摘要

BACKGROUND:Although patients with type 2 diabetes mellitus (T2DM) may fail to achieve adequate hemoglobin A1c (HbA1c) control despite metformin-sulfonylurea (Met-SU) dual therapy, a third-line glucose-lowering medication-including dipeptidyl peptidase-4 inhibitor (DPP4i), insulin, or thiazolidinedione (TZD)-can be added to achieve this. However, treatment effects of intensification with the medications on the risk of severe hypoglycemia (SH), cardiovascular disease (CVD), and all-cause mortality are uncertain. Study aim was to compare the risks of all-cause mortality, CVD, and SH among patients with T2DM on Met-SU dual therapy intensified with DPP4i, insulin, or TZD. METHODS AND FINDINGS:We analyzed a retrospective cohort data of 17,293 patients with T2DM who were free from CVD and on Met-SU dual therapy and who were intensified with DPP4i (n = 8,248), insulin (n = 6,395), or TZD (n = 2,650) from 2006 to 2017. Propensity-score weighting was used to balance out baseline covariates across groups. Hazard ratios (HRs) for all-cause mortality, CVD, and SH were assessed using Cox proportional hazard models. Mean age of all patients was 58.56 ± 11.41 years. All baseline covariates achieved a balance across the 3 groups. Over a mean follow-up period of 34 months with 49,299 person-years, cumulative incidences of all-cause mortality, SH, and CVD were 0.061, 0.119, and 0.074, respectively. Patients intensified with insulin had higher risk of all-cause mortality (HR = 2.648, 95% confidence interval [CI] 2.367-2.963, p < 0.001; 2.352, 95% CI 2.123-2.605, p < 0.001) than those intensified with TZD and DPP4i, respectively. Insulin users had the greatest risk of SH (HR = 1.198, 95% CI 1.071-1.340, p = 0.002; 1.496, 95% CI 1.342-1.668, p < 0.001) compared with TZD and DPP4i users, respectively. Comparing between TZDs and DPP4i, TZDs were associated with a higher risk of SH (HR = 1.249, 95% CI 1.099-1.419, p < 0.001) but not all-cause mortality (HR = 0.888, 95% CI 0.776-1.016, p = 0.084) or CVD (HR = 1.005, 95% CI 0.915-1.104, p = 0.925). Limitations of this study included the lack of data regarding lifestyle, drug adherence, time-varying factors, patients' motivation, and cost considerations. A limited duration of patients intensifying with TZD might also weaken the strength of study results. CONCLUSIONS:Our results indicated that, for patients with T2DM who are on Met-SU dual therapy, the addition of DPP4i was a preferred third-line medication among 3 options, with the lowest risks of mortality and SH and posing no increased risk for CVD events when compared to insulin and TZD. Intensification with insulin had the greatest risk of mortality and SH events.

译文

背景: 尽管 2 型糖尿病患者可能无法获得足够的血红蛋白 A1c (HbA1c) 控制，尽管二甲双胍-磺酰脲 (Met-SU) 双重治疗, 可以添加三线降糖药物 -- 包括二肽基 peptidase-4 抑制剂 (DPP4i) 、胰岛素或噻唑烷二酮 (TZD) -- 来实现这一目标。然而，药物强化对严重低血糖 (SH) 、心血管疾病 (CVD) 和全因死亡率的治疗效果尚不明确。研究目的是比较用 DPP4i 、胰岛素或 TZD 强化的 Met-SU 双重治疗的 2 型糖尿病患者的全因死亡率、 CVD 和 SH 的风险。方法和结果: 我们分析了 17,293 名没有心血管疾病和接受 Met-SU 双重治疗的 2 型糖尿病患者的回顾性队列数据，这些患者接受了 DPP4i 强化治疗 (n = 8,248), 从 2006年到 2017年，胰岛素 (n = 6,395)，或 TZD (n = 2,650)。使用倾向得分加权来平衡各组间的基线协变量。使用 Cox 比例风险模型评估全因死亡率、 CVD 和 SH 的风险比 (HRs)。所有患者的平均年龄为 58.56 ± 11.41 岁。所有基线协变量在 3 组间达到平衡。在平均 34 个月的随访期内，49,299 人年，全因死亡率、 SH 和 CVD 的累积发生率分别为 0.061 、 0.119 和 0.074。胰岛素强化的患者全因死亡风险更高 (HR = 2.648，95% 置信区间 [CI] 2.367-2.963，p <0.001; 2.352，95% CI 2.123-2.605, p & lt; 0.001) 分别比 TZD 和 DPP4i 增强。胰岛素使用者患 SH 的风险最大 (HR = 1.198，95% CI 1.071-1.340，p = 0.002; 1.496，95% CI 1.342-1.668，p <0.001) 分别与 TZD 和 DPP4i 用户进行比较。在 TZDs 和 DPP4i 之间比较，TZDs 与更高的 SH 风险相关 (HR = 1.249，95% CI 1.099-1.419，p & lt; 0.001) 但不是全因死亡率 (HR = 0.888，95% CI 0.776-1.016，p = 0.084) 或 CVD (HR = 1.005，95% CI 0.915-1.104，p = 0.925)。这项研究的局限性包括缺乏关于生活方式、药物依从性、时变因素、患者动机和成本考虑的数据。有限的 TZD 强化患者时间也可能削弱研究结果的强度。结论: 我们的结果表明，对于接受 Met-SU 双重治疗的 2 型糖尿病患者，在 3 种选择中，添加 DPP4i 是首选的三线药物, 死亡率和 SH 的风险最低，与胰岛素和 TZD 相比，CVD 事件的风险没有增加。胰岛素强化有最大的死亡风险和 SH 事件。