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

NCT00443755 | Completed Phase 2 Results DMC

• 4 other identifiers: 05-004002R01DK041973KL2RR024151UL1RR024150
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

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.

Conditions

Type 2 Diabetes; Insulin Resistance; Metabolic Syndrome

Keywords

Inflammatory cytokine; Cardiovascular Disease; Thrombotic factors; Dyslipidemia

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in Insulin Sensitivity as Measured by Glucose Infusion Rate (GIR)

  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.

  Baseline, 3 months

Secondary Outcomes (10)

• Change From Baseline in Fasting Blood Glucose Level

  Baseline, 3 months

• Change From Baseline in Glycosylated Hemoglobin (HbA1c)

  Baseline, 3 months

• Change From Baseline in Insulin Levels

  Baseline, 3 months

• Change From Baseline in Lipid Profile

  Baseline, 3 months

• Change From Baseline in the Thrombotic Biomarker Fibrinogen

  Baseline, 3 months

Other Outcomes (3)

• Change From Baseline in Body Mass Index

  Baseline, 3 months

• Change From Baseline in Body Fat

  Baseline, 3 months

• Change From Baseline in Fat-Free Mass (FFM)

  Baseline, 3 months

Study Arms (2)

Insulin Sensitizer Therapy

ACTIVE COMPARATOR

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

Drug: metformin; Drug: pioglitazone

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

metformin 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.

Also known as: Fortamet, Glucophage, Glucophage Extended Release (XR), Glumetza, Riomet

Insulin Sensitizer Therapy

pioglitazone 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.

Also known as: Actos

Insulin Sensitizer Therapy

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Mayo Clinic: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator
• Takeda Pharmaceuticals North America, Inc.: collaborator
• National Center for Research Resources (NCRR): collaborator

Study Sites (1)

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Related Publications (2)

• 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.

  PMID: 22677076 RESULT

• 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.

  PMID: 25733201 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Insulin Resistance; Metabolic Syndrome; Cardiovascular Diseases; Dyslipidemias

Interventions

Metformin; Pioglitazone

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism; Lipid Metabolism Disorders

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Thiazolidinediones; Thiazoles; Sulfur Compounds; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: K. Sreekumaran Nair, MD, Ph.D.
• Organization: Mayo Clinic

nair@mayo.edu

507-255-3605

Study Officials

• K. Sreekumaran Nair, M.D., Ph.D.

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: February 26, 2007
• First Posted: March 6, 2007
• Study Start: August 1, 2005
• Primary Completion: August 1, 2010
• Study Completion: August 1, 2010
• Last Updated: October 31, 2013
• Results First Posted: June 6, 2013

Record last verified: 2013-10

Locations

US (1)