Efficacy and Safety Study of Pioglitazone Combined With Metformin on Metabolic Syndrome in Subjects With Type 2 Diabetes (PRISMA)

Double-blind, Randomized, Multicenter, Parallel-Group Study to Evaluate the Effects of Pioglitazone on Metabolic Syndrome in Patients With Type 2 Diabetes Treated With Metformin

The purpose of this study was to determine the efficacy of pioglitazone taken with metformin on high-density lipoprotein cholesterol in subjects with Type 2 Diabetes.

Study Overview

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

Detailed Description

Diabetes is none of the most common, chronic diseases worldwide and affects nearly 200 million people. It is the fourth or fifth leading cause of death in developed countries, and it is expected that diabetes will reach epidemic proportions, affecting 333 million people globally by 2025.

The metabolic syndrome is a cluster of the most dangerous cardiovascular risk factors and includes diabetes and pre-diabetes in addition to abdominal obesity, low high-density lipoprotein cholesterol, high triglycerides and hypertension. It is estimated that around a quarter of the world's adult population has metabolic syndrome, and are twice as likely to die and three times as likely to have a heart attack or stroke when compared to people without the syndrome. In addition, non-diabetic people with metabolic syndrome have a fivefold greater risk of developing type 2 diabetes. The clustering of cardiovascular risk factors that typifies the metabolic syndrome is now considered the driving force for a cardiovascular disease epidemic.

Metabolic syndrome has been recently defined by a Consensus Conference of the International Diabetes Federation as a cluster of clinical and laboratory signs characterized by the presence of abnormal deposition of fat tissue in the abdomen and visceral districts, and at least two other clinical and laboratory abnormalities, including altered glucose metabolism or type 2 diabetes and decreased levels of high-density lipoprotein cholesterol. One of the underlying pathophysiological mechanisms of metabolic syndrome is insulin resistance, characterized by an increased glucose output from the liver, and reduced glucose uptake in the muscle and adipose tissue cells. Drugs whose mechanism of action consists of increasing insulin sensitivity in the target tissues are able to reduce the clinical manifestations and consequences of metabolic syndrome.

While each individual component of metabolic syndrome confers an increased risk of cardiovascular-related complications or death, this risk is more pronounced when the syndrome itself is present. The more components of metabolic syndrome are evident, the higher is the cardiovascular mortality rate.

• Study Type: Interventional
• Enrollment (Actual): 418
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of Type 2 Diabetes Mellitus.
• Has glycosylated hemoglobin levels between 6.0% and 8.0%.
• Treatment with metformin (2,000 to 3,000 mg daily) for at least 3 months.
• Has reduced high-density lipoprotein cholesterol levels less than 40 mg/dl in males and less than 50 mg/dl in females, irrespective of treatment with statins.
• Has central obesity defined as a waist circumference greater than or equal to 94 cm for men and greater than or equal to 80 cm for females.
• 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:

• Has a diagnosis of Type 1 Diabetes Mellitus.

• 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:

  • other oral antidiabetic drugs than metformin or with insulin in the 3 months preceding study entry.
  • Fibrates
  • Rifampicin
• Has any disease with malabsorption.
• Has acute or chronic pancreatitis.
• Has familial polyposis coli.
• Has a medical history of myocardial infarction, transient ischemic attacks or stroke in the past 6 months.
• Has heart failure as defined by the New York Heart Association classification I-IV.
• Has significant liver impairment, with an alanine aminotransferase level greater than 2.5 the upper limit of normal range.
• Has significant renal impairment, with a serum creatinine level greater than 1.5 mg/dl for men and greater than 1.2 mg/dl for women.
• Has anemia of any etiology (defined as hemoglobin levels less than 10.5 g/dL) or any other hematologic disease.
• Has a diagnosis or suspicion of neoplastic disease.
• History of chronic alcohol or drug abuse.
• Known allergy, sensitivity or intolerance to the study drugs and their formulation ingredients.
• Participation in another trial in the 3 months preceding study entry.

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
Active Comparator: Metformin	Drug: Metformin; Pioglitazone placebo-matching tablets, orally, two-times daily and metformin stable dose, orally, three-times daily for 4 weeks; then increased to pioglitazone placebo-matching tablets, orally, three-times daily and metformin stable dose, orally, three-times daily for up to 20 weeks.
Experimental: Pioglitazone + Metformin	Drug: Pioglitazone and Metformin; Pioglitazone 15 mg, tablets, orally, two-times daily and metformin stable dose, orally, three-times daily for 4 weeks; then increased to pioglitazone 15 mg, tablets, orally, three-times daily and metformin stable dose, orally, three-times daily for up to 20 weeks.; Other Names: ACTOS®; AD4833

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Increase in High-Density Lipoprotein cholesterol levels.	Final Visit.

Secondary Outcome Measures

Outcome Measure	Time Frame
The change from Baseline in Metabolic Syndrome, as defined by the International Diabetes Federation (aggregate waist circumference, fasting plasma glucose, triglycerides and high-density lipoprotein cholesterol).	Weeks: 8 and 24.
The change from Baseline in Metabolic Syndrome, as defined by the International Diabetes Federation (blood pressure).	At all Visits.
The change from Baseline in Individual Metabolic Parameters (insulin sensitivity and beta-cell function, inflammatory cytokines, adipokines, endothelial functionality).	Weeks: 8 and 24.
Adverse Events.	At all Visits.
The change from Baseline in Laboratory Parameters (hematology, chemistry and urinalysis).	Weeks: 8 and 24.

Collaborators and Investigators

• Sponsor: Takeda

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (Actual): February 1, 2008
• Study Completion (Actual): February 1, 2008

Study Registration Dates

• First Submitted: October 8, 2008
• First Submitted That Met QC Criteria: October 13, 2008
• First Posted (Estimate): October 15, 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; Insulin Resistance; Hyperinsulinism; Diabetes Mellitus; Metabolic Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin; Pioglitazone
• Other Study ID Numbers: IT-PIO-108; 2006-000725-54 (EudraCT Number); PIOc/LAN07/TIF (Other Identifier: Takeda ID); U1111-1115-9278 (Registry Identifier: WHO)