Aims/hypothesis

Limited evidence exists on the comparative safety and effectiveness of empagliflozin against alternative glucose-lowering medications in individuals with type 2 diabetes with the broad spectrum of cardiovascular risk. The EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) cohort study was designed to monitor the safety and effectiveness of empagliflozin periodically for a period of 5 years with data collection from electronic healthcare databases.

Methods

We identified individuals ≥18 years old with type 2 diabetes who initiated empagliflozin or dipeptidyl peptidase-4 inhibitors (DPP-4i) from 2014 to 2019 using US Medicare and commercial claims databases. After 1:1 propensity score matching using 143 baseline characteristics, we identified four a priori-defined effectiveness outcomes: (1) myocardial infarction (MI) or stroke; (2) hospitalisation for heart failure (HHF); (3) major adverse cardiovascular events (MACE); and (4) cardiovascular mortality or HHF. Safety outcomes included lower-limb amputations, non-vertebral fractures, diabetic ketoacidosis (DKA), acute kidney injury (AKI), severe hypoglycaemia, retinopathy progression, and short-term kidney and bladder cancers. We estimated HRs and rate differences (RDs) per 1000 person-years, overall and stratified by age, sex, baseline atherosclerotic cardiovascular disease (ASCVD) and heart failure.

Results

We identified 115,116 matched pairs. Compared with DPP-4i, empagliflozin was associated with lower risks of MI/stroke (HR 0.88 [95% CI 0.81, 0.96]; RD −2.08 [95% CI (−3.26, −0.90]), HHF (HR 0.50 [0.44, 0.56]; RD −5.35 [−6.22, −4.49]), MACE (HR 0.73 [0.62, 0.86]; RD −6.37 [−8.98, −3.77]) and cardiovascular mortality/HHF (HR 0.57 [0.47, 0.69]; RD −10.36 [−12.63, −8.12]). Absolute benefits were larger in older individuals and in those with ASCVD/heart failure. Empagliflozin was associated with an increased risk of DKA (HR 1.78 [1.44, 2.19]; RD 1.59 [1.08, 2.09]); decreased risks of AKI (HR 0.62 [0.54, 0.72]; RD −2.39 [−3.08, −1.71]), hypoglycaemia (HR 0.75 [0.67, 0.84]; RD −2.46 [−3.32, −1.60]) and retinopathy progression (HR 0.78 [0.63, 0.96)]; RD −9.49 [−16.97, −2.10]); and similar risks of other safety events.

Conclusions/interpretation

Empagliflozin relative to DPP-4i was associated with risk reductions of MI or stroke, HHF, MACE and the composite of cardiovascular mortality or HHF. Absolute risk reductions were larger in older individuals and in those who had history of ASCVD or heart failure. Regarding the safety outcomes, empagliflozin was associated with an increased risk of DKA and lower risks of AKI, hypoglycaemia and progression to proliferative retinopathy, with no difference in the short-term risks of lower-extremity amputation, non-vertebral fractures, kidney and renal pelvis cancer, and bladder cancer.

Graphical Abstract

中文翻译：

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恩格列净的有效性和安全性：EMPRISE 研究的最终结果

目标/假设

对于具有广泛心血管风险的 2 型糖尿病患者，恩格列净相对于替代降糖药物的相对安全性和有效性的证据有限。恩格列净比较疗效和安全性 (EMPRISE) 队列研究旨在通过电子医疗数据库收集数据，在 5 年内定期监测恩格列净的安全性和有效性。

方法

我们利用美国医疗保险和商业索赔数据库，确定了 2014 年至 2019 年期间开始使用恩格列净或二肽基肽酶 4 抑制剂 (DPP-4i) 的 18 岁以上 2 型糖尿病患者。使用 143 个基线特征进行 1:1 倾向评分匹配后，我们确定了四种先验定义的有效性结果：(1) 心肌梗死 (MI) 或中风； (2) 因心力衰竭(HHF)住院； （3）主要不良心血管事件（MACE）； (4) 心血管死亡率或 HHF。安全性结局包括下肢截肢、非椎体骨折、糖尿病酮症酸中毒（DKA）、急性肾损伤（AKI）、严重低血糖、视网膜病变进展以及短期肾癌和膀胱癌。我们估计了每 1000 人年的 HR 和比率差异 (RD)，总体并按年龄、性别、基线动脉粥样硬化性心血管疾病 (ASCVD) 和心力衰竭进行分层。

结果

我们确定了 115,116 个匹配对。与 DPP-4i 相比，恩格列净与 MI/卒中风险较低相关（HR 0.88 [95% CI 0.81, 0.96]；RD −2.08 [95% CI (−3.26, −0.90]）、HHF（HR 0.50 [0.44]） ，0.56]；RD -5.35 [-6.22，-4.49]），MACE（HR 0.73 [0.62，0.86]；RD -6.37 [-8.98，-3.77]）和心血管死亡率/HHF（HR 0.57 [0.47，0.69]） ；RD -10.36 [-12.63，-8.12]）。老年患者和患有 ASCVD/心力衰竭的患者的绝对获益更大，恩格列净与 DKA 风险增加相关（HR 1.78 [1.44，2.19]；RD 1.59 [ 1.08，2.09]）；AKI（HR 0.62 [0.54，0.72]；RD -2.39 [-3.08，-1.71]）、低血糖（HR 0.75 [0.67，0.84]；RD -2.46 [-3.32，-1.60]）风险降低]）和视网膜病变进展（HR 0.78 [0.63，0.96）]；RD -9.49 [-16.97，-2.10]）；以及其他安全事件的类似风险。

结论/解释

相对于 DPP-4i，恩格列净可降低 MI 或中风、HHF、MACE 以及心血管死亡率或 HHF 的综合风险。老年人和有 ASCVD 或心力衰竭病史的人的绝对风险降低幅度更大。关于安全性结果，恩格列净与 DKA 风险增加以及 AKI、低血糖和进展为增殖性视网膜病变的风险降低相关，而下肢截肢、非椎体骨折、肾脏和肾损伤的短期风险没有差异。盆腔癌和膀胱癌。

图形概要