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

NCT ID: NCT00443755

Last Updated: 2013-10-31

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

28 participants

Study Classification

INTERVENTIONAL

Study Start Date

2005-08-31

Study Completion Date

2010-08-31

Brief Summary

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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

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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).

Conditions

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Type 2 Diabetes Insulin Resistance Metabolic Syndrome

Keywords

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Inflammatory cytokine Cardiovascular Disease Thrombotic factors Dyslipidemia

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Caregivers

Study Groups

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Insulin Sensitizer Therapy

Two insulin sensitizing drugs will be taken together for 3 months; metformin 1000 mg twice daily plus pioglitazone 45 mg daily.

Group Type ACTIVE_COMPARATOR

metformin

Intervention Type DRUG

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.

pioglitazone

Intervention Type DRUG

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.

Placebo

Placebo tablets were used to match the active comparator drugs and dosing regimen.

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Placebo tablets matching the metformin and pioglitazone tablets are given in the same regimen as the active drug arm for 3 months.

Interventions

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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.

Intervention Type 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.

Intervention Type DRUG

Placebo

Placebo tablets matching the metformin and pioglitazone tablets are given in the same regimen as the active drug arm for 3 months.

Intervention Type DRUG

Other Intervention Names

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Fortamet Glucophage Glucophage Extended Release (XR) Glumetza Riomet Actos

Eligibility Criteria

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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.
Minimum Eligible Age

20 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role collaborator

Takeda Pharmaceuticals North America, Inc.

INDUSTRY

Sponsor Role collaborator

National Center for Research Resources (NCRR)

NIH

Sponsor Role collaborator

Mayo Clinic

OTHER

Sponsor Role lead

Responsible Party

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K. Sreekumaran Nair

Professor of Medicine

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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K. Sreekumaran Nair, M.D., Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

Locations

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Mayo Clinic

Rochester, Minnesota, United States

Site Status

Countries

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United States

References

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McCoy RG, Irving BA, Soop M, Srinivasan M, Tatpati L, Chow L, Weymiller AJ, Carter RE, Nair KS. Effect of insulin sensitizer therapy on atherothrombotic and inflammatory profiles associated with insulin resistance. Mayo Clin Proc. 2012 Jun;87(6):561-70. doi: 10.1016/j.mayocp.2012.02.014.

Reference Type RESULT
PMID: 22677076 (View on PubMed)

Irving BA, Carter RE, Soop M, Weymiller A, Syed H, Karakelides H, Bhagra S, Short KR, Tatpati L, Barazzoni R, Nair KS. Effect of insulin sensitizer therapy on amino acids and their metabolites. Metabolism. 2015 Jun;64(6):720-8. doi: 10.1016/j.metabol.2015.01.008. Epub 2015 Jan 22.

Reference Type DERIVED
PMID: 25733201 (View on PubMed)

Other Identifiers

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R01DK041973

Identifier Type: NIH

Identifier Source: secondary_id

View Link

KL2RR024151

Identifier Type: NIH

Identifier Source: secondary_id

View Link

UL1RR024150

Identifier Type: NIH

Identifier Source: secondary_id

View Link

05-004002

Identifier Type: -

Identifier Source: org_study_id