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

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.

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）双联治疗后，仍可能无法实现充足的糖化血红蛋白A1c（hemoglobin A1c, HbA1c）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）以达成控制目标。然而，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）及全因死亡率风险的影响仍不明确。本研究旨在比较接受Met-SU双联治疗后，分别加用DPP4i、胰岛素或TZD作为三线治疗的T2DM患者的全因死亡率、CVD及SH风险。
方法与结果
本研究分析了2006年至2017年间的17293例T2DM患者的回顾性队列数据，这些患者均无CVD病史且接受Met-SU双联治疗，其中分别加用DPP4i（n=8248）、胰岛素（n=6395）或TZD（n=2650）作为三线强化治疗。研究采用倾向得分加权法平衡各组间的基线协变量，并通过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达到均衡。在平均34个月的随访期（共计49299人年）中，全因死亡率、SH及CVD的累积发生率分别为0.061、0.119和0.074。与分别加用TZD和DPP4i的患者相比，接受胰岛素强化治疗的患者全因死亡率风险更高（HR=2.648，95%置信区间[CI] 2.367–2.963，P<0.001；HR=2.352，95%CI 2.123–2.605，P<0.001）。与分别使用TZD和DPP4i的患者相比，胰岛素使用者的SH风险最高（HR=1.198，95%CI 1.071–1.340，P=0.002；HR=1.496，95%CI 1.342–1.668，P<0.001）。对比TZD与DPP4i组，TZD与更高的SH风险相关（HR=1.249，95%CI 1.099–1.419，P<0.001），但与全因死亡率（HR=0.888，95%CI 0.776–1.016，P=0.084）或CVD风险（HR=1.005，95%CI 0.915–1.104，P=0.925）无显著关联。本研究的局限性包括缺乏生活方式、药物依从性、时变因素、患者就医动机及费用相关的数据；此外，TZD强化治疗患者的随访时长有限，也可能削弱本研究结果的效力。
结论
本研究结果显示，对于接受Met-SU双联治疗的T2DM患者，在三种三线治疗方案中，加用DPP4i为最优选择，其死亡率和SH风险最低，且与胰岛素和TZD相比，不会增加CVD事件风险。而胰岛素强化治疗的患者死亡率及SH事件风险最高。