Division of Cardiology, Medical University of Vienna, Vienna, Austria.
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
JAMA Cardiol. 2023 May 1;8(5):503-509. doi: 10.1001/jamacardio.2023.0019.
Dapagliflozin reduces the risk of hospitalizations for heart failure and the progression of chronic kidney disease in patients with and without type 2 diabetes (T2D), whereas the effects on reducing atherosclerotic events appear less clear.
To explore whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) levels can identify a subset of patients with T2D at higher risk and who might benefit more from dapagliflozin with regard to atherosclerotic events.
DESIGN, SETTING, AND PARTICIPANTS: This was a secondary analysis of the DECLARE-TIMI 58 trial, a randomized clinical trial of dapagliflozin in patients with T2D and either multiple risk factors for atherosclerotic cardiovascular disease (ASCVD; approximately 60%) or established ASCVD (approximately 40%). All patients with available blood samples at randomization were included in these analyses. Data were collected from May 2013 to September 2018, and data were analyzed from May 2019 to June 2022.
Dapagliflozin vs placebo.
Major adverse cardiovascular events (MACE), the composite of myocardial infarction, ischemic stroke, or cardiovascular death, which was one of dual primary outcomes of the main trial.
Of 14 565 included patients, 9143 (62.8%) were male, and the mean (SD) age was 63.9 (6.8) years. When tested individually in a multivariable model for MACE risk, NT-proBNP and hsTnT were each significantly associated with the risk of MACE (adjusted hazard ratio [aHR] per 1 SD in log-transformed biomarker: NT-proBNP, 1.62; 95% CI, 1.49-1.76; hsTnT: 1.59; 95% CI, 1.46-1.74). The magnitude of the association was similar in patients with ASCVD (NT-proBNP: aHR, 1.60; 95% CI, 1.45-1.77; hsTnT: aHR, 1.62; 95% CI, 1.45-1.81) and multiple risk factors for ASCVD (NT-proBNP: aHR, 1.62; 95% CI, 1.40-1.88; hsTnT: aHR, 1.51; 95% CI, 1.29-1.77). Moreover, both biomarkers remained independently associated with MACE when both were included in the multivariable model (NT-proBNP: aHR, 1.46; 95% CI, 1.34-1.60; hsTnT: aHR, 1.39; 95% CI, 1.26-1.53). Modeled as a continuous variable, baseline biomarker levels did not modify the relative treatment effect of dapagliflozin vs placebo with MACE. However, the relative risk reduction numerically grew with higher biomarker levels, as did the baseline risk. Thus, MACE event rates were nominally lower in dapagliflozin-treated vs placebo-treated patients with biomarker concentrations in the top quartile (NT-proBNP: HR, 0.83; 95% CI, 0.71-0.97; absolute risk reduction [ARR], 2.4%; hsTnT: HR, 0.85; 95% CI, 0.72-0.99; ARR, 2.7%), whereas there was no significant treatment effect in patients with biomarkers levels in quartiles 1 to 3 (NT-proBNP: HR, 1.02; 95% CI, 0.88-1.18; ARR, 0%; hsTnT: HR, 0.97; 95% CI, 0.84-1.13; ARR, 0.2%).
In this study, NT-proBNP and hsTnT levels were associated with the risk for future cardiovascular events in both primary and secondary prevention patients with T2D. Both cardiac biomarkers were helpful to identify patients at very high risk for atherosclerotic events that may derive reduction in risk of MACE with dapagliflozin.
ClinicalTrials.gov Identifier: NCT01730534.
重要性：达格列净可降低有或无 2 型糖尿病（T2D）患者的心衰住院风险和慢性肾脏病进展，但对减少动脉粥样硬化事件的效果似乎不太明确。
目的：探究 N 末端脑利钠肽前体（NT-proBNP）和高敏心肌肌钙蛋白 T（hsTnT）水平是否可以识别出 T2D 患者中的亚组人群，这些患者的动脉粥样硬化事件风险更高，可能从达格列净治疗中获益更多。
设计、地点和参与者：这是 DECLARE-TIMI 58 试验的二次分析，该试验是一项在 T2D 患者中进行的达格列净随机临床试验，这些患者有动脉粥样硬化性心血管疾病（ASCVD）的多种危险因素（约 60%）或已确诊 ASCVD（约 40%）。所有随机时具有可检测血样的患者均纳入这些分析。数据收集于 2013 年 5 月至 2018 年 9 月，数据分析于 2019 年 5 月至 2022 年 6 月进行。
干预措施：达格列净与安慰剂。
主要结局和测量指标：主要复合终点事件（MACE），包括心肌梗死、缺血性卒中和心血管死亡，这是主要试验的双重主要结局之一。
结果：在纳入的 14565 例患者中，9143 例（62.8%）为男性，平均（SD）年龄为 63.9（6.8）岁。在多变量模型中单独检测时，NT-proBNP 和 hsTnT 均与 MACE 风险显著相关（按生物标志物的 1 个标准差进行对数转换后的调整后危险比[aHR]：NT-proBNP，1.62；95%CI，1.49-1.76；hsTnT：1.59；95%CI，1.46-1.74）。在 ASCVD 患者（NT-proBNP：aHR，1.60；95%CI，1.45-1.77；hsTnT：aHR，1.62；95%CI，1.45-1.81）和 ASCVD 多种危险因素患者（NT-proBNP：aHR，1.62；95%CI，1.40-1.88；hsTnT：aHR，1.51；95%CI，1.29-1.77）中，这种关联的程度相似。当将两种生物标志物同时纳入多变量模型时，它们仍与 MACE 独立相关（NT-proBNP：aHR，1.46；95%CI，1.34-1.60；hsTnT：aHR，1.39；95%CI，1.26-1.53）。将生物标志物水平建模为连续变量时，基线生物标志物水平并不改变达格列净与安慰剂治疗 MACE 的相对治疗效果。然而，随着生物标志物水平的升高，相对风险降低呈数值性增加，基础风险也随之增加。因此，与安慰剂治疗相比，在生物标志物浓度处于四分位值最高的达格列净治疗患者中，MACE 事件发生率名义上更低（NT-proBNP：HR，0.83；95%CI，0.71-0.97；绝对风险降低[ARR]，2.4%；hsTnT：HR，0.85；95%CI，0.72-0.99；ARR，2.7%），而在生物标志物水平处于 1 至 3 四分位值的患者中，没有显著的治疗效果（NT-proBNP：HR，1.02；95%CI，0.88-1.18；ARR，0%；hsTnT：HR，0.97；95%CI，0.84-1.13；ARR，0.2%）。
结论和相关性：在这项研究中，NT-proBNP 和 hsTnT 水平与 T2D 患者一级和二级预防患者未来心血管事件的风险相关。这两种心脏生物标志物有助于识别出发生动脉粥样硬化事件风险极高的患者，这些患者可能会因达格列净治疗而降低 MACE 风险。
试验注册：ClinicalTrials.gov 标识符：NCT01730534。
