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

• ClinicalTrials.gov Identifier: NCT00443755
• Recruitment Status: Completed
• First Posted: March 6, 2007
• Results First Posted: June 6, 2013
• Last Update Posted: October 31, 2013
• 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)
• Information provided by (Responsible Party): K. Sreekumaran Nair, Mayo Clinic

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Type 2 Diabetes; Insulin Resistance; Metabolic Syndrome	Drug: metformin; Drug: pioglitazone; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 28 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: Effect of Insulin Sensitizer Therapy on Atherothrombotic and Inflammatory Profiles Associated With Insulin Resistance
• Study Start Date: August 2005
• Actual Primary Completion Date: August 2010
• Actual Study Completion Date: August 2010

Arms and Interventions

Arm	Intervention/treatment
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.	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 Name: Actos
Placebo Comparator: Placebo; Placebo tablets were used to match the active comparator drugs and dosing regimen.	Drug: Placebo; Placebo tablets matching the metformin and pioglitazone tablets are given in the same regimen as the active drug arm for 3 months.

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Insulin Sensitivity as Measured by Glucose Infusion Rate (GIR) [ Time Frame: Baseline, 3 months ]
   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.

Secondary Outcome Measures :

1. Change From Baseline in Fasting Blood Glucose Level [ Time Frame: Baseline, 3 months ]
   Glucose (sugar) was measured in the blood and reported in milligrams per deciliter (mg/dL).
2. Change From Baseline in Glycosylated Hemoglobin (HbA1c) [ Time Frame: Baseline, 3 months ]
   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.
3. Change From Baseline in Insulin Levels [ Time Frame: Baseline, 3 months ]
   Insulin levels in the blood were measured by immunoenzymatic assay and reported in micro International Units per milliliter (mcIU/mL).
4. Change From Baseline in Lipid Profile [ Time Frame: Baseline, 3 months ]
   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).
5. Change From Baseline in the Thrombotic Biomarker Fibrinogen [ Time Frame: Baseline, 3 months ]
   Fibrinogen was measured by thrombin clotting rate assay (Beckman Coulter, Inc. Brea, California) and reported in milligrams/deciliter (mg/dL).
6. Change From Baseline in the Thrombotic Biomarker Plasminogen Activator Inhibitor-1 (PAI-1) [ Time Frame: Baseline, 3 months ]
   PAI-1 was measured by enzyme-linked immunosorbent assay (Diagnostica Stago Inc., Parsippany, New Jersey) and reported in nanograms per milliliter (ng/mL).
7. Change From Baseline in the Inflammatory Biomarker Interleukin 6 (IL-6) [ Time Frame: Baseline, 3 months ]
   IL-6 is an inflammatory cytokine and reported in picograms per deciliter (pg/dL).
8. Change From Baseline in the Inflammatory Biomarker C-Reactive Protein (CRP) [ Time Frame: Baseline, 3 months ]
   CRP is an inflammatory cytokine and is reported in milligrams per deciliter (mg/dL).
9. Change From Baseline in Inflammatory Biomarker Tumor Necrosis Factor-alpha (TNF-α) [ Time Frame: Baseline, 3 month ]
   TNF-α is an inflammatory cytokine and is reported in picograms/milliliter (pg/mL).
10. Change From Baseline in the Inflammatory Biomarker Adiponectin [ Time Frame: Baseline, 3 months ]
    Adiponectin is an anti-inflammatory cytokine and is reported in milligrams per milliliter (mg/mL).

Other Outcome Measures:

1. Change From Baseline in Body Mass Index [ Time Frame: Baseline, 3 months ]
   Body Mass Index (BMI) is a health index for comparing weight to height. BMI is a person's weight in kilograms (kg) divided by his or her height in meters squared. The body mass index is an indication if a person is at a suitable weight for his height on an approximation of body fat.
2. Change From Baseline in Body Fat [ Time Frame: Baseline, 3 months ]
   Body fat is reported as a percentage of body weight.
3. Change From Baseline in Fat-Free Mass (FFM) [ Time Frame: Baseline, 3 months ]
   FFM was measured using dual energy x-ray absorptiometry (DEXA) scans and is reported in kilograms (kg).

Eligibility Criteria

• Ages Eligible for Study: 20 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55905

Sponsors and Collaborators

Mayo Clinic

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

More Information

Additional Information:

Mayo Clinic Clinical Trials 

Publications of Results:

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. Erratum In: Mayo Clin Proc. 2013 Aug;88(8):903-4.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: K. Sreekumaran Nair, Professor of Medicine, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00443755
• Other Study ID Numbers: 05-004002; R01DK041973 ( U.S. NIH Grant/Contract ); KL2RR024151 ( U.S. NIH Grant/Contract ); UL1RR024150 ( U.S. NIH Grant/Contract )
• First Posted: March 6, 2007
• Results First Posted: June 6, 2013
• Last Update Posted: October 31, 2013
• Last Verified: October 2013

Keywords provided by K. Sreekumaran Nair, Mayo Clinic:

Inflammatory cytokine; Cardiovascular Disease; Thrombotic factors; Dyslipidemia

Additional relevant MeSH terms:

Metabolic Syndrome; Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Metformin; Pioglitazone; Hypoglycemic Agents; Physiological Effects of Drugs