Efficacy of Pioglitazone and Glimepiride Combination Therapy in Treating Subjects With Type 2 Diabetes Mellitus.

Effects of Pioglitazone in Combination With Glimepiride in Comparison to Glimepiride Monotherapy on Metabolic Control in Patients With Type 2 Diabetes Mellitus

The purpose of this study is to determine the effect of pioglitazone, once daily (QD), and glimepiride combination therapy compared to glimepiride monotherapy in subjects with Type 2 Diabetes.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus
• Intervention / Treatment: Drug: Pioglitazone and Glimepiride; Drug: Glimepiride

Detailed Description

Tight glycemic control is mandatory for the prevention and treatment of vascular complications in patients suffering from diabetes mellitus. After onset of Type 2 Diabetes, patients are usually treated with diet along with or without different combinations of oral drugs. One first-line drug class are sulfonylurea drugs that are preferably provided to patients who are not obese. The mode of action of sulfonylurea drugs is to increase beta-cell secretion, but it could be shown that they lead to deterioration of the beta-cell secretion product over time, resulting in increased proinsulin secretion. Since proinsulin is an independent cardiovascular risk factor, recent publications have demonstrated an increased risk for cardiovascular events in patients treated with sulfonylurea drugs as compared to other treatment methods.

Combination therapy of sulfonylurea drugs with glitazones has been shown to counterbalance the effect of deteriorated beta-cell secretion and to improve insulin sensitivity and the levels of proinsulin, C-peptide and other laboratory surrogate markers for cardiovascular risk. Proving that the treatment of diabetic patients with higher doses of beta cytotropic agents can be avoided and beta-cell function can be preserved by using pioglitazone in combination with low dose sulfonylurea drugs, it will be possible to optimize the treatment of patients with type 2 diabetes who are not controlled efficiently by sulfonylurea drugs monotherapy.

In this study patients will be enrolled who are inefficiently treated with a Glimepiride monotherapy. Patients will be either randomized to a combinational therapy of Pioglitazone and Glimepiride or Glimepiride monotherapy. If possible, study medication will be up-titrated to maximal dosage levels in both treatment arms to observe maximal and comparable treatment effects. Stable effects on beta-cell function will be observed after 24 weeks of treatment.

• Study Type: Interventional
• Enrollment (Actual): 91
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany
  • Baden-Württemberg
    • Villingen-Schwenningen, Baden-Württemberg, Germany
  • Bayern
    • Aschaffenburg, Bayern, Germany
    • Ingolstadt, Bayern, Germany
  • Hessen
    • Frankfurt, Hessen, Germany
    • Frielendorf, Hessen, Germany
    • Rotenburg, Hessen, Germany
  • Niedersachsen
    • Hannover, Niedersachsen, Germany
  • Nordrhein-Westfalen
    • Dortmund, Nordrhein-Westfalen, Germany
    • Siegen, Nordrhein-Westfalen, Germany
  • Rheinland-Pfalz
    • Kallstadt, Rheinland-Pfalz, Germany
    • Mainz, Rheinland-Pfalz, Germany
    • Mayen, Rheinland-Pfalz, Germany
    • Neuwied, Rheinland-Pfalz, Germany
    • Rhaunen, Rheinland-Pfalz, Germany
  • Saarland
    • Friedrichsthal, Saarland, Germany
  • Sachsen
    • Meißen, Sachsen, Germany

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Type 2 Diabetes according to the American Diabetes Association Criteria.
• Treatment with Glimepiride monotherapy (1-3 mg per day) 3 months before entering the study.
• Glycosylated hemoglobin greater than 6.5%, but less than 8.5% and/ or fasting plasma glucose greater than 7 mmol/l within the last 4 weeks.
• Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.

Exclusion Criteria:

• Type 1 Diabetes mellitus.
• History of hypersensitivity to the study drugs or to drugs with similar chemical structures.
• Progressive fatal disease.
• History of drug or alcohol abuse during the last 5 years.
• More than one unexplained episode of severe hypoglycemia within 6 months prior to entering the study.
• A history of significant cardiovascular (New York Heart Association stage I - IV), respiratory, gastrointestinal, hepatic (alanine aminotransferase greater than 2.5 times the upper limit of the normal reference range), renal (serum creatinine greater than 1.8 mg/dl; glomerular filtration rate less than 40 ml/min as estimated by the Cockroft-Gault formula), neurological, psychiatric and/or hematological disease, history of macular edema.
• Blood donation within the last 30 days.

• Is required to take or intends to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:

  • CYP2C9 inductors
  • CYP2C9 inhibitors
  • rifampicin
  • fluconazole
  • drugs used for treating type 2 diabetes (insulin, insulin analogous compounds and oral antidiabetic drugs)
• Pretreatment with thiazolidinediones within the last 12 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pioglitazone 30 mg to 45 mg QD + Glimepiride 2 mg to 4 mg QD	Drug: Pioglitazone and Glimepiride; Pioglitazone 30 mg, tablets, orally, once daily and Glimepiride 2 mg, tablets, orally once daily for two weeks; increased to: Pioglitazone 30 mg, tablets, orally, once daily and Glimepiride 4 mg, tablets, orally, once daily for two weeks; increased to: Pioglitazone 45 mg, tablets, orally, once daily and Glimepiride 4 mg, orally, once daily for up to 20 weeks.; Other Names: ACTOS®
Active Comparator: Glimepiride 4 mg to 6 mg QD	Drug: Glimepiride; Pioglitazone placebo-matching tablets, orally, once daily and Glimepiride 4 mg, tablets, orally once daily for two weeks; increased to: Pioglitazone placebo-matching tablets, orally, once daily and Glimepiride 5 mg, tablets, orally once daily for two weeks; increased to: Pioglitazone placebo-matching tablets, orally, once daily and Glimepiride 6 mg, tablets, orally once daily for up to 20 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change from Baseline in Homeostatic Model Assessment - Beta cell.	Week: 24 or Final Visit beyond week 12.

Secondary Outcome Measures

Outcome Measure	Time Frame
Change from Baseline in Glycosylated Hemoglobin.	Week: 24 or Final Visit beyond week 12.
Change from Baseline in oral glucose tolerance testing.	Week: 24 or Final Visit beyond week 12.
Change from Baseline in Insulin.	Week: 24 or Final Visit beyond week 12.
Change from Baseline in Proinsulin.	Week: 24 or Final Visit beyond week 12.
Change from Baseline in C-peptide.	Week: 24 or Final Visit beyond week 12.
Change from Baseline in High sensitivity C-Reactive Protein.	Week: 24 or Final Visit beyond week 12.
Change from Baseline in Adiponectin.	Week: 24 or Final Visit beyond week 12.
Change from Baseline in Homeostatic Model Assessment - Sensitivity.	Week: 24 or Final Visit beyond week 12.
Change from Baseline in Triglycerides	Week: 24 or Final Visit beyond week 12.
Change from Baseline in Low Density Lipoprotein-Cholesterol	Week: 24 or Final Visit beyond week 12.
Change from Baseline in High Density Lipoprotein-Cholesterol	Week: 24 or Final Visit beyond week 12.
Change from Baseline in Total Cholesterol	Week: 24 or Final Visit beyond week 12.

Collaborators and Investigators

• Sponsor: Takeda

Study record dates

Study Major Dates

• Study Start: December 1, 2006
• Primary Completion (Actual): December 1, 2008
• Study Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: October 9, 2008
• First Submitted That Met QC Criteria: October 9, 2008
• First Posted (Estimate): October 10, 2008

Study Record Updates

• Last Update Posted (Estimate): July 5, 2010
• Last Update Submitted That Met QC Criteria: July 1, 2010
• Last Verified: July 1, 2010

More Information

Terms related to this study

• Keywords: Drug Therapy; Dyslipidemia; Type II Diabetes; Glucose Metabolism Disorder; Dysmetabolic Syndrome; Diabetes Mellitus, Lipoatrophic
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Immunosuppressive Agents; Immunologic Factors; Pioglitazone; Glimepiride
• Other Study ID Numbers: ATS K020; 2006-002271-41 (EudraCT Number); D-PIO-112 (Other Identifier: Takeda ID); U1111-1114-3221 (Registry Identifier: WHO)