Effects of Acarbose Versus Glibenclamide on MAGE and Oxidative Stress in Patients With Type 2 DM

Official Title: “Phase 4 Study Evaluation of the Effects of Acarbose Versus Glibenclamide on Mean Amplitude of Glycemic Excursions and Oxidative Stress in Patients With Type 2 Diabetes Insufficiently Controlled by Metformin”

To compare effect of acarbose versus glibenclamide treatment on mean amplitude of glyclemic excursion and oxidative stress in diabetes individuals who failed to control their glucose by metformin therapy alone

This is a randomised and open-label study conducted in 2 medical centers in central part of Taiwan. Type 2 diabetic outpatients were eligible if they were aged 30-70 years, were on mono- or dual oral antidiabetic drugs for at least 3 months, and had a glycated hemoglobin (HbA1c) value between 7.0% and 11.0%. Patients who were treated with insulin or drugs that promote weight loss, had impaired renal (serum creatinine concentration greater than 132.6 μmol/l) or liver (AST or ALT 2.5 times upper limit of normal range) function, had a history of hemoglobinopathy or chronic anemia, or women of child-bearing potential without adequate contraception were excluded. All patients provided their informed consent before they were enrolled in this study.

After an 8-week period of metformin monotherapy (500 mg t.i.d.), all patients were randomised to add on either acarbose or glibenclamide. The doses of acarbose and glibenclamide were 50 mg t.i.d. and 2.5 mg t.i.d., respectively, for 4 weeks and force-titrated to 100 mg t.i.d. and 5 mg t.i.d., respectively, for the last 12 weeks. A complete 72 hours of glucose monitoring using a continuous glucose monitoring (CGM) system and meal tolerance test (MTT) after a 10-h overnight fasting were performed before randomisation and in the end of study. Morning urine samples were collected for measurement of 8-iso prostaglandin F2α (8-iso PGF2α), a commonly used parameter of oxidative stress (13-14). The primary objectives are the changes of MAGE obtained from CGM and urinary excretion rate of 8-iso PGF2α. The secondary objectives include changes of HbA1c, lipid profiles including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides, oxidized low-density lipoprotein (ox-LDL), high-sensitivity C-reactive protein (hs-CRP), total adiponectin, and high-molecular weight (HMW) adiponectin.

Intervention(s) in this Clinical Trial

• Drug: Acarbose
  • After an 8-week period of metformin monotherapy (500 mg t.i.d.), all patients were randomised to add on either acarbose or glibenclamide. The doses of acarbose and glibenclamide were 50 mg t.i.d. and 2.5 mg t.i.d., respectively, for 4 weeks and force-titrated to 100 mg t.i.d. and 5 mg t.i.d., respectively, for the last 12 weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: acarbose, glibenclamide
  • acarbose vs. glibenclamide (background metformin therapy)

Primary Measures

• Mean Amplitude Glycemic Excursion
  • Time Frame: before randomisation and end of study
    Safety Issue?: No
• Oxidative stress
  • Time Frame: before randomisation and end of study
    Safety Issue?: No

Secondary Measures

• HbA1c
  • Time Frame: before randomisation and end of study
    Safety Issue?: No
• fasting glucose
  • Time Frame: before randomisation and end of study
    Safety Issue?: No
• Insulin response
  • Time Frame: before randomisation and end of study
    Safety Issue?: No
• Fasting lipids
  • Time Frame: before randomisation and end of study
    Safety Issue?: No
• hsCRP
  • Time Frame: before randomisation and end of study
    Safety Issue?: No
• oxLDL
  • Time Frame: before randomisation and end of study
    Safety Issue?: No
• Adiponectin
  • Time Frame: before randomisation and end of study
    Safety Issue?: No

Inclusion Criteria:

• Patients may be included in the clinical trial only if they meet all of the following criteria:
• 1. Male or female outpatients;
• 2. Age 30 - 70 years;
• 3. Patients have failed to achieve glycemic control with diet, exercise and max. 2
• OHA; Hemoglobin A1c level between 7.0 to 11.0 % at V1 and 7-11.5 % at V4.
• 4. Diagnosis of diabetes mellitus is over a minimum 3-month period;
• 5. All patients give written informed consent;
• 6. For female patients of childbearing potential, the following criteria will be applied:
• Using adequate contraception since last menses and will continue to use adequate contraception during the clinical trial.
• Not lactating.
• Negative pregnancy test (urine) within 7 days prior to the first dose of study medication. (Note: the inclusion criterion 6 does not apply to menopausal female).

Exclusion Criteria:

• Patients will be excluded from the clinical trial for any of the following reasons:
• 1. Patients with a serum creatinine concentration greater than 132.6 mmol/L (1.5 mg/dL) or liver function impairment (AST and ALT 2.5 times upper limit of normal range);
• 2. Patients have laboratory test abnormality (biochemistry, hematology, or urinalysis), which in the investigator's opinion might confound the clinical trial. However, patients with hyperlipemia, elevated cholesterol or triglyceride levels, or lipid metabolism disorders are eligible;
• 3. Use of chronic insulin therapy;
• 4. Patients with medical conditions that could promote lactic acidosis, such as renal or hepatic disease, unstable angina, congestive heart failure (New York
• Heart Association Functional Classification III and IV), or chronic obstructive pulmonary disease, e.g. respiratory insufficiency, hypoxemic condition;
• 5. Patients with a history of hypersensitivity to metformin hydrochloride, glibenclamide or acarbose;
• 6. Patients receive an investigational drug within 30 days prior to admission to the clinical trial;
• 7. Patients with significant alcohol, drug or medication abuse as judged by the investigator.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 30 Years

Maximum Age for this Clinical Trial: 70 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Taichung Veterans General Hospital Other

Overall Clinical Trial Officials and Contacts

Wayne H Sheu, MD, PhD Principal Investigator Taichung Veterans General Hospital  

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00417729

Study ID Number: IRB951004/C06211

ClinicalTrials.gov Identifier: NCT00417729

Health Authority: Taiwan: Department of Health