Cardiac Rehabilitation Unit, San Raffaele Scientific Institute, Milan, Italy.
Vita-Salute San Raffaele University and San Raffaele Scientific Institute, Milan, Italy.
Adv Exp Med Biol. 2021;1307:129-152. doi: 10.1007/5584_2020_514.
Diabetes mellitus is constantly increasing worldwide. Vascular complications are the most common in the setting of long-standing disease, claiming the greatest burden in terms of morbidity and mortality. Glucotoxicity is involved in vascular damage through different metabolic pathways, such as production of advanced glycation end-products, activation of protein kinase C, polyol pathway activation and production of reactive oxygen species. Vascular complications can be classified according to the calibre of the vessels involved as microvascular (such as diabetic retinopathy, nephropathy and neuropathy) or macrovascular (such as cerebrovascular, coronary and peripheral artery disease). Previous studies showed that the severity of vascular complications depends on duration and degree of hyperglycaemia and, as consequence, early trials were designed to prove that intensive glucose control could reduce the number of vascular events. Unfortunately, results were not as satisfactory as expected. Trials showed good results in reducing incidence of microvascular complications but coronary heart diseases, strokes and peripheral artery diseases were not affected despite optimal glycemia control. In 2008, after the demonstration that rosiglitazone increases cardiovascular risk, FDA demanded stricter rules for marketing glucose-lowering drugs, marking the beginning of cardiovascular outcome trials, whose function is to demonstrate the cardiovascular safety of anti-diabetic drugs. The introduction of new molecules led to a change in diabetes treatment, as some new glucose-lowering drugs showed not only to be safe but also to ensure cardiovascular benefit to diabetic patients. Empaglifozin, a sodium-glucose cotransporter 2 inhibitor, was the first molecule to show impressing results, followed on by glucagon-like peptide 1 receptor agonists, such as liraglutide. A combination of anti-atherogenic effects and hemodynamic improvements are likely explanations of the observed reduction in cardiovascular events and mortality. These evidences have opened a completely new era in the field of glucose-lowering drugs and of diabetes treatment in particular with respect to vascular complications.
糖尿病在全球范围内不断增加。血管并发症是长期疾病中最常见的，在发病率和死亡率方面造成了最大的负担。糖毒性通过不同的代谢途径参与血管损伤，例如产生晚期糖基化终产物、蛋白激酶 C 的激活、多元醇途径的激活和活性氧的产生。血管并发症可以根据涉及的血管的口径进行分类，例如微血管（如糖尿病视网膜病变、肾病和神经病）或大血管（如脑血管、冠状动脉和外周动脉疾病）。先前的研究表明，血管并发症的严重程度取决于高血糖的持续时间和程度，因此，早期试验旨在证明强化血糖控制可以减少血管事件的发生。不幸的是，结果并不如预期的那样令人满意。试验表明，降低微血管并发症的发生率效果良好，但尽管血糖控制最佳，冠心病、中风和外周动脉疾病仍未受到影响。2008 年，在证明罗格列酮增加心血管风险之后，FDA 对降低血糖药物的营销提出了更严格的规定，标志着心血管结局试验的开始，其功能是证明抗糖尿病药物的心血管安全性。新分子的引入改变了糖尿病的治疗方法，因为一些新的降糖药物不仅安全，而且还能确保糖尿病患者的心血管获益。钠-葡萄糖共转运蛋白 2 抑制剂恩格列净是第一个显示出令人印象深刻结果的分子，其次是胰高血糖素样肽 1 受体激动剂，如利拉鲁肽。抗动脉粥样硬化作用和血液动力学改善的结合可能是观察到心血管事件和死亡率降低的解释。这些证据为降糖药物领域，特别是糖尿病血管并发症的治疗开辟了一个全新的时代。
