Scheen André J
Division of Diabetes, Nutrition and Metabolic Disorders, CHU Liège, and Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), Liège University, Liège, Belgium.
Diabetes Metab. 2021 Jul;47(4):101209. doi: 10.1016/j.diabet.2020.11.001. Epub 2020 Nov 12.
Preliminary data have suggested that metformin might potentiate cardiovascular (CV) protection by dipeptidyl peptidase-4 inhibitors (DPP-4is), but reduce CV protection by sodium-glucose cotransporter type-2 inhibitors (SGLT2is), in patients with type 2 diabetes (T2DM) at high CV-related risk. For this reason, the present meta-analyses aimed to compare metformin moderation of the CV effects of the two pharmacological classes.
Major adverse CV events (3-point MACEs) were counted in high-risk patients with T2DM treated with or without metformin as background therapy in five CV outcome trials with DPP-4is (SAVOR-TIMI 53, EXAMINE, TECOS, CARMELINA, CAROLINA) involving 24,821 patients (17,870 with and 6951 without metformin) and 2550 events (1696 with and 854 without metformin), and four trials with SGLT2is (EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, VERTIS CV) involving 24,563 patients (19,090 with and 5473 without metformin) and 1829 events (1300 with and 529 without metformin).
DPP-4is failed to reduce 3-point MACEs in both metformin users (OR: 0.96, 95% CI: 0.89-1.03) and non-users (OR: 1.05, 95% CI: 0.95-1.16), with no heterogeneity between trials and no significant between-subgroup differences (P = 0.4074), whereas SGLT2is significantly reduced 3-point MACEs in both patients with (OR: 0.91, 95% CI: 0.84-0.98) and without (OR: 0.81, 95% CI: 0.71-0.91) metformin, but again with no heterogeneity between trials and no significant between-subgroup differences (P = 0.2977). Overall, metformin non-users had a poorer risk profile than metformin users.
Our meta-analyses involving a larger number of trials than before have revealed that background metformin therapy has no significant influence on either the neutral impact of DPP-4is or the positive impact of SGLT2is on CV events (3-point MACEs) in T2DM patients at high CV risk.
初步数据表明，在心血管疾病（CV）相关风险较高的2型糖尿病（T2DM）患者中，二甲双胍可能增强二肽基肽酶-4抑制剂（DPP-4is）的心血管保护作用，但会降低钠-葡萄糖协同转运蛋白2抑制剂（SGLT2is）的心血管保护作用。因此，本荟萃分析旨在比较二甲双胍对这两类药物心血管效应的调节作用。
在五项使用DPP-4is的心血管结局试验（SAVOR-TIMI 53、EXAMINE、TECOS、CARMELINA、CAROLINA）中，对24821例患者（17870例使用二甲双胍，6951例未使用二甲双胍）和2550起事件（1696起使用二甲双胍，854起未使用二甲双胍）进行了计数，这些试验将使用或不使用二甲双胍作为背景治疗的高危T2DM患者的主要不良心血管事件（3分主要不良心血管事件）进行了统计；在四项使用SGLT2is的试验（EMPA-REG OUTCOME、CANVAS、DECLARE-TIMI 58、VERTIS CV）中，对24563例患者（19090例使用二甲双胍，5473例未使用二甲双胍）和1829起事件（1300起使用二甲双胍，529起未使用二甲双胍）进行了统计。
DPP-4is在使用二甲双胍的患者（比值比：0.96，95%置信区间：0.89-1.03）和未使用二甲双胍的患者（比值比：1.05，95%置信区间：0.95-1.16）中均未能降低3分主要不良心血管事件，试验间无异质性，亚组间无显著差异（P = 0.4074）；而SGLT2is在使用（比值比：0.91，95%置信区间：0.84-0.98）和未使用（比值比：0.81，95%置信区间：0.71-0.91）二甲双胍的患者中均显著降低了3分主要不良心血管事件，但试验间同样无异质性，亚组间无显著差异（P = 0.2977）。总体而言，未使用二甲双胍的患者风险状况比使用二甲双胍的患者更差。
我们的荟萃分析纳入的试验数量比以前更多，结果显示，背景二甲双胍治疗对DPP-4is的中性影响或SGLT2is对高心血管风险T2DM患者心血管事件（3分主要不良心血管事件） 的积极影响均无显著影响。
