Chu Neelima V, Kong Alice P S, Kim Dennis D, Armstrong Debra, Baxi Sunita, Deutsch Reena, Caulfield Michael, Mudaliar Sunder R, Reitz Richard, Henry Robert R, Reaven Peter D
Department of Endocrinology and Metabolism, VA San Diego Healthcare System/University of California, San Diego, California 92161, USA.
Diabetes Care. 2002 Mar;25(3):542-9. doi: 10.2337/diacare.25.3.542.
Traditional cardiovascular risk factors (CVRF) only partly explain the excessive risk of cardiovascular disease in patients with type 2 diabetes. There is now an increasing appreciation for many novel CVRF that occur largely as a result of insulin resistance and hyperinsulinemia. Therefore, we investigated whether diabetes medications that vary in their mechanism of action and ability to reduce insulin resistance may differ in their effects on both traditional and novel CVRF.
We compared the addition of metformin or troglitazone therapy on CVRF in 22 subjects with type 2 diabetes who remained in poor glycemic control (with HbA1c >8.5%) while taking glyburide 10 mg twice daily. Subjects were initially randomized to either metformin 850 mg once daily or troglitazone 200 mg once daily. Both medications were then titrated upward as needed to achieve fasting plasma glucose <120 mg/dl. Measures of glucose control, insulin resistance, and CVRF (blood pressure, lipids, plasminogen activator inhibitor-1, C-reactive protein, fibrinogen, and small dense LDL) were assessed both before and after therapy.
After 4 months of treatment, both metformin and troglitazone led to similar decreases in fasting plasma glucose and HbA1c. The reduction in insulin resistance determined by hyperinsulinemic-euglycemic clamp was nearly twofold greater with troglitazone than metformin. Metformin did not induce significant changes in blood pressure, LDL cholesterol, LDL size, HDL cholesterol, triglycerides, or plasminogen activator inhibitor-1. However, C-reactive protein did decrease by 33% (6 +/- 1 to 4 +/- 1 mg/l; P < 0.01) [corrected]. Troglitazone therapy was associated with increases in LDL size (26.21 +/- 0.22 to 26.56 +/- 0.25 nm; P=0.04) and HDL cholesterol (33 +/- 3 to 36 +/- 3 mg/dl; P=0.05) and decreases in triglycerides (197 +/- 19 to 155 +/- 23 mg/dl; P=0.07) and C-reactive protein by 60% (8 +/- 3 to 3 +/- 1 mg/l, P < 0.01) [corrected].
For patients with type 2 diabetes in whom maximal sulfonylurea therapy failed, the addition of the insulin sensitizer troglitazone seemed to have greater benefits on several traditional and novel CVRF than metformin therapy. These differences were not related to glycemic improvement but reflected, in part, the greater reduction in insulin resistance obtained with addition of troglitazone. These data suggest that medications that more effectively address this underlying metabolic defect may be more beneficial in reducing cardiovascular risk in type 2 diabetes.
传统心血管危险因素（CVRF）仅部分解释了2型糖尿病患者心血管疾病风险过高的原因。现在人们越来越认识到许多新的CVRF，它们主要是由胰岛素抵抗和高胰岛素血症引起的。因此，我们研究了作用机制和降低胰岛素抵抗能力不同的糖尿病药物对传统和新型CVRF的影响是否存在差异。
我们比较了二甲双胍或曲格列酮治疗对22例2型糖尿病患者CVRF的影响，这些患者在每日两次服用10 mg格列本脲的情况下血糖控制仍较差（糖化血红蛋白>8.5%）。受试者最初被随机分为每日一次服用850 mg二甲双胍或每日一次服用200 mg曲格列酮。然后根据需要增加两种药物的剂量，以使空腹血糖<120 mg/dl。在治疗前后评估血糖控制、胰岛素抵抗和CVRF（血压、血脂、纤溶酶原激活物抑制剂-1、C反应蛋白、纤维蛋白原和小而密低密度脂蛋白）的指标。
治疗4个月后，二甲双胍和曲格列酮均使空腹血糖和糖化血红蛋白有相似程度的下降。通过高胰岛素-正常血糖钳夹测定的胰岛素抵抗降低幅度，曲格列酮比二甲双胍大近两倍。二甲双胍未引起血压、低密度脂蛋白胆固醇、低密度脂蛋白大小、高密度脂蛋白胆固醇、甘油三酯或纤溶酶原激活物抑制剂-1的显著变化。然而，C反应蛋白确实下降了33%（从6±1降至4±1 mg/l；P<0.01）[校正后]。曲格列酮治疗与低密度脂蛋白大小增加（从26.21±0.22增至26.56±0.25 nm；P=0.04）、高密度脂蛋白胆固醇增加（从33±3增至36±3 mg/dl；P=0.05）以及甘油三酯降低（从197±19降至155±23 mg/dl；P=0.07）和C反应蛋白下降60%（从8±3降至3±1 mg/l，P<0.01）[校正后]有关。
对于最大剂量磺脲类治疗失败的2型糖尿病患者，加用胰岛素增敏剂曲格列酮似乎比二甲双胍治疗对几种传统和新型CVRF有更大益处。这些差异与血糖改善无关，部分反映了加用曲格列酮后胰岛素抵抗降低幅度更大。这些数据表明，更有效地解决这种潜在代谢缺陷的药物可能在降低2型糖尿病患者心血管风险方面更有益。
