Effects of Acarbose Versus Glibenclamide on Glycemic Excursion and Oxidative Stress in Type 2 Diabetic Patients Inadequately Controlled by Metformin: A 24-Week, Randomized, Open-Label, Parallel-Group Comparison
Effects of Acarbose Versus Glibenclamide on Glycemic Excursion and Oxidative Stress in Type 2 Diabetic Patients Inadequately Controlled by Metformin: A 24-Week, Randomized, Open-Label, Parallel-Group Comparison
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DOI：
10.1016/j.clinthera.2011.10.014
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发表时间：
2011-12-01
影响因子：
3.2
通讯作者：
Sheu, Wayne Huey-Herng
中科院分区：
文献类型：
--
作者：
Wang, Jun-Sing;Lin, Shi-Dou;Sheu, Wayne Huey-Herng
背景：血糖漂移与氧化应激密切相关，氧化应激在2型糖尿病(T2 DM)慢性并发症的发生发展中起着重要作用。据报道，阿卡波糖可以降低糖耐量受损和2型糖尿病患者的心血管风险。我们假设阿卡波糖治疗可以减轻2型糖尿病患者的血糖漂移和氧化应激。目的：本研究旨在评价阿卡波糖和格列本脲对二甲双胍控制不充分的T2 DM患者血糖漂移平均幅度(MAGE)和氧化应激的影响。方法：30~70岁，单、双联口服降糖药物治疗3个月，糖化血红蛋白(HbA1c)在7.0%~11.0%之间的T2 DM门诊患者符合条件。患者接受二甲双胍单药治疗(每天1500毫克)，为期8周，然后随机服用阿卡波糖或格列本脲附加剂，为期16周。阿卡波糖和格列本脲剂量前4周分别为50mgtid和2.5mgtid。在接下来的12周里，两组的剂量都增加了一倍。在随机分组前和研究结束时分别进行72h连续血糖监测(CGM)和隔夜禁食10h后的进食耐量试验(MTT值)。MAGE由CGM数据计算得出。胰岛β细胞对餐后血糖增加的反应是通过在四甲基偶氮唑蓝试验中胰岛素增加的AUC与葡萄糖的比率来评估的。氧化应激通过血浆氧化低密度脂蛋白(ox-LDL)和尿8-iso前列腺素F(2α)排泄率(8-iso PGF(2α))来评估。主要结果包括MAGE、血浆oxLDL和尿8-iso PGF(2α)排泄量的变化。结果：55例患者(平均年龄54岁；男性47%；平均体重指数25.9 kg/m(2)；平均糖尿病病程6.9年；平均糖化血红蛋白(1c)8.3%)和矽肺患者(阿卡波糖28例；格列本脲23例)完成本研究。两组HbA(1c)c均显著降低(阿卡波糖：8.2[0.8]%至7.5[0.8]%[P<；0.001]；格列本脲：8.6[1.6]%至7.4[1.2]%[P<；0.001])。格列本脲治疗后MAGE无明显变化(6.22.8mmol.L至6.3mmol.L；P=0.82.)，而氧化型低密度脂蛋白(242.4[180.9]ng/mLvs470.7[247.3]ng/mLp=0.004)和尿8-iso PGF(2α)排泄量(121.6[39.6pmol/mmolcreatinine，152.5[41.8pmoL/mmocinine；P=0.004])显著增加。阿卡波糖降低MAGE(5.61.5-1.4mmol.L；P<；0.001)，但对氧化低密度脂蛋白水平(254.4[269.1]ng/mLvs298.5[249.8]ng/mL0.62)或8-iso PGF(2α)排泄率(117.9[58.1pmol/mmoL肌酐至137.8[64.4pmoL/mmol肌酐；P=0.001)]无明显影响。阿卡波糖治疗后体重和血清甘油三酯(空腹及餐后2小时)下降(P<0.01)，脂联素升高(P<；0.05)，而高密度脂蛋白胆固醇(HDLc)下降(P<；0.01)。P细胞对餐后血糖升高的反应与MAGE呈负相关(r=0.570，P<；0.001)，阿卡波糖显著改善P细胞对餐后血糖的反应(35.6[32.2]pmol/mmo1~56.4[43.7pmo1/mmo1]，P=0.001)，而格列本脲则无明显改善作用(27.9[17.6]pmol/mmo1~36.5[24.2]pmo1/mmo1；P=0.12)。然而，阿卡波糖治疗降低了MAGE、体重和血清甘油三酯，升高了血清脂联素，但对氧化应激没有显著影响。格列本脲治疗对MAGE无统计学意义，但增加氧化应激，降低高密度脂蛋白胆固醇。ClinicalTrials.gov标识符：NCT00417729。(CLIN THER.2011；33：1932-1942)(C)2011 Elsevier HS Journal，Inc.保留所有权利。
Background: Glycemic excursion is significantly associated with oxidative stress, which plays a role in the development of chronic complications in type 2 diabetes mellitus (T2DM). Acarbose has been reported to reduce cardiovascular risk in patients with impaired glucose tolerance and T2DM. We hypothesize that treatment with acarbose could attenuate glycemic excursions and reduce oxidative stress in patients with T2DM.Objective: This study aimed to evaluate the effects of acarbose versus glibenclamide on mean amplitude of glycemic excursions (MAGE) and oxidative stress in patients with T2DM who are insufficiently controlled by metformin.Methods: T2DM outpatients aged 30 to 70 years who were taking single or dual oral antidiabetic drugs for >= 3 months and had a glycosylated hemoglobin (HbA(1c)) value between 7.0% and 11.0% were eligible. Patients were treated with metformin monotherapy (1500 mg daily) for 8 weeks, followed by randomization to either acarbose or glibenclamide add-on for 16 weeks. The dosage of acarbose and glibenclamide was 50 mg TID and 2.5 mg TID, respectively, for the first 4 weeks. In the following 12 weeks, the dosage was doubled in both groups. Continuous glucose monitoring (CGM) for 72 hours and a meal tolerance test (MTT) after a 10-hour overnight fast were conducted before randomization and at the end of study. MAGE was calculated from CGM data. beta-cell response to postprandial glucose increments was assessed by the ratio between incremental AUC of insulin and glucose during MTT. Oxidative stress was estimated by plasma oxidized LDL (ox-LDL) and urinary excretion rates of 8-iso prostaglandin F(2 alpha) (8-iso PGF(2 alpha)). The primary outcomes included changes in MAGE, plasma oxLDL, and urinary excretion of 8-iso PGF(2 alpha). Adverse events, including hypoglycemia, were recorded.Results: A total of 55 patients were randomized (mean age, 54 years; males, 47%; mean body mass index, 25.9 kg/m(2); mean duration of diabetes, 6.9 years; mean HbA(1c), 8.3%) and Si patients completed this study (acarbose, n = 28; glibenclamide, n = 23). HbA(1c) c decreased significantly in both treatment groups (acarbose: 8.2 [0.8]% to 7.5 [0.8]% [P < 0.001]; glibenclamide: 8.6 [1.6]% to 7.4 [1.2]% [P < 0.001]). MAGE did not change significantly in glibenclamide-treated patients (6.2 [2.8] mmol/L to 6.3 [2.3] mmol/L; P = 0.82), whereas ox-LDL (242.4 [180.9] ng/mL to 470.7 [247.3] ng/mL; P = 0.004) and urinary excretion of 8-iso PGF(2 alpha) (121.6 [39.6] pmol/mmol creatinine to 152.5 [41.8] pmol/mmol creatinine; P = 0.03) increased significantly. Acarbose decreased MAGE (5.6 [1.5] mmol/L to 4.0 [1.4] mmol/L; P < 0.001) without significant change in ox-LDL levels (254.4 [269.1] ng/mL to 298.5 [249.8] ng/mL; P = 0.62) or 8-iso PGF(2 alpha) excretion rates (117.9 [58.1] pmol/mmol creatinine to 137.8 [64.4] pmol/mmol creatinine; P = 0.12). Body weight and serum triglycerides (fasting and 2-hour postprandial) decreased (all, P < 0.01) and serum adiponectin increased (P < 0.05) after treatment with acarbose, whereas HDL-C decreased (P < 0.01) after treatment with glibenclamide. P-cell response to postprandial glucose increments was negatively correlated with MAGE (r = 0.570, P < 0.001) and improved significantly with acarbose (35.6 [32.2] pmol/mmol to 56.4 [43.7] pmol/mmol; P = 0.001) but not with glibenclamide (27.9 [17.6] pmol/mmol to 36.5 [24.2] pmol/mmol; P = 0.12).Conclusions: In this select population of adult Taiwanese patients with T2DM who were inadequately controlled by metformin, add-on acarbose or glibenclamide significantly reduced HbA(1c). However, treatment with acarbose decreased MAGE, body weight, and serum triglyceride and increased serum adiponectin without significant effect on oxidative stress. Treatment with glibenclamide had no statistically significant effect on MAGE but increased oxidative stress and decreased HDL-C. ClinicalTrials.gov identifier: NCT00417729. (Clin Ther. 2011;33:1932-1942) (C) 2011 Elsevier HS Journals, Inc. All rights reserved.