Kusatsu General Hospital, Kusatsu, Japan.
Department of Medicine, Shiga University of Medical Science, Otsu, Japan.
J Diabetes Investig. 2021 Jan;12(1):6-20. doi: 10.1111/jdi.13329. Epub 2020 Aug 5.
Recent major clinical trials of the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes have shown that they reduce three-point major adverse cardiovascular events, cardiovascular death, hospitalization for heart failure (HF) and a composite renal outcome. These beneficial effects of SGLT2 inhibitors are also evident in type 2 diabetes patients with a previous history of atherosclerotic cardiovascular disease or advanced renal disease. HF is a major determinant of the prognosis of diabetes patients. Although HF with low ejection fraction can be effectively treated with antihypertensive drugs, these treatments do not reduce mortality in HF patients with preserved ejection fraction (HFpEF). HFpEF is clinically characterized by left ventricular diastolic dysfunction, perivascular fibrosis and stiffness of cardiomyocytes, defined as "cardiomyopathy". Therefore, HFpEF is considered to be an entirely separate entity to HF with low ejection fraction. Recent studies have suggested that HFpEF might be treatable using SGLT2 inhibitors, which ameliorate visceral adiposity, insulin resistance, hyperglycemia, hyperlipidemia, volume overload, hypertension and cardiac inflammation. In the final part of the present review, we discuss the biochemical and molecular mechanisms of the effects of SGLT2 inhibitors in type 2 diabetes patients with HFpEF. These involve amelioration of the low nitric oxide production and oxidative stress, a reduction in cardiac inflammatory cytokine signaling, inhibition of Ca overload, and an improvement in cardiac energy metabolism as a result of ketone body production. Investigations of the beneficial effects of SGLT2 inhibitors on cardiorenal outcomes, including hospitalization for HF, are now being carried out in preclinical and clinical studies.
最近，钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂在 2 型糖尿病患者中的应用的大型临床试验表明，SGLT2 抑制剂可降低三项主要不良心血管事件、心血管死亡、心力衰竭（HF）住院和复合肾脏结局。在有动脉粥样硬化性心血管疾病或晚期肾脏疾病史的 2 型糖尿病患者中，SGLT2 抑制剂也具有这些有益作用。HF 是糖尿病患者预后的主要决定因素。虽然使用降压药物可以有效治疗射血分数降低的 HF，但这些治疗并不能降低射血分数保留的 HF（HFpEF）患者的死亡率。HFpEF 的临床特征为左心室舒张功能障碍、血管周围纤维化和心肌细胞僵硬，定义为“心肌病”。因此，HFpEF 被认为与射血分数降低的 HF 是完全不同的实体。最近的研究表明，SGLT2 抑制剂可能可用于治疗 HFpEF，其可改善内脏肥胖、胰岛素抵抗、高血糖、高血脂、容量超负荷、高血压和心脏炎症。在本综述的最后一部分，我们讨论了 SGLT2 抑制剂在 HFpEF 合并 2 型糖尿病患者中的作用的生化和分子机制。这些机制涉及改善低一氧化氮产生和氧化应激、减少心脏炎症细胞因子信号传导、抑制钙超载以及由于酮体产生而改善心脏能量代谢。目前正在进行临床前和临床研究，以调查 SGLT2 抑制剂对包括 HF 住院在内的心肾结局的有益作用。
