title: 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.
abstract: 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. 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.
  
  
  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 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).
  
  
  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.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Jun-Sing
authors.initials: JS
authors.lastname: Wang
authors.forename: Shi-Dou
authors.initials: SD
authors.lastname: Lin
authors.forename: Wen-Jane
authors.initials: WJ
authors.lastname: Lee
authors.forename: Shih-Li
authors.initials: SL
authors.lastname: Su
authors.forename: I-Te
authors.initials: IT
authors.lastname: Lee
authors.forename: Shih-Te
authors.initials: ST
authors.lastname: Tu
authors.forename: Yao-Hsien
authors.initials: YH
authors.lastname: Tseng
authors.forename: Shih-Yi
authors.initials: SY
authors.lastname: Lin
authors.forename: Wayne Huey-Herng
authors.initials: WH
authors.lastname: Sheu
mesh_terms: D020909:Acarbose / Q000009:adverse effects / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000652:urine; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D004359:Drug Therapy, Combination; D005260:Female; D005905:Glyburide / Q000009:adverse effects / Q000627:therapeutic use*; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D055118:Medication Adherence; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D010045:Outpatients; D018384:Oxidative Stress / Q000187:drug effects*; D012044:Regression Analysis; D013624:Taiwan; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D020909:Acarbose; D015415:Biomarkers; D001786:Blood Glucose; D015237:Dinoprost; D005905:Glyburide; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D008077:Lipoproteins, LDL; D008687:Metformin; C517652:hemoglobin A1c protein, human; C099252:oxidized low density lipoprotein; C075750:8-epi-prostaglandin F2alpha