Can the cardiovascular risk reductions observed with empagliflozin in the EMPA-REG OUTCOME trial be explained by concomitant changes seen in conventional cardiovascular risk factor levels?
Can the cardiovascular risk reductions observed with empagliflozin in the EMPA-REG OUTCOME trial be explained by concomitant changes seen in conventional cardiovascular risk factor levels?
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DOI：
10.1111/dom.14017
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发表时间：
2020-03-20
影响因子：
5.8
通讯作者：
Holman, Rury R.
中科院分区：
文献类型：
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作者：
Coleman, Ruth L.;Gray, Alastair M.;Holman, Rury R.
目的 对 EMPA-REG OUTCOME 试验进行事后分析，检查恩格列净引起的传统心血管 (CV) 危险因素的变化在多大程度上可以解释观察到的 CV 益处。 材料和方法 我们使用应用于年度患者水平数据的 2 型糖尿病特异性临床结果模拟模型来估计 3 年 EMPA-REG OUTCOME CV 事件率。变量包括心房颤动、吸烟、白蛋白尿、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、收缩压、糖化血红蛋白、心率、白细胞计数、血红蛋白、估计肾小球滤过率以及缺血性心脏病、心力衰竭、截肢、失明、肾衰竭、中风、心肌梗塞或糖尿病溃疡病史。对每个参与者进行多次模拟，以最大程度地减少不确定性并优化 CV 风险点估计的置信区间精度。比较观察到的和模拟的心血管相对风险降低。结果 模型预测的相对风险降低小于试验中观察到的结果，恩格列净相关的传统心血管风险因素值的变化似乎只能解释观察到的全因死亡相对风险降低的 12%（32% 中的 4%）、心血管死亡的 7%（39% 中的 3%）和心力衰竭的 15%（3% 中的 4%）。 29%)。结论 EMPA-REG OUTCOME 中传统 CV 危险因素与恩格列净相关的变化似乎只能解释观察到的 CV 和全因死亡减少的一小部分。需要探索替代的风险降低机制，以确定观察到的心血管风险变化是否可以通过其他因素或可能通过直接的药物特异性效应来解释。
Aim To perform post-hoc analyses of the EMPA-REG OUTCOME trial examining the degree to which empagliflozin-induced changes in conventional cardiovascular (CV) risk factors might explain the observed CV benefits.Materials and methods We estimated 3-year EMPA-REG OUTCOME CV event rates using a type 2 diabetes-specific clinical outcomes simulation model applied to annual patient-level data. Variables included were atrial fibrillation, smoking, albuminuria, HDL cholesterol, LDL cholesterol, systolic blood pressure, glycated haemoglobin, heart rate, white cell count, haemoglobin, estimated glomerular filtration rate, and histories of ischaemic heart disease, heart failure, amputation, blindness, renal failure, stroke, myocardial infarction or diabetic ulcer. Multiple simulations were performed for each participant to minimize uncertainty and optimize confidence interval precision around CV risk point estimates. Observed and simulated cardiovascular relative risk reductions were compared.Results Model-predicted relative risk reductions were smaller than those observed in the trial, with empagliflozin-associated changes in conventional CV risk factor values appearing to explain only 12% of the observed relative risk reduction for all-cause death (4% of 32%), 7% for CV death (3% of 39%) and 15% for heart failure (4% of 29%).Conclusions Empagliflozin-associated changes in conventional CV risk factors in EMPA-REG OUTCOME appear to explain only a small proportion of the CV and all-cause death reductions observed. Alternative risk-reduction mechanisms need to be explored to determine if the observed CV risk changes can be explained by other factors, or possibly by a direct drug-specific effect.