TIMI Study Group, Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Duke Clinical Research Institute, Durham, North Carolina, USA.
Clin Cardiol. 2022 Jul;45(7):794-801. doi: 10.1002/clc.23844. Epub 2022 Jun 17.
Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) assessed the cardiovascular (CV) safety of sitagliptin versus placebo on CV outcomes in patients with type 2 diabetes and CV disease and found sitagliptin noninferior to placebo. Subsequently, based on feedback from FDA, the Sponsor of the trial, Merck & Co., Inc., engaged a separate academic research organization, the TIMI Study Group, to re-adjudicate a prespecified set of originally adjudicated events.
TIMI adjudicated in a blinded fashion all potential hospitalization for heart failure (HHF) events, all potential MACE+ events previously adjudicated as not an endpoint event, and a random subset (~10%) of MACE+ events previously adjudicated as an endpoint event. An updated study-level meta-analysis of four randomized, placebo-controlled, CV outcomes trials with dipeptidyl peptidase 4 (DPP-4) inhibitors was then performed.
After re-adjudication of potential HHF events in the intent-to-treat population, there were 224 patients with a confirmed event in the sitagliptin arm (1.05/100 person-years) and 239 patients in the placebo arm (1.13/100 person-years), corresponding to a hazard ratio (HR) of 0.94 (95% confidence interval [95% CI]: 0.78-1.13, p = .49). Concordance between the outcome of the original adjudication and the re-adjudication for HHF events was 82.7%. The meta-analysis of CV outcomes trials with DPP-4 inhibitors with placebo and involving 43 522 patients yielded an HR of 1.07 (95% CI: 0.83-1.39), with moderate heterogeneity (p = .45, I = 62.07%).
The results of this independent re-adjudication process and analyses of CV outcomes from TECOS were consistent with the original adjudication results and overall study findings. An updated study-level meta-analysis showed no overall significant risk for HHF with DPP-4 inhibitors, but with statistical heterogeneity.
评估西格列汀心血管结局的临床试验（TECOS）评估了在患有 2 型糖尿病和心血管疾病的患者中，西格列汀与安慰剂在心血管结局方面的安全性，结果显示西格列汀不劣于安慰剂。随后，基于美国食品和药物管理局（FDA）的反馈，试验的赞助商默克公司（Merck & Co.， Inc.）委托一个独立的学术研究组织，即血栓形成研究治疗干预方法（TIMI）研究小组，重新裁定最初裁定的一组预定事件。
TIMI 以盲法方式裁定所有潜在的心衰（HF）住院事件、所有最初裁定为非终点事件的潜在主要心血管不良事件（MACE）+事件以及最初裁定为终点事件的 MACE+事件的一个随机亚组（约 10%）。随后对四项随机、安慰剂对照、心血管结局试验中使用二肽基肽酶 4（DPP-4）抑制剂的研究进行了更新的研究水平荟萃分析。
在意向治疗人群中重新裁定潜在的 HF 事件后，西格列汀组有 224 例患者确诊发生事件（1.05/100 人年），安慰剂组有 239 例患者（1.13/100 人年），风险比（HR）为 0.94（95%置信区间[95%CI]：0.78-1.13，p=0.49）。HF 事件的原始裁定结果与重新裁定结果之间的一致性为 82.7%。对包含 43522 例患者的 DPP-4 抑制剂与安慰剂的心血管结局试验进行荟萃分析，结果显示 HR 为 1.07（95%CI：0.83-1.39），存在中度异质性（p=0.45，I²=62.07%）。
这一独立重新裁定过程和 TECOS 心血管结局分析的结果与原始裁定结果和总体研究结果一致。更新的研究水平荟萃分析显示，DPP-4 抑制剂与 HF 总体无显著风险，但存在统计学异质性。
