Diabetes Mellitus “Comorbidity” or an Important Risk Factor?

Diabetes is a complex metabolic syndrome and its involvement in cardiovascular disease is manifold with varying manifestations and different clinical symptoms and prognosis. Although being probably the most important risk factor, diabetes is often considered an “accompanying comorbidity” for cardiac or peripheral artery disease, hypertension, or stroke. We should focus more on diabetes being an independent disease with a “2-faced appearance” of diabetes-related cardiomyopathy. One form being the restrictive type with preserved LVEF, the other form appearing as dilative cardiomyopathy with reduced LVEF. The restrictive form with diastolic dysfunction seems to be a coronary microvascular endothelial dysfunction problem induced by hyperglycemia, lipotoxicity, and hyperinsulinemia and is more often encountered in obese patients with type 2 diabetes; the dilative form is linked to cardiomyocyte cell death induced by an autoimmune-prone pathophysiologic mechanism and occurs more often in patients with type 1 diabetes. Both types of diabetic cardiomyopathy are caused by impaired glucose metabolism, seem not to be successive stages, and develop independently. They should be separated from macrocoronary artery disease and other forms of nonischemic cardiomyopathy. How much diabetic cardiomyopathy affects outcome of other cardiac diseases is still a matter of research. Situations with hypogylcemia or hyperglycemia increase the risk of cardiovascular events, arrhythmias, sudden death, and all-cause mortality. An interesting study demonstrated that the risk of sudden cardiac death is at least 2-fold higher in patients who are diabetic compared with those who are nondiabetic, regardless of the extent of cardiac dysfunction or symptoms of heart failure. In contrast, the risk of nonsudden cardiac death was not significantly different between the 2 groups. The question arises which pathophysiologic mechanism is responsible for the higher risk of arrhythmic death in patients who are diabetic? One actual focus of interest is the diabetic autonomic neuropathy with autonomic dysfunction, which is present in at least one-third of patients who are diabetic. Noninvasive electrocardiography-based risk stratification should become the most important field of risk stratification for ICD therapy, particularly in patients who are diabetic with normal or only mildly reduced LVEF. However, further research is needed in this field prior to launching randomized studies. In summary, the presented data from this registry demonstrate that less impaired LV function in patients who are diabetic carries a higher mortality risk than low LVEF in patients who are nondiabetic. These findings stimulate us to reconsider the accepted LVEF-guided ICD therapy, particularly for patients with diabetes. However, the discussed ICD protection for patients who are diabetic with less reduced LV function seems to be premature when based only on global overall outcome data. The data calls for future prospective, randomized trials focusing specifically on diabetes patients. It clearly signals to the cardiology community that patients with diabetes are at high risk of arrhythmic risk, even without severely reduced LVEF. Future studies should not fail because of poor patient enrollment. Perhaps, sodium-glucose cotransporter inhibitors will become the new “medical defibrillators”. However, even this important new study did not reveal the effect of sodium-glucose cotransporter inhibitors specifically on sudden cardiac death outcome.

糖尿病是一种复杂的代谢综合征，其与心血管疾病的关联机制复杂多样，临床表现、临床症状及预后均存在异质性。尽管糖尿病或许是最为重要的心血管疾病危险因素，但其常被视为心脏或外周动脉疾病、高血压或脑卒中的伴随合并症。我们应更重视糖尿病作为一种独立疾病，其所伴发的糖尿病心肌病（diabetic cardiomyopathy）存在"2-faced appearance"（双面表型）：其一为左心室射血分数（Left Ventricular Ejection Fraction, LVEF）保留的限制型心肌病，其二为左心室射血分数降低的扩张型心肌病。伴舒张功能障碍的限制型心肌病，其本质为高血糖、脂毒性及高胰岛素血症诱发的冠状动脉微血管内皮功能障碍，多见于2型糖尿病肥胖患者；而扩张型心肌病则与自身免疫倾向的病理生理机制诱导的心肌细胞死亡相关，更常见于1型糖尿病患者。两类糖尿病心肌病均由糖代谢受损所致，二者并非进展的连续阶段，而是独立发生发展的。临床需将其与大冠状动脉疾病及其他类型非缺血性心肌病相鉴别。糖尿病心肌病对其他心脏疾病预后的影响程度，目前仍有待进一步研究阐明。低血糖或高血糖状态均会升高心血管事件、心律失常、心源性猝死及全因死亡风险。一项颇具意义的研究显示，无论心功能障碍程度或心力衰竭症状如何，糖尿病患者的心源性猝死风险至少较非糖尿病患者高出2倍。与之相反，两组患者的非心源性猝死风险并无显著差异。由此引出一个问题：何种病理生理机制导致了糖尿病患者的心律失常性死亡风险升高？当前的研究热点之一为糖尿病自主神经病变伴自主功能障碍，该并发症在至少三分之一的糖尿病患者中存在。基于无创心电图的危险分层，或将成为植入式心律转复除颤器（Implantable Cardioverter Defibrillator, ICD）治疗风险分层的核心方向，尤其适用于左心室射血分数正常或仅轻度降低的糖尿病患者。然而，在开展相关随机对照研究之前，该领域仍需更多研究积累证据。综上，本注册研究的相关数据显示，左心室功能仅轻度受损的糖尿病患者，其死亡风险高于左心室射血分数降低的非糖尿病患者。该研究结果促使我们重新审视目前公认的以左心室射血分数为指导的ICD治疗策略，尤其是针对糖尿病患者的相关方案。不过，若仅基于整体预后数据，针对左心室功能轻度降低的糖尿病患者开展ICD保护治疗的结论似乎为时过早。上述数据表明，未来需开展专门针对糖尿病患者的前瞻性随机对照研究。该研究明确向心血管学界传递了一个信号：即便左心室射血分数未严重降低，糖尿病患者仍存在较高的心律失常风险。未来的相关研究应避免因患者招募困难而终止。或许钠-葡萄糖协同转运蛋白抑制剂（sodium-glucose cotransporter inhibitors）将成为新型"药物性除颤器"。不过，即便这项重要的新研究也未阐明钠-葡萄糖协同转运蛋白抑制剂对心源性猝死预后的具体影响。