Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes
Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes
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DOI：
10.1161/circulationaha.119.043353
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发表时间：
2020-04-28
期刊：
影响因子：
37.8
通讯作者：
Holman, Rury R.
中科院分区：
文献类型：
--
作者：
Bethel, M. Angelyn;Stevens, Susanna R.;Holman, Rury R.
背景：EXSCEL（降低心血管事件的艾塞那肽研究）评估了每周一次的艾塞那肽 2 mg 与安慰剂对 2 型糖尿病患者的影响，同时旨在实现血糖平衡。因此，安慰剂组中开放标签降糖药物的使用量更大。因此，考虑到其中一些药物具有心脏保护作用，我们探讨了它们的不平衡使用对主要不良心血管事件 (MACE) 的潜在影响，MACE 定义为心血管死亡、非致命性心肌梗塞或非致命性中风以及全因死亡率 (ACM)。 方法：通过对发生 > 5% 开放标签滴入降糖药物的药物类别和胰高血糖素样肽 1 受体激动剂 (GLP-1) 进行随机治疗，进行 Cox 风险模型。 RA；3.0%）使用三种方法：随机访视右删失、治疗加权逆概率 (IPTW) 以及应用药物类别风险降低。结果：14 752 名 EXSCEL 参与者（73.1% 患有既往心血管疾病）的基线降糖药物在治疗组之间没有差异。在中位 3.2 年的随访期间，33.4% 的参与者出现开放标签停药，其中安慰剂组比艾塞那肽组更常见（38.1% 对 28.8%），二甲双胍组（6.1% 对 4.9%）、磺酰脲类药物（8.7% 对 6.9%）、二肽基肽酶 4 抑制剂（10.6% 对 7.5%）、 SGLT-2i（10.3% vs 8.1%）、GLP-1 RA（3.4% vs 2.4%）和胰岛素（13.8% vs 9.4%）。右删失并没有显着改变 MACE 效应大小，但艾塞那肽的有利 HR 在磺酰脲类和任何降糖药物组中变得名义上显着，而 ACM HR 和 p 值基本不变。 IPTW 将 MACE HR 从 0.91 (P=0.061) 降低至 0.85 (P=0.008)，将 ACM HR 从 0.86 (P=0.016) 降低至 0.81 (P=0.012)。应用文献衍生的风险降低表明 MACE 或 ACM HR 或 P 值没有有意义的变化，尽管模拟更多地使用滴用心脏保护性降糖药表明信号检测减弱。结论：在正确审查或应用文献衍生的风险降低后，EXSCEL 观察到的 MACE 和 ACM HR 仍然稳健，但 IPTW 增加了艾塞那肽与安慰剂 MACE 的效应大小和统计显着性。在血糖平衡的前提下，设计、实施和分析降糖药物的心血管结局试验时，需要仔细考虑开放标签滴入式心脏保护药物的作用。唯一标识符：NCT01144338。
Background:EXSCEL (Exenatide Study of Cardiovascular Event Lowering) assessed the impact of once-weekly exenatide 2 mg versus placebo in patients with type 2 diabetes mellitus, while aiming for glycemic equipoise. Consequently, greater drop-in of open-label glucose-lowering medications occurred in the placebo group. Accordingly, we explored the potential effects of their unbalanced use on major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, and all-cause mortality (ACM), given that some of these agents are cardioprotective.Methods:Cox hazard models were performed by randomized treatment for drug classes where >5% open-label drop-in glucose-lowering medication occurred, and for glucagon-like peptide-1 receptor agonists (GLP-1 RAs; 3.0%) using three methodologies: drop-in visit right censoring, inverse probability for treatment weighting (IPTW), and applying drug class risk reductions.Results:Baseline glucose-lowering medications for the 14 752 EXSCEL participants (73.1% with previous cardiovascular disease) did not differ between treatment groups. During median 3.2 years follow-up, open-label drop-in occurred in 33.4% of participants, more frequently with placebo than exenatide (38.1% versus 28.8%), with metformin (6.1% versus 4.9%), sulfonylurea (8.7% versus 6.9%), dipeptidyl peptidase-4 inhibitors (10.6% versus 7.5%), SGLT-2i (10.3% versus 8.1%), GLP-1 RA (3.4% versus 2.4%), and insulin (13.8% versus 9.4%). The MACE effect size was not altered meaningfully by right censoring, but the favorable HR for exenatide became nominally significant in the sulfonylurea and any glucose-lowering medication groups, while the ACM HR and p-values were essentially unchanged. IPTW decreased the MACE HR from 0.91 (P=0.061) to 0.85 (P=0.008) and the ACM HR from 0.86 (P=0.016) to 0.81 (P=0.012). Application of literature-derived risk reductions showed no meaningful changes in MACE or ACM HRs or P values, although simulations of substantially greater use of drop-in cardioprotective glucose-lowering agents demonstrated blunting of signal detection.Conclusions:EXSCEL-observed HRs for MACE and ACM remained robust after right censoring or application of literature-derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by IPTW. Effects of open-label drop-in cardioprotective medications need to be considered carefully when designing, conducting, and analyzing cardiovascular outcome trials of glucose-lowering agents under the premise of glycemic equipoise.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01144338.