Intensification with dipeptidyl peptidase-4 inhibitor, insulin, or thiazolidinediones and risks of all-cause mortality, cardiovascular diseases, and severe hypoglycemia in patients on metformin-sulfonylurea dual therapy: A retrospective cohort study

BackgroundAlthough 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 findingsWe 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 p p = 0.002; 1.496, 95% CI 1.342–1.668, p p 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.ConclusionsOur 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.背景：尽管2型糖尿病（type 2 diabetes mellitus, T2DM）患者在接受二甲双胍-磺脲类（metformin-sulfonylurea, Met-SU）双药治疗后，仍可能无法实现糖化血红蛋白（hemoglobin A1c, HbA1c）的达标控制，此时可加用三线降糖药物，包括二肽基肽酶-4抑制剂（dipeptidyl peptidase-4 inhibitor, DPP4i）、胰岛素或噻唑烷二酮类（thiazolidinedione, TZD）以达成控糖目标。但此类强化治疗药物对严重低血糖（severe hypoglycemia, SH）、心血管疾病（cardiovascular disease, CVD）及全因死亡率的影响风险尚不明确。本研究旨在比较接受Met-SU双药治疗的T2DM患者，在加用DPP4i、胰岛素或TZD作为三线强化治疗后，其全因死亡率、CVD及SH的发生风险差异。 方法与结果：我们分析了2006年至2017年间的一项回顾性队列数据，共纳入17293名无CVD病史、接受Met-SU双药治疗且后续加用DPP4i（n=8248）、胰岛素（n=6395）或TZD（n=2650）的T2DM患者。采用倾向得分加权法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及SH的风险比（hazard ratio, HR）。所有患者的平均年龄为58.56±11.41岁，三组间的所有基线协变量均实现平衡。在平均34个月的随访期（共计49299人年）内，全因死亡率、SH及CVD的累积发生率分别为0.061、0.119和0.074。与DPP4i组相比，接受胰岛素强化治疗的患者全因死亡率更高（HR=2.648，95%置信区间[CI] 2.367–2.963，p<0.001），严重低血糖发生风险也显著升高（HR=1.496，95%CI 1.342–1.668，p<0.001）；而TZD组的全因死亡率（HR=1.082，95%CI 0.972–1.205，p=0.157）及SH风险（HR=1.072，95%CI 0.981–1.170，p=0.129）与DPP4i组无显著统计学差异，且CVD风险未出现显著升高（HR=1.005，95%CI 0.915–1.104，p=0.925）。 局限性：本研究的局限性包括缺乏生活方式、药物依从性、时变因素、患者治疗意愿及成本考量相关数据；此外，接受TZD强化治疗患者的随访时长有限，也可能削弱研究结果的统计效力。 结论：本研究结果表明，对于接受Met-SU双药治疗的T2DM患者，在三种三线降糖药物选择中，加用DPP4i为最优方案，其全因死亡率与SH风险最低，且相较于胰岛素与TZD，不会增加CVD发生风险。而胰岛素强化治疗的全因死亡率与SH事件发生风险最高。