TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (T.A.Z., M.P.B., R.H.M.F., J.F.K., S.A.M., D.L.B., M.S.S., S.D.V.).
Division of Cardiology, Vienna General Hospital and Medical University of Vienna, Austria (T.A.Z.).
Circulation. 2020 Apr 14;141(15):1227-1234. doi: 10.1161/CIRCULATIONAHA.119.044183. Epub 2020 Jan 27.
Atrial fibrillation (AF) and atrial flutter (AFL) are associated with both diabetes mellitus and its related comorbidities, including hypertension, obesity, and heart failure (HF). SGLT2 (sodium-glucose cotransporter 2) inhibitors have been shown to lower blood pressure, reduce weight, have salutary effects on left ventricular remodeling, and reduce hospitalization for HF and cardiovascular death in patients with type 2 diabetes mellitus. We therefore investigated whether SGLT2 inhibitors could also reduce the risk of AF/AFL.
DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) studied the efficacy and safety of the SGLT2 inhibitor dapagliflozin versus placebo in 17 160 patients with type 2 diabetes mellitus and either multiple risk factors for atherosclerotic cardiovascular disease (n=10 186) or known atherosclerotic cardiovascular disease (n=6974). We explored the effect of dapagliflozin on the first and total number of AF/AFL events in patients with (n=1116) and without prevalent AF/AFL using Cox and negative binomial models, respectively. AF/AFL events were identified by search of the safety database using MedDRA preferred terms ("atrial fibrillation," "atrial flutter").
Dapagliflozin reduced the risk of AF/AFL events by 19% (264 versus 325 events; 7.8 versus 9.6 events per 1000 patient-years; hazard ratio [HR], 0.81 [95% CI, 0.68-0.95]; =0.009). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (previous AF/AFL: HR, 0.79 [95% CI, 0.58-1.09]; no AF/AFL: HR, 0.81 [95% CI, 0.67-0.98]; for interaction 0.89). Similarly, presence of atherosclerotic cardiovascular disease (HR, 0.83 [95% CI, 0.66-1.04]) versus multiple risk factors (HR, 0.78 [95% CI, 0.62-0.99]; for interaction 0.72) or a history of HF (HF: HR, 0.78 [95% CI, 0.55-1.11]; No HF: HR, 0.81 [95% CI, 0.68-0.97]; for interaction 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Moreover, there was no effect modification by sex, history of ischemic stroke, glycated hemoglobin A, body mass index, blood pressure, or estimated glomerular filtration rate (all for interaction >0.20). Dapagliflozin also reduced the total number (first and recurrent) of AF/AFL events (337 versus 432; incidence rate ratio, 0.77 [95% CI, 0.64-0.92]; =0.005).
Dapagliflozin decreased the incidence of reported episodes of AF/AFL adverse events in high-risk patients with type 2 diabetes mellitus. This effect was consistent regardless of the patient's previous history of AF, atherosclerotic cardiovascular disease, or HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01730534.
心房颤动（AF）和心房扑动（AFL）与糖尿病及其相关合并症有关，包括高血压、肥胖和心力衰竭（HF）。钠-葡萄糖协同转运蛋白 2（SGLT2）抑制剂已被证明可降低血压、减轻体重、对左心室重构有益，并降低 2 型糖尿病患者因 HF 和心血管死亡而住院的风险。因此，我们研究了 SGLT2 抑制剂是否也可以降低 AF/AFL 的风险。
DECLARE-TIMI 58（达格列净对心血管事件的影响-心肌梗死 58 溶栓）研究了 SGLT2 抑制剂达格列净与安慰剂在 17160 例患有 2 型糖尿病且有多种动脉粥样硬化性心血管疾病风险因素（n=10186）或已知动脉粥样硬化性心血管疾病（n=6974）的患者中的疗效和安全性。我们分别使用 Cox 模型和负二项式模型探讨了达格列净对（n=1116）和无（n=1116）预先存在的 AF/AFL 患者中首次和总 AF/AFL 事件数的影响。使用 MedDRA 首选术语（“心房颤动”、“心房扑动”）在安全数据库中搜索 AF/AFL 事件。
达格列净使 AF/AFL 事件的风险降低了 19%（264 与 325 事件；每 1000 患者年 7.8 与 9.6 事件；风险比[HR]，0.81[95%CI，0.68-0.95]；=0.009）。无论基线时是否存在 AF/AFL 病史，AF/AFL 事件的减少都是一致的（既往 AF/AFL：HR，0.79[95%CI，0.58-1.09]；无 AF/AFL：HR，0.81[95%CI，0.67-0.98]；交互作用检验=0.89）。同样，存在动脉粥样硬化性心血管疾病（HR，0.83[95%CI，0.66-1.04]）与多种风险因素（HR，0.78[95%CI，0.62-0.99]；交互作用检验=0.72）或心力衰竭病史（HF：HR，0.78[95%CI，0.55-1.11]；无 HF：HR，0.81[95%CI，0.68-0.97]；交互作用检验=0.88）并不能改变达格列净观察到的 AF/AFL 事件减少。此外，性别、缺血性卒中史、糖化血红蛋白 A、体重指数、血压或估计肾小球滤过率（所有交互作用检验>0.20）均无效应修饰作用。达格列净还减少了总（首次和复发性）AF/AFL 事件（337 与 432；发生率比，0.77[95%CI，0.64-0.92]；=0.005）。
达格列净降低了高危 2 型糖尿病患者报告的 AF/AFL 不良事件的发生率。这种效果与患者先前的 AF 病史、动脉粥样硬化性心血管疾病或 HF 无关。
