Cersosimo Eugenio, Miles John M
Department of Medicine, Division of Diabetes, University of Texas Health Science Center, San Antonio, TX, United States.
Department of Medicine, Division of Metabolism, Endocrinology & Genetics, University of Kansas Medical Center, Kansas City, KS, United States.
Curr Diabetes Rev. 2019;15(4):314-327. doi: 10.2174/1573399814666180813124645.
BACKGROUND & INTRODUCTION: The advent of the sodium-glucose cotransporter-2 inhibitors [SGLT-2i] provides an additional tool to combat diabetes and complications. The use of SGLT-2i leads to effective and durable glycemic control with important reductions in body weight/fat and blood pressure. These agents may delay beta-cell deterioration and improve tissue insulin sensitivity, which might slow the progression of the disease.
METHODS & RESULTS: In response to glycosuria, a compensatory rise in endogenous glucose production, sustained by a decrease in plasma insulin with an increase in glucagon has been described. Other possible mediators have been implicated and preliminary findings suggest that a sympathoadrenal discharge and/or rapid elevation in circulating substrates (i.e., fatty acids) or some yet unidentified humoral factors may have a role in a renal-hepatic inter-organ relationship. A possible contribution of enhanced renal gluconeogenesis to glucose entry into the systemic circulation has not yet been ruled out. Additionally, tissue glucose utilization decreases, whereas adipose tissue lipolysis is stimulated and, there is a switch to lipid oxidation with the formation of ketone bodies; the risk for keto-acidosis may limit the use of SGLT-2i. These metabolic adaptations are part of a counter-regulatory response to avoid hypoglycemia and, as a result, limit the SGLT-2i therapeutic efficacy. Recent trials revealed important cardiovascular [CV] beneficial effects of SGLT-2i drugs when used in T2DM patients with CV disease. Although the underlying mechanisms are not fully understood, there appears to be "class effect". Changes in hemodynamics and electrolyte/body fluid distribution are likely involved, but there is no evidence for anti-atherosclerotic effects.
It is anticipated that, by providing durable diabetes control and reducing CV morbidity and mortality, the SGLT-2i class of drugs is destined to become a priority choice in diabetes management.
钠-葡萄糖协同转运蛋白2抑制剂（SGLT-2i）的出现为对抗糖尿病及其并发症提供了一种新工具。使用SGLT-2i可实现有效且持久的血糖控制，同时能显著减轻体重/体脂并降低血压。这些药物可能会延缓β细胞功能衰退并改善组织胰岛素敏感性，进而可能减缓疾病进展。
针对糖尿现象，已有研究描述了内源性葡萄糖生成的代偿性增加，这一过程由血浆胰岛素减少及胰高血糖素增加所维持。其他可能的介质也被提及，初步研究结果表明，交感肾上腺系统激活和/或循环底物（如脂肪酸）的快速升高或某些尚未明确的体液因子可能在肾-肝器官间关系中发挥作用。增强的肾糖异生对葡萄糖进入体循环的可能贡献尚未被排除。此外，组织葡萄糖利用减少，而脂肪组织脂解受到刺激，并且会转向脂质氧化并生成酮体；酮症酸中毒风险可能会限制SGLT-2i的使用。这些代谢适应性变化是避免低血糖的反调节反应的一部分，因此限制了SGLT-2i的治疗效果。近期试验显示，SGLT-2i类药物用于患有心血管疾病的2型糖尿病患者时具有重要的心血管（CV）有益作用。尽管其潜在机制尚未完全明确，但似乎存在“类效应”。血流动力学以及电解质/体液分布的变化可能参与其中，但尚无抗动脉粥样硬化作用的证据。
预计通过提供持久的糖尿病控制并降低心血管疾病的发病率和死亡率，SGLT-2i类药物注定会成为糖尿病管理中的优先选择。
