (). Codelists to create exposure, outcome, and covariates are published on LSHTM DataCompass ().

中文翻译：

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2 型糖尿病患者二线口服抗糖尿病治疗的有效性比较：使用常规收集的健康数据模拟目标试验

目的 比较常规临床实践中三种常用口服降糖药联合二甲双胍治疗需要二线治疗的 2 型糖尿病患者的疗效。设计模拟比较有效性试验（目标试验）的队列研究。设置 2015-21 年英格兰关联的初级保健、医院和死亡数据。参与者 75 739 名 2 型糖尿病成人患者，他们开始二线口服抗糖尿病治疗，在二甲双胍中添加磺酰脲类、DPP-4 抑制剂或 SGLT-2 抑制剂。主要结果指标 主要结果是基线和一年随访期间糖化血红蛋白 (HbA1c) 的绝对变化。次要结局是一年和两年时体重指数 (BMI)、收缩压和估计肾小球滤过率 (eGFR) 的变化，两年时 HbA1c 的变化，以及 eGFR 下降 ≥40% 的时间，主要不良反应肾脏事件、心力衰竭入院、主要不良心血管事件 (MACE) 以及全因死亡。工具变量分析用于降低由于未观察到的基线测量而造成混淆的风险。结果 75 739 人开始二线口服抗糖尿病治疗，药物为磺脲类药物（n=25 693，33.9%）、DPP-4 抑制剂（n=34 464，45.5%）或 SGLT-2 抑制剂（n=15 582，20.6%） 。 SGLT-2 抑制剂在降低基线和一年之间的平均 HbA1c 值方面比 DPP-4 抑制剂或磺酰脲类药物更有效。工具变量分析后，SGLT-2抑制剂与磺脲类药物相比，基线和一年之间 HbA1c 变化的平均差异为 -2.5 mmol/mol（95% 置信区间 (CI) -3.7 至 -1.3），而磺脲类药物为 -3.2 mmol/mol SGLT-2 抑制剂与 DPP-4 抑制剂相比（-4.6 至 -1.8）。 SGLT-2 抑制剂在降低 BMI 和收缩压方面比磺酰脲类或 DPP-4 抑制剂更有效。对于一些次要终点，缺乏 SGLT-2 抑制剂更有效的证据，例如，与磺脲类药物相比，MACE 的风险比为 0.99（95% CI 0.61 至 1.62），与 DPP-4 抑制剂相比，MACE 的风险比为 0.91（0.51 至 1.63） 。与 DPP-4 抑制剂（0.32，0.12 至 0.90）和磺脲类药物（0.46，0.20 至 1.05）相比，SGLT-2 抑制剂降低了因心力衰竭入院的风险。 eGFR 下降 ≥40% 的风险比表明与磺脲类药物相比具有保护作用（0.42、0.22 至 0.82），而与 DPP-4 抑制剂相比，估计的风险比具有高度不确定性（0.64、0.29 至 1.43）。结论 这项目标试验模拟研究发现，SGLT-2 抑制剂比磺酰脲类或 DPP-4 抑制剂在降低平均 HbA1c、BMI 和收缩压以及降低因心力衰竭入院的风险方面更有效（v DPP- 4抑制剂）和肾脏疾病进展（v磺酰脲类），没有证据表明其他临床终点存在差异。由于数据共享的限制，本研究中使用的数据无法直接共享。然而，研究人员可以申请使用与其他健康数据集链接的临床实践研究数据链（CPRD）数据。进一步说明请访问 CPRD 网站（）。用于创建暴露、结果和协变量的代码列表发布在 LSHTM DataCompass 上（）。