Effect of Insulin Sensitizer Therapy on Atherothrombotic and Inflammatory Profiles Associated With Insulin Resistance | RxWiki

Effect of Insulin Sensitizer Therapy on Atherothrombotic and Inflammatory Profiles Associated With Insulin Resistance

Overview[ - collapse ][ - ]

Purpose	The objective of this study is to determine whether targeted pharmacological improvement of insulin sensitivity will normalize the associated elevations of thrombotic and inflammatory cardiovascular disease (CVD) biomarkers in individuals with insulin resistance.
Condition	Type 2 Diabetes Insulin Resistance Metabolic Syndrome
Intervention	Drug: metformin Drug: pioglitazone Drug: Placebo
Phase	Phase 2
Sponsor	Mayo Clinic
Responsible Party	Mayo Clinic
ClinicalTrials.gov Identifier	NCT00443755
First Received	February 26, 2007
Last Updated	October 7, 2013
Last verified	October 2013

Tracking Information[ + expand ][ + ]

First Received Date	February 26, 2007
Last Updated Date	October 7, 2013
Start Date	August 2005
Estimated Primary Completion Date	August 2010
Current Primary Outcome Measures	Change From Baseline in Insulin Sensitivity as Measured by Glucose Infusion Rate (GIR) [Time Frame: Baseline, 3 months] [Designated as safety issue: Yes]Insulin sensitivity was measured the morning after an overnight fast during an in-patient stay in the Clinical Research Unit & was determined by the mean GIR necessary to maintain euglycemia during a hyperinsulinemic (1.5 mcIU/kg of FFM per minute)-euglycemic (85-95 mg/dL) clamp. The clamp is an 8 hour process where a hand vein is catheterized to collect blood samples and intravenous lines are used to infuse glucose, saline, insulin, phenylalanine and amino acid solutions at at pre-specified times/rates. The mean GIR was calculated as the rate per kilograms of fat-free mass (FFM) during 4 hours of steady-state (hours 4-8 of the 8 hour clamp) reported as micromols/kilogram of FFM per minute. The FFM was measured by dual-energy x-ray absorptiometry (DEXA) scan. Insulin was infused with 5% essential amino acid solution (3mL/kg of FFM/hour) to prevent the insulin-dependent decrease of amino acids during insulin infusion.
Current Secondary Outcome Measures	Change From Baseline in Fasting Blood Glucose Level [Time Frame: Baseline, 3 months] [Designated as safety issue: No]Glucose (sugar) was measured in the blood and reported in milligrams per deciliter (mg/dL). Change From Baseline in Glycosylated Hemoglobin (HbA1c) [Time Frame: Baseline, 3 months] [Designated as safety issue: No]HbA1c is a measure of average blood sugar levels over the preceding 3 month period. HbA1c was measured by ion-exchange chromatography and reported as a percentage. Change From Baseline in Insulin Levels [Time Frame: Baseline, 3 months] [Designated as safety issue: Yes]Insulin levels in the blood were measured by immunoenzymatic assay and reported in micro International Units per milliliter (mcIU/mL). Change From Baseline in Lipid Profile [Time Frame: Baseline, 3 months] [Designated as safety issue: No]Change in lipids were measured by the change from baseline to 3 months of triglycerides, high-density lipoprotein cholesterol (HDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C). All were reported in milligrams/deciliter (mg/dL). Change From Baseline in the Thrombotic Biomarker Fibrinogen [Time Frame: Baseline, 3 months] [Designated as safety issue: No]Fibrinogen was measured by thrombin clotting rate assay (Beckman Coulter, Inc. Brea, California) and reported in milligrams/deciliter (mg/dL). Change From Baseline in the Thrombotic Biomarker Plasminogen Activator Inhibitor-1 (PAI-1) [Time Frame: Baseline, 3 months] [Designated as safety issue: No]PAI-1 was measured by enzyme-linked immunosorbent assay (Diagnostica Stago Inc., Parsippany, New Jersey) and reported in nanograms per milliliter (ng/mL). Change From Baseline in the Inflammatory Biomarker Interleukin 6 (IL-6) [Time Frame: Baseline, 3 months] [Designated as safety issue: No]IL-6 is an inflammatory cytokine and reported in picograms per deciliter (pg/dL). Change From Baseline in the Inflammatory Biomarker C-Reactive Protein (CRP) [Time Frame: Baseline, 3 months] [Designated as safety issue: No]CRP is an inflammatory cytokine and is reported in milligrams per deciliter (mg/dL). Change From Baseline in Inflammatory Biomarker Tumor Necrosis Factor-alpha (TNF-α) [Time Frame: Baseline, 3 month] [Designated as safety issue: No]TNF-α is an inflammatory cytokine and is reported in picograms/milliliter (pg/mL). Change From Baseline in the Inflammatory Biomarker Adiponectin [Time Frame: Baseline, 3 months] [Designated as safety issue: No]Adiponectin is an anti-inflammatory cytokine and is reported in milligrams per milliliter (mg/mL).

Descriptive Information[ + expand ][ + ]

Brief Title	Effect of Insulin Sensitizer Therapy on Atherothrombotic and Inflammatory Profiles Associated With Insulin Resistance
Official Title	Effect of Insulin Sensitizer Therapy on Atherothrombotic and Inflammatory Profiles Associated With Insulin Resistance
Brief Summary	The objective of this study is to determine whether targeted pharmacological improvement of insulin sensitivity will normalize the associated elevations of thrombotic and inflammatory cardiovascular disease (CVD) biomarkers in individuals with insulin resistance.
Detailed Description	Individuals with diabetes mellitus (DM) are disproportionately affected by atherothrombotic disorders, including cardiovascular, cerebrovascular, and peripheral vascular diseases. Atherothrombotic disease risk and mortality are also increased with metabolic syndrome, a constellation of risk factors present in more than 34% of adults, even in absence of diabetes. Yet, large clinical trials of diabetes therapies have shown that conventional cardiovascular disease (CVD) risk factors, specifically hyperglycemia and hypertension, do not fully account for increased CVD risk associated with DM. There may be an etiologic link among insulin resistance, inflammation and thrombotic events. This study seeks to determine if certain two diabetes medications (the insulin sensitizing medications) will affect certain biomarkers (or laboratory tests) for CVD in individuals with untreated DM or impaired fasting glucose. Patients will be screened for inclusion into this this double-blinded, randomized), placebo-controlled study. If inclusion criteria are met and exclusion criteria not met, patients will be enrolled in the the study. Half of the subjects will be randomized (like the flip of a coin) to take two insulin sensitizing, anti-diabetic drugs pioglitazone (Actos) and metformin (Glucophage) taken together for three months and the other half of the subjects will take corresponding placebo (dummy) tablets. Laboratory measurements will be obtained on the morning(s) following the two in-patient overnight stays in the Mayo Clinic Clinical Research Unit. The first stay will be at baseline and the second stay will be 3 months after baseline. Insulin sensitivity will be measured in the morning following a standardized meal the preceding night, and after an overnight fast. The changes (from baseline to 3 months) in insulin sensitivity, glycemic control, the lipid profile, thrombotic markers and inflammatory markers will be determined and compared between the two arms of the study (placebo versus insulin sensitizing drugs).
Study Type	Interventional
Study Phase	Phase 2
Study Design	Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment
Condition	Type 2 Diabetes Insulin Resistance Metabolic Syndrome
Intervention	Drug: metformin To minimize side effects the metformin will be initiated at 500 mg twice daily with meals and increased to 1 gm twice daily with meals after two weeks and continue to a total of 3 months of dosing. Other Names: Fortamet Glucophage Glucophage Extended Release (XR) Glumetza Riomet Drug: pioglitazone To minimize side effects, the pioglitazone will be initiated at 30 mg daily and increased to 45 mg daily after two weeks, and continue to a total of 3 months of dosing. Other Names: ActosDrug: Placebo Placebo tablets matching the metformin and pioglitazone tablets are given in the same regimen as the active drug arm for 3 months.
Study Arm (s)	Active Comparator: Insulin Sensitizer Therapy Two insulin sensitizing drugs will be taken together for 3 months; metformin 1000 mg twice daily plus pioglitazone 45 mg daily. Placebo Comparator: Placebo Placebo tablets were used to match the active comparator drugs and dosing regimen.

Recruitment Information[ + expand ][ + ]

Recruitment Status	Completed
Estimated Enrollment	28
Estimated Completion Date	August 2010
Estimated Primary Completion Date	August 2010
Eligibility Criteria	Inclusion criteria: - We will study 30 patients with Type 2 Diabetes or impaired fasting glucose (15 men & 15 women) who are > 20 years old. - Only patients who use lifestyle modification to manage their diabetes and are not on any oral hypoglycemic agents or insulin will be included. - We will enroll subjects who have fasting glucose concentration greater than 100 mg/dl on two consecutive occasions and have a Body Mass Index between 27-36 kg/m^2. Exclusion Criteria: - We will exclude patients whose blood glucose is above 180 mg/dl. This will avoid the need to perform home glucose monitoring and the potential of unblinding the study by the volunteers. - Patients taking oral hypoglycemic agents or insulin would be excluded. - Any diseases such as active cardiovascular disease, liver diseases, kidney failure (males with serum creatinine >= 1.5mg/dl, females >=1.4 mg/dl), active endocrinopathies, debilitating chronic disease, anemia, symptoms of undiagnosed illness, history of alcoholism (alcohol use > 4oz/day) or substance abuse, chronic neurological diseases including Alzheimer's disease, stroke, etc, myopathies or any other active disease that may potentially affect the outcome measures. - Patients on medicines such as beta blockers, corticosteroids, tricyclics, benzodiazepines, opiates, barbiturates, anticoagulants and any other drugs or preparations that may affect mitochondrial function will be excluded. - People allergic to any of the class of drug such as lidocaine will also be excluded. - People with pacemakers, certain aneurysm clips and claustrophobia will also be excluded as they cannot undergo magnetic resonance imaging.
Gender	Both
Ages	20 Years
Accepts Healthy Volunteers	No
Contacts	Not Provided
Location Countries	United States

Administrative Information[ + expand ][ + ]

NCT Number	NCT00443755
Other Study ID Numbers	05-004002
Has Data Monitoring Committee	Yes
Information Provided By	Mayo Clinic
Study Sponsor	Mayo Clinic
Collaborators	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Takeda Pharmaceuticals North America, Inc. National Center for Research Resources (NCRR)
Investigators	Principal Investigator: K. Sreekumaran Nair, M.D., Ph.D. Mayo Clinic
Verification Date	October 2013

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