Four large-scale trials in type 2 diabetes have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent the occurrence of serious heart failure events. Additionally, the DAPA-HF trial demonstrated a benefit of dapagliflozin to reduce major adverse outcomes in patients with established heart failure with a reduced ejection fraction. The trial sheds light on potential mechanisms. In DAPA-HF, the benefits of dapagliflozin on heart failure were seen to a similar extent in both patients with or without diabetes, thus undermining the hypothesis that these drugs mitigate glycemia-related cardiotoxicity. The action of SGLT2 inhibitors to promote ketogenesis is also primarily a feature of the action of these drugs in patients with diabetes, raising doubts that enhanced ketogenesis contributes to the benefit on heart failure. Also, dapagliflozin does not have a meaningful effect to decrease circulating natriuretic peptides, and it did not potentiate the actions of diuretics in DAPA-HF; moreover, intensification of diuretics therapy does not reduce cardiovascular death, questioning a benefit of SGLT2 inhibitors that is mediated by an action on renal sodium excretion. Finally, although hematocrit increases with SGLT2 inhibitors might favorably affect patients with coronary artery disease, in DAPA-HF, the benefit of dapagliflozin was similar in patients with or without an ischemic cardiomyopathy; furthermore, increases in hematocrit do not favorably affect the clinical course of patients with heart failure. Therefore, the results of DAPA-HF do not support many currently-held hypotheses about the mechanism of action of SGLT2 inhibitors in heart failure. Ongoing trials are likely to provide further insights.

中文翻译：

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从DAPA-HF试验中汲取的经验教训涉及在即将完成的其他大型试验中SGLT2抑制剂对心力衰竭事件有益的机制。

两项针对2型糖尿病的大规模试验表明，钠-葡萄糖共转运蛋白2（SGLT2）抑制剂可预防严重的心力衰竭事件的发生。此外，DAPA-HF试验证明达格列净对减少已确立的心力衰竭且射血分数降低的患者的主要不良结局具有益处。该试验揭示了潜在的机制。在DAPA-HF中，无论有无糖尿病患者，达格列净对心力衰竭的益处均相似，从而破坏了这些药物减轻与血糖有关的心脏毒性的假设。SGLT2抑制剂促进生酮的作用也主要是这些药物在糖尿病患者中的作用特征，引起人们怀疑增生作用是否有助于改善心力衰竭。还，达格列净对减少循环中的利钠肽没有有意义的作用，并且不能增强DAPA-HF中利尿剂的作用。此外，加强利尿剂治疗并不能减少心血管死亡，这质疑了通过对肾钠排泄的作用介导的SGLT2抑制剂的益处。最后，尽管用SGLT2抑制剂增加血细胞比容可能会对冠心病患者产生有利影响，但在DAPA-HF中，达格列净的获益与缺血性心肌病或无缺血性心肌病的患者相似。此外，血细胞比容的增加不会对心力衰竭患者的临床病程产生有利的影响。因此，DAPA-HF的结果不支持关于SGLT2抑制剂在心力衰竭中的作用机理的许多当前存在的假设。