OBJECTIVE We sought to confirm a bidirectional association between severe hypoglycemic events (SHEs) and cardiovascular (CV) event risk and to characterize individuals at dual risk. RESEARCH DESIGN AND METHODS In a post hoc analysis of 14,752 Exenatide Study of Cardiovascular Event Lowering (EXSCEL) participants, we examined time-dependent associations between SHEs and subsequent major adverse cardiac events (CV death, nonfatal myocardial infarction [MI] or stroke), fatal/nonfatal MI, fatal/nonfatal stroke, hospitalization for acute coronary syndrome (hACS), hospitalization for heart failure (hHF), and all-cause mortality (ACM), as well as time-dependent associations between nonfatal CV events and subsequent SHEs. RESULTS SHEs were uncommon and not associated with once-weekly exenatide therapy (hazard ratio 1.13 [95% CI 0.94-1.36], P = 0.179). In fully adjusted models, SHEs were associated with an increased risk of subsequent ACM (1.83 [1.38-2.42], P < 0.001), CV death (1.60 [1.11-2.30], P = 0.012), and hHF (2.09 [1.37-3.17], P = 0.001), while nonfatal MI (2.02 [1.35-3.01], P = 0.001), nonfatal stroke (2.30 [1.25-4.23], P = 0.007), hACS (2.00 [1.39-2.90], P < 0.001), and hHF (3.24 [1.98-5.30], P < 0.001) were all associated with a subsequent increased risk of SHEs. The elevated bidirectional time-dependent hazards linking SHEs and a composite of all CV events were approximately constant over time, with those individuals at dual risk showing higher comorbidity scores compared with those without. CONCLUSIONS These findings, showing greater risk of SHEs after CV events as well as greater risk of CV events after SHEs, validate a bidirectional relationship between CV events and SHEs in patients with high comorbidity scores.

中文翻译：

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确认2型糖尿病中严重低血糖事件与心血管事件之间的关联具有双向性：来自EXSCEL的见解。

目的我们试图确认严重的低血糖事件（SHE）与心血管事件（CV）事件风险之间存在双向关联，并确定具有双重风险的个体的特征。研究设计和方法在对14,752例艾塞那肽降低心血管事件（EXSCEL）参与者的事后分析中，我们研究了SHE与随后的主要不良心脏事件（CV死亡，非致命性心肌梗塞[MI]或中风）之间的时间相关性，致命/非致命性心肌梗死，致命/非致命性中风，急性冠状动脉综合征（hACS）住院，心衰（hHF）住院和全因死亡率（ACM），以及非致命性CV事件与随后的SHE之间的时间相关性。结果SHE很少见，并且与每周一次艾塞那肽治疗无关（危险比1.13 [95％CI 0.94-1.36]，P = 0.179）。在完全调整的模型中，SHE与随后的ACM（1.83 [1.38-2.42]，P <0.001），CV死亡（1.60 [1.11-2.30]，P = 0.012）和hHF（2.09 [1.37- 3.17]，P = 0.001），非致死性MI（2.02 [1.35-3.01]，P = 0.001），非致死性卒中（2.30 [1.25-4.23]，P = 0.007），hACS（2.00 [1.39-2.90]，P < 0.001）和hHF（3.24 [1.98-5.30]，P <0.001）均与随后增加的SHE风险相关。与SHE和所有CV事件的综合相关的双向时间依赖性危险性升高，随时间推移大致恒定，与处于双重危险状态的个体相比，处于双重危险状态的个体显示出更高的合并症评分。结论这些发现表明，发生CV事件后发生SHE的风险较高，以及发生SHE后发生CV事件的风险较高，