OBJECTIVE Severe hypoglycemic events (SHEs) in type 2 diabetes are associated with subsequent cardiovascular (CV) event risk. We examined whether CV events were associated with subsequent SHE risk.

RESEARCH DESIGN AND METHODS Time-dependent associations between SHEs and a composite CV end point (fatal/nonfatal myocardial infarction or stroke, hospitalization for unstable angina, hospitalization for heart failure [hHF]) were examined post hoc in 14,671 TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) participants with type 2 diabetes and CV disease followed for a median of 3.0 years.

RESULTS SHEs were uncommon and unassociated with sitagliptin therapy (N = 160 [2.2%], 0.78/100 patient-years vs. N = 143 [1.9%], 0.70/100 patient-years for placebo; hazard ratio [HR] 1.12 [95% CI 0.89, 1.40], P = 0.33). Patients with (versus without) SHEs were older with longer diabetes duration, lower body weight, and lower estimated glomerular filtration rate; were more frequently women, nonwhite, and insulin treated; and more often had microalbuminuria or macroalbuminuria. Analyses adjusted for clinical factors showed SHEs were associated with increased risk of the primary composite CV end point (1.55 [1.06, 2.28], P = 0.025), all-cause death (1.83 [1.22, 2.75], P = 0.004), and CV death (1.72 [1.02, 2.87], P = 0.040). Conversely, nonfatal myocardial infarction (3.02 [1.83, 4.96], P < 0.001), nonfatal stroke (2.77 [1.36, 5.63], P = 0.005), and hHF (3.68 [2.13, 6.36], P < 0.001) were associated with increased risk of SHEs. Fully adjusted models showed no association between SHEs and subsequent CV or hHF events, but the association between CV events and subsequent SHEs remained robust.

CONCLUSIONS These findings, showing greater risk of SHEs after CV events and greater risk of CV events after SHEs, suggest a common at-risk type 2 diabetes frail patient phenotype.

目的2型糖尿病的严重低血糖事件（SHE）与随后的心血管（CV）事件风险相关。我们检查了心血管事件是否与随后的SHE风险相关。

研究设计与方法研究了14,671个TECOS事后对SHE和复合CV终点（致命/非致命性心肌梗塞或中风，不稳定型心绞痛的住院治疗，心力衰竭[hHF]的住院治疗）之间的时间依赖性关系。使用西他列汀的2型糖尿病和CV疾病参与者的中位随访时间为3.0年。

结果SHE与西格列汀治疗罕见且不相关（安慰剂组N = 160 [2.2％]，0.78 / 100患者-年，N = 143 [1.9％]，0.70 / 100患者-年；危险比[HR] 1.12 [ 95％CI 0.89，1.40]，P = 0.33）。患有（相对于没有）SHE的患者年龄较大，糖尿病病程更长，体重更低，估计的肾小球滤过率更低；女性，非白人和接受胰岛素治疗的女性更多；并且更经常有微量白蛋白尿或大型白蛋白尿。根据临床因素进行调整后的分析表明，SHE与主要复合CV终点风险增加（1.55 [1.06，2.28]，P = 0.025），全因死亡（1.83 [1.22，2.75]，P）相关= 0.004）和CV死亡（1.72 [1.02，2.87]，P = 0.040）。相反，非致命性心肌梗死（3.02 [1.83，4.96]，P <0.001），非致命性中风（2.77 [ 1.36，5.63 ]，P = 0.005）和hHF（3.68 [2.13，6.36]，P <0.001）与SHE的风险增加。完全调整的模型显示SHE与后续CV或hHF事件之间没有关联，但是CV事件与后续SHE之间的关联仍然很稳健。

结论这些发现表明，发生CV事件后发生SHE的风险较高，而发生SHE后发生CV事件的风险较高，表明常见的2型糖尿病脆弱患者风险表型。