Division of Diabetes, Nutrition and Metabolic Disorders, CHU Liège, Liège, Belgium.
Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), Liège University, Liège, Belgium.
Drugs. 2024 Nov;84(11):1347-1364. doi: 10.1007/s40265-024-02090-9. Epub 2024 Sep 28.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have proven efficacy and safety in randomized clinical trials and observational real-life studies. Besides improving glucose control, reducing body weight, and lowering arterial blood pressure (surrogate endpoints), the breakthroughs were the demonstration of a significant reduction in cardiovascular and renal events in patients with type 2 diabetes at high risk. GLP-1RAs reduce events linked to atherogenic cardiovascular disease (especially ischemic stroke) and also renal outcomes (FLOW trial with semaglutide), with a limited effect on heart failure. The most striking protective effects of SGLT2is were a marked reduction in hospitalization for heart failure and a remarkable reduced progression of chronic kidney disease. These benefits have been attributed to numerous pleiotropic effects beyond glucose-lowering action. Underlying mechanisms contributing to cardiovascular and renal protection are at least partially different between GLP-1RAs (mainly anti-atherogenic and vascular effects) and SGLT2is (mainly systemic and intrarenal hemodynamic changes). Thus, patients at high risk may benefit from complementary actions when being treated with a GLP-1RA/SGLT2i combination. Such combination has proven its efficacy on surrogate endpoints. Furthermore, post hoc subgroup analyses of cardiovascular outcome trials have suggested a greater cardiorenal protection in patients treated with a combination versus either monotherapy. The benefits of a combined therapy have been confirmed in a few retrospective cohort studies. A dedicated prospective trial comparing a combined therapy versus either monotherapy is ongoing (PRECIDENTD); however, several challenges still remain, especially the higher cost of a combined therapy and the worldwide underuse of either GLP-1RAs or SGLT2is in clinical practice, even in patients at high cardiorenal risk.
胰高血糖素样肽-1 受体激动剂（GLP-1RAs）和钠-葡萄糖共转运蛋白 2 抑制剂（SGLT2is）在随机临床试验和观察性真实研究中已被证明具有疗效和安全性。除了改善血糖控制、减轻体重和降低动脉血压（替代终点）外，这些突破性进展还在于证明 2 型糖尿病高危患者的心血管和肾脏事件显著减少。GLP-1RAs 可减少与动脉粥样硬化性心血管疾病（尤其是缺血性中风）相关的事件，也可改善肾脏结局（用司美格鲁肽进行的 FLOW 试验），对心力衰竭的影响有限。SGLT2is 最显著的保护作用是心力衰竭住院率显著降低，慢性肾脏病进展显著减少。这些益处归因于除降低血糖作用之外的许多多效性作用。GLP-1RAs（主要是抗动脉粥样硬化和血管作用）和 SGLT2is（主要是全身和肾内血流动力学变化）之间导致心血管和肾脏保护的潜在机制至少部分不同。因此，高危患者在接受 GLP-1RA/SGLT2i 联合治疗时可能受益于互补作用。这种联合治疗已被证明在替代终点上有效。此外，心血管结局试验的事后亚组分析表明，与单药治疗相比，联合治疗的患者具有更大的心脏肾脏保护作用。几项回顾性队列研究证实了联合治疗的益处。一项比较联合治疗与单药治疗的专门前瞻性试验（PRECIDENTD）正在进行中；然而，仍存在一些挑战，尤其是联合治疗的成本更高，以及全球范围内 GLP-1RAs 或 SGLT2is 在临床实践中的使用率较低，即使在心脏肾脏风险较高的患者中也是如此。
