Institute for Clinical Chemistry, University Hospital Zurich and University of Zürich, Zurich, Switzerland; Department of Cardiology, Heart Center, University Hospital Zurich and University of Zürich, Zurich, Switzerland.
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
Pharmacol Res. 2023 Feb;188:106667. doi: 10.1016/j.phrs.2023.106667. Epub 2023 Jan 16.
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective, well-tolerated, and safe glucose-lowering compounds for patients with type 2 diabetes mellitus (T2DM). SGLT2i benefit encompasses protection from heart and kidney failure, independently of the presence of diabetes. In addition, SGLT2i consistently reduce the risk of hospitalization for heart failure and, although with some heterogeneity between specific members of the class, favourably affect the risk of cardiovascular outcomes. The molecular mechanisms underlying the cardiovascular favourable effect are not fully clarified. Studies testing the efficacy of SGLT2i in human cohorts and experimental models of atherosclerotic cardiovascular disease (ASCVD) have reported significant differences in circulating levels and composition of lipoprotein classes. In randomized clinical trials, small but significant increases in low-density lipoprotein cholesterol (LDL-C) levels have been observed, with a still undefined clinical significance; on the other hand, favourable (although modest) effects on high-density lipoprotein cholesterol (HDL-C) and triglycerides have been reported. At the molecular level, glycosuria may promote a starving-like state that ultimately leads to a metabolic improvement through the mobilization of fatty acids from the adipose tissue and their oxidation for the production of ketone bodies. This, however, may also fuel hepatic cholesterol synthesis, thus inhibiting atherogenic lipoprotein uptake from the liver. Long-term studies collecting detailed information on lipid-lowering therapies at baseline and during the trials with SGLT2i, as well as regularly monitoring lipid profiles are warranted to disentangle the potential implications of SGLT2i in modulating lipoprotein-mediated atherosclerotic cardiovascular risk.
钠-葡萄糖共转运蛋白 2 抑制剂（SGLT2i）是治疗 2 型糖尿病（T2DM）患者的有效、耐受良好且安全的降糖药物。SGLT2i 的益处包括对心力衰竭和肾脏衰竭的保护作用，且独立于糖尿病的存在。此外，SGLT2i 可一致降低心力衰竭住院风险，虽然在该类药物的特定成员之间存在一定的异质性，但可有利地影响心血管结局风险。心血管保护作用的分子机制尚未完全阐明。在人类队列和动脉粥样硬化性心血管疾病（ASCVD）的实验模型中测试 SGLT2i 疗效的研究报告称，脂蛋白类别的循环水平和组成存在显著差异。在随机临床试验中，观察到低密度脂蛋白胆固醇（LDL-C）水平出现微小但显著的升高，但临床意义仍不明确；另一方面，高密度脂蛋白胆固醇（HDL-C）和甘油三酯也有有利（尽管幅度较小）的影响。在分子水平上，糖尿可能会导致类似于饥饿的状态，通过从脂肪组织动员脂肪酸并将其氧化为酮体，最终导致代谢改善。然而，这也可能促进肝脏胆固醇的合成，从而抑制肝脏摄取致动脉粥样硬化的脂蛋白。需要进行长期研究，在基线和 SGLT2i 试验期间收集有关降脂治疗的详细信息，并定期监测血脂谱，以阐明 SGLT2i 调节脂蛋白介导的动脉粥样硬化心血管风险的潜在意义。
