TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA.
The Diabetes Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel.
Am Heart J. 2018 Jun;200:83-89. doi: 10.1016/j.ahj.2018.01.012. Epub 2018 Feb 7.
Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT-2) inhibitor that reduces blood glucose in patients with type 2 diabetes mellitus (T2DM) by promoting glycosuria via inhibiting urinary glucose reabsorption. In addition to improving blood glucose control, treatment with dapagliflozin results in glucose-induced osmotic diuresis, weight loss, and blood pressure lowering. Previous trials of SGLT-2 inhibitors showed reductions in cardiovascular (CV) events, including CV death and hospitalization for heart failure, and ischemic events in patients with atherosclerotic cardiovascular disease (ASCVD).
DECLARE-TIMI 58 (NCT01730534) is a phase 3b randomized, double-blind, placebo-controlled trial designed to evaluate the CV safety and efficacy of dapagliflozin that has completed randomization of 17,160 patients with T2DM and a history of either established ASCVD (n=6,971) or multiple risk factors for ASCVD (n=10,189). Patients were randomized in a 1:1 fashion to dapagliflozin 10 mg or matching placebo. The primary safety outcome is the time to the first event of the composite of CV death, myocardial infarction, or ischemic stroke (major adverse cardiovascular events; MACEs). The co-primary efficacy outcomes are the composite of CV death, myocardial infarction, or ischemic stroke and the composite of CV death or hospitalization for heart failure. This event-driven trial will continue until at least 1,390 subjects have a MACE outcome, thereby providing >99% power to test for the primary outcome of safety of dapagliflozin measured by rejecting the hypothesis that the upper bound of the CI >1.3 for the primary outcome of MACE, as well as 85% power to detect a 15% relative risk reduction in MACE and an estimated 87% power to detect a 20% reduction in the composite of CV death or hospitalization for heart failure at a 1-sided α level of .0231.
The DECLARE-TIMI 58 trial is testing the hypotheses that dapagliflozin is safe (does not increase) and may reduce the occurrence of major CV events. DECLARE-TIMI 58 is the largest study to address this question with an SGLT-2 inhibitor in patients with T2DM and with established CV disease and without CV disease but with multiple risk factors.
达格列净是一种钠-葡萄糖协同转运蛋白 2（SGLT-2）抑制剂，通过抑制尿糖重吸收促进糖尿，从而降低 2 型糖尿病（T2DM）患者的血糖。除了改善血糖控制外，达格列净治疗还可导致葡萄糖诱导的渗透性利尿、体重减轻和血压降低。先前的 SGLT-2 抑制剂试验显示，在有或没有心血管疾病（CVD）但有多种 CVD 危险因素的动脉粥样硬化性心血管疾病（ASCVD）患者中，CVD 事件（包括 CVD 死亡和心力衰竭住院）和缺血性事件减少。
DECLARE-TIMI 58（NCT01730534）是一项 3b 期随机、双盲、安慰剂对照试验，旨在评估达格列净的心血管安全性和疗效，该试验已完成 17160 例 T2DM 合并有或无 ASCVD 病史（n=6971）或多种 ASCVD 危险因素（n=10189）的患者的随机分组。患者以 1:1 的比例随机分配至达格列净 10mg 或匹配安慰剂。主要安全性结局是首次发生心血管死亡、心肌梗死或缺血性卒中（主要不良心血管事件；MACEs）复合事件的时间。共同主要疗效结局是心血管死亡、心肌梗死或缺血性卒中复合事件和心血管死亡或心力衰竭住院复合事件。该事件驱动试验将继续进行，直到至少 1390 例出现 MACE 结局，从而提供 >99%的效能来检验达格列净安全性的主要结局，即拒绝主要结局的 CI 上限>1.3 的假设，以及 85%的效能来检测 MACE 相对风险降低 15%，并估计 87%的效能来检测心血管死亡或心力衰竭住院复合事件降低 20%，单侧 α 水平为.0231。
DECLARE-TIMI 58 试验正在检验达格列净安全（不会增加）并可能降低主要心血管事件发生风险的假设。DECLARE-TIMI 58 是在有或没有 CVD 但有多种 CVD 危险因素的 T2DM 合并 ASCVD 患者中，用 SGLT-2 抑制剂进行的最大规模研究来解决这一问题。
