Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
Clin Ther. 2011 Dec;33(12):1932-42. doi: 10.1016/j.clinthera.2011.10.014. Epub 2011 Nov 10.
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.
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.
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. β-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(2α) (8-iso PGF(2α)). The primary outcomes included changes in MAGE, plasma ox-LDL, and urinary excretion of 8-iso PGF(2α). Adverse events, including hypoglycemia, were recorded.
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 51 patients completed this study (acarbose, n = 28; glibenclamide, n = 23). HbA(1c) 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(2α) (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(2α) 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. β-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).
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.
血糖波动与氧化应激显著相关，氧化应激在 2 型糖尿病（T2DM）慢性并发症的发生发展中起作用。阿卡波糖已被报道可降低糖耐量受损和 T2DM 患者的心血管风险。我们假设阿卡波糖治疗可减轻 T2DM 患者的血糖波动并降低氧化应激。
本研究旨在评估阿卡波糖与格列本脲对接受二甲双胍单药治疗但血糖控制仍不达标的 T2DM 患者的平均血糖波动幅度（MAGE）和氧化应激的影响。
年龄在 30 至 70 岁之间、接受单药或双药口服降糖药物治疗≥3 个月且糖化血红蛋白（HbA1c）值在 7.0%至 11.0%之间的 T2DM 门诊患者符合入选标准。患者接受二甲双胍单药治疗（1500mg 每日 1 次）8 周，然后随机接受阿卡波糖或格列本脲加用治疗 16 周。阿卡波糖和格列本脲的起始剂量分别为 50mg 每日 3 次和 2.5mg 每日 3 次，持续 4 周。在接下来的 12 周内，两组的剂量均加倍。在随机分组前和研究结束时分别进行 72 小时连续血糖监测（CGM）和 10 小时过夜禁食后的口服糖耐量试验（MTT）。MAGE 由 CGM 数据计算得出。通过 MTT 期间胰岛素和葡萄糖增量曲线下面积（AUC）之间的比值评估餐后血糖增量的β细胞反应。氧化应激通过血浆氧化型低密度脂蛋白（ox-LDL）和尿 8-异前列腺素 F2α（8-iso PGF2α）排泄率进行评估。主要结局包括 MAGE、血浆 ox-LDL 和尿 8-iso PGF2α 排泄率的变化。记录不良事件，包括低血糖。
共 55 例患者被随机分组（平均年龄 54 岁；男性占 47%；平均体重指数 25.9kg/m2；糖尿病病程平均 6.9 年；HbA1c 平均 8.3%），其中 51 例患者完成了本研究（阿卡波糖组 28 例，格列本脲组 23 例）。两组患者的 HbA1c 均显著下降（阿卡波糖组：8.2[0.8]%降至 7.5[0.8]%[P<0.001]；格列本脲组：8.6[1.6]%降至 7.4[1.2]%[P<0.001]）。格列本脲组患者的 MAGE 无显著变化（6.2[2.8]mmol/L 降至 6.3[2.3]mmol/L；P=0.82），而 ox-LDL（242.4[180.9]ng/mL 升至 470.7[247.3]ng/mL；P=0.004）和尿 8-iso PGF2α 排泄率（121.6[39.6]pmol/mmol 肌酐升至 152.5[41.8]pmol/mmol 肌酐；P=0.03）显著增加。阿卡波糖降低了 MAGE（5.6[1.5]mmol/L 降至 4.0[1.4]mmol/L；P<0.001），而 ox-LDL 水平（254.4[269.1]ng/mL 升至 298.5[249.8]ng/mL；P=0.62）或 8-iso PGF2α 排泄率（117.9[58.1]pmol/mmol 肌酐升至 137.8[64.4]pmol/mmol 肌酐；P=0.12）无显著变化。阿卡波糖治疗后体重和血清三酰甘油（空腹和餐后 2 小时）下降（均 P<0.01），血清脂联素升高（P<0.05），而格列本脲治疗后高密度脂蛋白胆固醇（HDL-C）下降（P<0.01）。餐后血糖增量的β细胞反应与 MAGE 呈负相关（r=0.570，P<0.001），阿卡波糖治疗后显著改善（35.6[32.2]pmol/mmol 升至 56.4[43.7]pmol/mmol；P=0.001），而格列本脲治疗后无显著改善（27.9[17.6]pmol/mmol 升至 36.5[24.2]pmol/mmol；P=0.12）。
在接受二甲双胍单药治疗但血糖控制仍不达标的台湾成年 T2DM 患者中，阿卡波糖或格列本脲加用治疗均可显著降低 HbA1c。然而，阿卡波糖治疗可降低 MAGE、体重和血清三酰甘油、升高血清脂联素，而对氧化应激无显著影响。格列本脲治疗对 MAGE 无统计学显著影响，但可增加氧化应激并降低 HDL-C。临床试验注册号：NCT00417729。
