Goldstein Barry J, Weissman Peter N, Wooddell Margaret J, Waterhouse Brian R, Cobitz Alexander R
Division of Endocrinology, Diabetes and Metabolic Diseases, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA.
Curr Med Res Opin. 2006 Sep;22(9):1715-23. doi: 10.1185/030079906X115720.
To compare the effects of rosiglitazone added to metformin with dose escalation of metformin on cardiovascular risk biomarkers in type 2 diabetes mellitus.
Cardiovascular biomarkers were assessed in a sub-population of 122 subjects with type 2 diabetes mellitus (mean age 54.6 and 56.0 years, BMI 34.7 and 32.1 kg/m2; for the rosiglitazone plus metformin and metformin groups, respectively) from the multicenter (63 centers in the USA), double-blind, randomized parallel-group Escalation of Metformin theraPy vs. Initiation of Rosiglitazone Early (EMPIRE) study. Treatment group sizes were slightly imbalanced owing to central, rather than local, randomization. Subjects receiving metformin 1000 mg/day at baseline were randomized to rosiglitazone 4 mg/day plus metformin 1000 mg/day (RSG + MET) or metformin 1500 mg/day (up-titrated MET) for 24 weeks. At 8-weeks, rosiglitazone was increased to 8 mg/day in RSG + MET recipients and metformin to 2000 mg/day in up-titrated MET recipients.
Reductions from baseline in HbA1c at week 24 (mean +/- SD) occurred in both groups (RSG + MET: -0.61% +/- 1.16%; up-titrated MET: -0.65% +/- 1.18%). Post-prandial glucose levels (AUC(0-3h)) decreased with RSG + MET (-3.5 mmol/L.h; 95% confidence interval [CI]: -5.2 to -1.8) and up-titrated MET (-1.3 mmol/L.h; 95% CI: -3.8 to 1.1). Homeostasis Model Assessment (HOMA)-estimated insulin sensitivity increased by 37.7% (95% CI: 22.8 to 54.5) in RSG + MET and 6.9% (95% CI: -6.2 to 21.9) in up-titrated MET recipients. RSG + MET reduced C-reactive protein (CRP; -23.9%; 95% CI: -40.4 to -2.8), plasminogen activator inhibitor-1 (PAI-1) activity (-30.1%; 95% CI: -44.5 to -11.9), PAI-1 antigen (-15.5%; 95% CI: -28.3 to -0.3) and matrix metalloproteinase-9 (MMP-9; -13.8%; 95% CI: -25.1 to -0.9), but increased tumor necrosis factor-alpha (TNF-alpha; 27.0%; 95% CI: 6.8 to 50.9). Corresponding values for up-titrated MET were CRP -9.3% (95% CI: -36.9 to 30.2), PAI-1 activity -7.2% (95% CI: -28.2 to 20.0), PAI-1 antigen -1.5% (95% CI: -17.4 to 17.5), MMP-9 29.0% (95% CI: -1.3 to 68.6) and TNF-alpha -6.0% (95% CI: -22.0 to 13.2).
These results suggest that rosiglitazone plus metformin has positive cardiovascular effects against a background of similar glycemic improvements.
比较在二甲双胍基础上加用罗格列酮与增加二甲双胍剂量对2型糖尿病患者心血管风险生物标志物的影响。
在多中心（美国63个中心）、双盲、随机平行组二甲双胍治疗剂量递增与早期起始罗格列酮治疗（EMPIRE）研究中，对122例2型糖尿病患者亚组（罗格列酮加二甲双胍组和二甲双胍组的平均年龄分别为54.6岁和56.0岁，体重指数分别为34.7和32.1kg/m²）的心血管生物标志物进行评估。由于采用中央随机而非局部随机，治疗组规模略有失衡。基线时接受每日1000mg二甲双胍治疗的受试者被随机分为每日4mg罗格列酮加1000mg二甲双胍（RSG+MET）组或每日1500mg二甲双胍（剂量递增二甲双胍）组，治疗24周。8周时，RSG+MET组罗格列酮增至每日8mg，剂量递增二甲双胍组二甲双胍增至每日2000mg。
两组在第24周时糖化血红蛋白（HbA1c）较基线均有降低（RSG+MET组：-0.61%±1.16%；剂量递增二甲双胍组：-0.65%±1.18%）。餐后血糖水平（AUC(0-3h)）在RSG+MET组降低（-3.5mmol/L·h；95%置信区间[CI]：-5.2至-1.8），在剂量递增二甲双胍组降低（-1.3mmol/L·h；95%CI：-3.8至1.1）。稳态模型评估（HOMA）估计的胰岛素敏感性在RSG+MET组增加37.7%（95%CI：22.8至54.5），在剂量递增二甲双胍组增加6.9%（95%CI：-6.2至21.9）。RSG+MET组降低了C反应蛋白（CRP；-23.9%；95%CI：-40.4至-2.8）、纤溶酶原激活物抑制剂-1（PAI-1）活性（-30.1%；95%CI：-44.5至-11.9）、PAI-1抗原（-15.5%；95%CI：-28.3至-0.3）和基质金属蛋白酶-9（MMP-9；-13.8%；95%CI：-25.1至-0.9），但增加了肿瘤坏死因子-α（TNF-α；27.0%；95%CI：6.8至50.9）。剂量递增二甲双胍组的相应值为CRP -9.3%（95%CI：-36.9至30.2）、PAI-1活性 -7.2%（95%CI：-28.2至20.0）、PAI-1抗原 -1.5%（95%CI：-17.4至17.5）、MMP-9 29.0%（95%CI：-1.3至68.6）和TNF-α -6.0%（95%CI：-22.0至13.2）。
这些结果表明，在血糖改善程度相似的背景下，罗格列酮加二甲双胍具有积极的心血管效应。
