Efficacy of Pioglitazone/Metformin Combination Therapy in Subjects With Type 2 Diabetes Mellitus and Dyslipidemia.

Effects of a Pioglitazone/Metformin Fixed Combination in Comparison to Metformin in Combination With Glimepiride on Diabetic Dyslipidemia

The purpose of this study is to compare pioglitazone and metformin combination therapy, twice daily (BID), to glimepiride and metformin combination therapy for treating diabetic subjects with dyslipidemia.

Study Overview

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

Detailed Description

Insulin resistance is a major endocrinopathy preceding the development of hyperglycemia, diabetic dyslipidemia and cardiovascular disease in type 2 diabetes. The most common pattern of dyslipidemia in patients with type 2 diabetes are elevated triglyceride levels, decreased hih-density lipoprotein cholesterol and a predominance of small dense low-density lipoprotein particles. Each of these dyslipidemia features is associated with an increased risk of cardiovascular events.

Pioglitazone and Metformin are established drugs which can be used for the treatment of type 2 diabetes. This study will investigate the effects of treatment with fixed Pioglitazone/Metformin combination therapy of Metformin and Glimepiride in Metformin-pretreated type 2 diabetic patients with dyslipidemia.

Total participation time in this study is anticipated to be approximately 24 weeks.

• Study Type: Interventional
• Enrollment (Actual): 305
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany
  • Hamburg, Germany
  • Baden-Württemberg
    • Bretten, Baden-Württemberg, Germany
    • Deggingen, Baden-Württemberg, Germany
    • Dettenheim, Baden-Württemberg, Germany
    • Künzelsau, Baden-Württemberg, Germany
    • Rottweil, Baden-Württemberg, Germany
    • Spaichingen, Baden-Württemberg, Germany
    • Stockach, Baden-Württemberg, Germany
    • Wangen, Baden-Württemberg, Germany
  • Bayern
    • Augsburg, Bayern, Germany
    • Feldafing, Bayern, Germany
    • Furth im Wald, Bayern, Germany
    • Immenstadt, Bayern, Germany
    • Lichtenfels, Bayern, Germany
    • München, Bayern, Germany
    • Schweinfurt, Bayern, Germany
    • Waldkraiburg, Bayern, Germany
    • Wallerfing, Bayern, Germany
    • Weilersbach, Bayern, Germany
    • Würzburg, Bayern, Germany
  • Brandenburg
    • Ketzin, Brandenburg, Germany
    • Rüdersdorf, Brandenburg, Germany
  • Bremen
    • Bermerhaven, Bremen, Germany
  • Hessen
    • Bensheim, Hessen, Germany
    • Ehrenberg, Hessen, Germany
    • Gersfeld, Hessen, Germany
    • Kassel, Hessen, Germany
    • Kelkheim, Hessen, Germany
    • Offenbach, Hessen, Germany
  • Mecklenburg-Vorpommern
    • Schwerin, Mecklenburg-Vorpommern, Germany
  • Niedersachsen
    • Celle, Niedersachsen, Germany
    • Einbeck, Niedersachsen, Germany
    • Hannover, Niedersachsen, Germany
    • Hildesheim, Niedersachsen, Germany
  • Nordrhein-Westfalen
    • Bad Berleburg, Nordrhein-Westfalen, Germany
    • Bad Laasphe, Nordrhein-Westfalen, Germany
    • Bad Oeynhausen, Nordrhein-Westfalen, Germany
    • Bocholt, Nordrhein-Westfalen, Germany
    • Dinslaken, Nordrhein-Westfalen, Germany
    • Dorsten, Nordrhein-Westfalen, Germany
    • Duisburg, Nordrhein-Westfalen, Germany
    • Essen, Nordrhein-Westfalen, Germany
    • Frechen, Nordrhein-Westfalen, Germany
    • Isselburg, Nordrhein-Westfalen, Germany
    • Kamen, Nordrhein-Westfalen, Germany
    • Köln, Nordrhein-Westfalen, Germany
    • Marl, Nordrhein-Westfalen, Germany
    • Menden, Nordrhein-Westfalen, Germany
    • Münster, Nordrhein-Westfalen, Germany
    • Siegen, Nordrhein-Westfalen, Germany
  • Rheinland-Pfalz
    • Diez, Rheinland-Pfalz, Germany
    • Mainz, Rheinland-Pfalz, Germany
    • Neuwied, Rheinland-Pfalz, Germany
    • Rodenbach, Rheinland-Pfalz, Germany
    • Simmern, Rheinland-Pfalz, Germany
  • Sachsen
    • Borna, Sachsen, Germany
    • Dresden, Sachsen, Germany
    • Meißen, Sachsen, Germany
    • Mittweida, Sachsen, Germany
  • Sachsen-Anhalt
    • Magdeburg, Sachsen-Anhalt, Germany
  • Schleswig-Holstein
    • Reinfeld, Schleswig-Holstein, Germany
  • Thüringen
    • Altenburg, Thüringen, Germany
    • Blankenhain, Thüringen, Germany

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 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 individual maximal tolerated dose of metformin (850 - 2000 mg) as monotherapy within the last 12 weeks.
• Glycosylated Hemoglobin greater than or equal to 6.5% and less than or equal to 9%.
• Dyslipidemia defined as high-density lipoprotein cholesterol less than or equal to 1.03 mmol/l (40 mg/dL) and/or triglycerides greater than or equal to 1.7 mmol/l (150 mg/dL).
• 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.
• Insulin-dependent type 2 diabetes mellitus.
• Treatment or history of treatment with any insulin formulation other than emergency for more than 2 weeks.
• Treatment with other oral antidiabetic drugs in addition to metformin within the last 12 weeks.
• Anamnestic history of hypersensitivity to the study drugs or to drugs with similar chemical structures.

• 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:

  • Heparin (and heparin-like drugs)
  • coumarin
  • phenprocoumon
  • hirudin
  • Protein C
  • Fondaparinux
  • antithrombin III
  • Peroxisome Proliferation Activating Receptor (gamma) agonists

  • Treatment within the last 12 weeks with:

    • fibrates
    • gemfibrozil
    • niacin
    • months
    • Rifampicin
  • Changes in dosage of any statin treatment to lower low-density lipoprotein within 2 weeks before study entry and during study participation interval.
  • Changes in dosage of any anticoagulant treatment with acetyl salicylic acid and/or clopidogrel within 2 weeks before study entry and during study participation interval.
  • Start of statin and/or anticoagulant treatment during study participation interval.
• History of severe or multiple allergies and/ or acute severe infections.
• Have had more than one unexplained episode of severe hypoglycemia (defined as requiring assistance of another person due to disabling hypoglycemia) within 6 months prior to screening visit.
• Progressive fatal disease.
• Any elective surgery during study participation.
• History of drug or alcohol abuse within the last 5 years.
• A history of significant cardiovascular (New York Heart Association stage I - IV), respiratory, gastrointestinal, hepatic (alanine aminotransferase and/or aspartate aminotransferase greater than 2.5 times the upper limit of the normal reference range), renal (serum creatinine greater than 1.2 mg/dL in women and greater than 1.5 mg/dL in men, glomerular filtration rate less than 60 ml/min as estimated by the Cockroft-Gault formula), neurological, psychiatric and/or hematological disease as judged by the investigator, history of macular edema.
• Blood donation within the last 30 days.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Pioglitazone 15 mg and Metformin 850 mg BID	Drug: Pioglitazone and Metformin; Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.; Other Names: AD-4833; ACTOS®; OPIMET
ACTIVE_COMPARATOR: Glimepiride 2 mg and Metformin 850 mg BID	Drug: Glimepiride and Metformin; Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.; Other Names: Amaryl; Glista

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Mean Increase From Baseline in High-Density Lipoprotein Cholesterol.	The increase in High-Density Lipoprotein (HDL) Cholesterol collected at week 24 or final visit and HDL-Cholesterol collected at baseline.	Baseline and Week 24.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in High-Density Lipoprotein Cholesterol.	The change between HDL-Cholesterol collected at week 24 or final visit and HDL-Cholesterol collected at baseline.	Baseline and Week 24.
Change From Baseline in High-Density Lipoprotein/Low-Density Lipoprotein Ratio.	The change between High-Density Lipoprotein/Low-Density Lipoprotein Ratio collected at week 24 or final visit and High-Density Lipoprotein/Low-Density Lipoprotein Ratio collected at baseline.	Baseline and Week 24.
Change From Baseline in Triglycerides.	The change between the value of Triglycerides collected at week 24 or final visit and Triglycerides collected at baseline.	Baseline and Week 24.
Change From Baseline in Low-Density Lipoprotein Subfractions.	The change between the value of Low-Density Lipoprotein Subfractions collected at week 24 or final visit and Low-Density Lipoprotein Subfractions collected at baseline.	Baseline and Week 24.
Change From Baseline in Low-Density Lipoprotein Cholesterol.	The change between Low-Density Lipoprotein Cholesterol collected at week 24 or final visit and Low-Density Lipoprotein Cholesterol collected at baseline.	Baseline and Week 24.
Change From Baseline in Glycosylated Hemoglobin.	The change between the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 24 or final visit and Glycosylated Hemoglobin collected at baseline.	Baseline and Week 24.
Change From Baseline in Fasting Intact Proinsulin.	The change between Fasting Intact Proinsulin collected at week 24 or final visit and Fasting Intact Proinsulin collected at baseline.	Baseline and Week 24.
Change From Baseline in Fasting Glucose.	The change between Fasting Glucose collected at week 24 or final visit and Fasting Glucose collected at baseline.	Baseline and Week 24.
Change From Baseline in Adiponectin.	The change between Adiponectin collected at week 24 or final visit and Adiponectin collected at baseline.	Baseline and Week 24.
Change From Baseline in High Sensitivity C-reactive Protein (Original).	The change between the value of High Sensitivity C-reactive Protein collected at week 24 or final visit and High Sensitivity C-reactive Protein collected at baseline.	Baseline and Week 24.
Change From Baseline in High Sensitivity C-reactive Protein (≤ 10 mg/L).	The change between the value of High Sensitivity C-reactive Protein less than or equal to 10 mg/L collected at week 24 or final visit and High Sensitivity C-reactive Protein less than or equal to 10 mg/L collected at baseline.	Baseline and Week 24.
Change From Baseline in Systolic Blood Pressure.	The change between Systolic Blood Pressure measured at week 24 or final visit and Systolic Blood Pressure measured at baseline.	Baseline and Week 24.
Change From Baseline in Diastolic Blood Pressure.	The change between Diastolic Blood Pressure measured at week 24 or final visit and Diastolic Blood Pressure measured at baseline.	Baseline and Week 24.
Intake of Study Medication Greater Than 80% and Less Than 120%.	The change between the Intake of study medication greater than 80% at week 24 or final visit and Baseline and the Intake of study medication greater than 80% at baseline.	Baseline and Week 24.
Change From Baseline in Nitrotyrosine.	The change between the value of Nitrotyrosine collected at week 24 or final visit and Nitrotyrosine collected at baseline.	Baseline and Week 24.
Change From Baseline in Soluble CD40 Ligand.	The change between the value of Soluble CD40 Ligand collected at week 24 or final visit and Soluble CD40 Ligand collected at baseline.	Baseline and Week 24.
Change From Baseline in Matrix Metallo Proteinase-9.	The change between the value of Baseline in Matrix Metallo Proteinase-9 collected at week 24 or final visit and Baseline in Matrix Metallo Proteinase-9 collected at baseline.	Baseline and Week 24.
Change From Baseline in Soluble Intracellular Adhesion Molecule.	The change between the value of Baseline in Soluble Intracellular Adhesion molecule at week 24 or final visit and Baseline in Soluble Intracellular Adhesion molecule collected at baseline.	Baseline and Week 24.
Change From Baseline in Soluble Vascular Cell Adhesion Molecule.	The change between the value of Soluble Vascular Cell Adhesion Molecule collected at week 24 or final visit and Soluble Vascular Cell Adhesion Molecule collected at baseline.	Baseline and Week 24.
Change From Baseline in Thromboxane B2.	The change between the value of Thromboxane B2 collected at week 24 or final visit and Thromboxane B2 collected at baseline.	Baseline and Week 24.
Change From Baseline in Platelet Function.	The change between the value of Platelet Function by PFA 100 collected at week 24 or final visit and Platelet Function by PFA 100 collected at baseline.	Baseline and Week 24.
Change From Baseline in E-Selectin.	The change between the value of E-Selectin collected at week 24 or final visit and E-Selectin collected at baseline.	Baseline and Week 24.
Change From Baseline in Von-Willebrand Factor.	The change between the value of Von-Willebrand Factor collected at week 24 or final visit and Von-Willebrand Factor collected at baseline.	Baseline and Week 24.
Change From Baseline in Erythrocyte Deformability (0.30%).	The change between the 0.30 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.	Baseline and Week 24.
Change From Baseline in Erythrocyte Deformability (0.60%)	The change between the 0.60 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.	Baseline and Week 24.
Change From Baseline in Erythrocyte Deformability (1.20).	The change between the 1.20 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.	Baseline and Week 24.
Change From Baseline in Erythrocyte Deformability (3.00).	The change between the 3.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.	Baseline and Week 24.
Change From Baseline in Erythrocyte Deformability (6.00).	The change between the 6.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.	Baseline and Week 24.
Change From Baseline in Erythrocyte Deformability (12.00).	The change between the 12.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.	Baseline and Week 24.
Change From Baseline in Erythrocyte Deformability (30.00).	The change between the 30.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.	Baseline and Week 24.
Change From Baseline in Erythrocyte Deformability (60.00).	The change between the 60.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.	Baseline and Week 24.

Collaborators and Investigators

• Sponsor: Takeda

Publications and helpful links

General Publications

• Pfutzner A, Schondorf T, Tschope D, Lobmann R, Merke J, Muller J, Lehmann U, Fuchs W, Forst T. PIOfix-study: effects of pioglitazone/metformin fixed combination in comparison with a combination of metformin with glimepiride on diabetic dyslipidemia. Diabetes Technol Ther. 2011 Jun;13(6):637-43. doi: 10.1089/dia.2010.0233. Epub 2011 Apr 2.

Study record dates

Study Major Dates

• Study Start: April 1, 2007
• Primary Completion (ACTUAL): May 1, 2009
• Study Completion (ACTUAL): May 1, 2009

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): October 6, 2010
• Last Update Submitted That Met QC Criteria: September 13, 2010
• Last Verified: September 1, 2010

More Information

Terms related to this study

• Keywords: Drug Therapy; Dyslipidemia; Type II Diabetes; Hyperlipidemias; Glucose Metabolism Disorder; Dysmetabolic Syndrome; Diabetes Mellitus, Lipoatrophic
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Lipid Metabolism Disorders; Diabetes Mellitus; Dyslipidemias; Hypoglycemic Agents; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Immunosuppressive Agents; Immunologic Factors; Metformin; Pioglitazone; Glimepiride
• Other Study ID Numbers: ATS K024; 2006-004455-37 (EUDRACT_NUMBER); D-PIO-114 (OTHER: Takeda Pharma GmbH); U1111-1114-1678 (REGISTRY: WHO)