Clinic for Internal Medicine III, University of the Saarland, Homburg 66421, Germany.
Cardiology Unit, IRCCS Policlinic Hospital San Martino & Department of Internal Medicine, University of Genova, Genova 16132, Italy.
Cardiovasc Res. 2018 Jan 1;114(1):12-18. doi: 10.1093/cvr/cvx149.
The effects of intense glycaemic control on macrovascular complications in patients with type 2 diabetes are incompletely resolved, and many glucose-lowering medications negatively affect cardiovascular outcomes. Recently, the EMPA-REG OUTCOME trial revealed that empagliflozin, an inhibitor of the sodium-glucose cotransporter 2 (SGLT2), substantially reduced the risk of hospitalization for heart failure, death from cardiovascular causes, and all-cause mortality in patients with type 2 diabetes mellitus at high cardiovascular risk. Although several mechanisms may explain this benefit, plasma volume contraction and a metabolic switch favouring cardiac ketone bodies oxidation have recently been proposed as the major drivers. Recent experimental work has prompted a novel and intriguing hypothesis, according to which empagliflozin may reduce intracellular sodium (Na+) load observed in failing cardiac myocytes by inhibiting the sarcolemmal Na+/H+ exchanger. Since elevated intracellular Na+ hampers mitochondrial Ca2+ handling and thereby, deteriorates energy supply and demand matching and the mitochondrial antioxidative defence systems, empagliflozin may positively affect cardiac function by restoring mitochondrial function, and redox state in the failing heart. Here, we review the current evidence for such a third mechanistic hypothesis, which may foster heart failure and diabetes research into a new direction which harbours several potential targets for therapeutic intervention.
强化血糖控制对 2 型糖尿病患者大血管并发症的影响仍不明确，且许多降糖药物对心血管结局产生负面影响。最近，EMPA-REG OUTCOME 试验表明，钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂恩格列净可显著降低高心血管风险的 2 型糖尿病患者因心力衰竭住院、心血管原因死亡和全因死亡率的风险。尽管有几种机制可以解释这种益处，但最近提出了两个主要驱动因素，即血容量收缩和代谢转换有利于心脏酮体氧化。最近的实验工作提出了一个新颖而有趣的假设，即恩格列净可能通过抑制肌细胞膜 Na+/H+交换器来减少衰竭心肌细胞中观察到的细胞内钠离子（Na+）负荷。由于细胞内 Na+升高会干扰线粒体 Ca2+处理，从而恶化能量供应和需求匹配以及线粒体抗氧化防御系统，因此恩格列净可能通过恢复线粒体功能和氧化还原状态来改善衰竭心脏的功能，从而对心脏功能产生积极影响。在这里，我们回顾了这种第三种机制假说的现有证据，这可能会将心力衰竭和糖尿病的研究推向一个新的方向，其中包含几个潜在的治疗干预靶点。
