Clinical trial NCT00443755: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Type 2 Diabetes
Insulin Resistance
Metabolic Syndrome
Keywords: Inflammatory cytokine
Cardiovascular Disease
Thrombotic factors
Dyslipidemia
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Takeda Pharmaceuticals North America, Inc.
name: National Center for Research Resources (NCRR)
First posted: 2007-03-06
Enrollment: 28
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Primary outcomes:
measure: Change From Baseline in Insulin Sensitivity as Measured by Glucose Infusion Rate (GIR)
timeFrame: Baseline, 3 months
Secondary outcomes:
measure: Change From Baseline in Fasting Blood Glucose Level
timeFrame: Baseline, 3 months
measure: Change From Baseline in Glycosylated Hemoglobin (HbA1c)
timeFrame: Baseline, 3 months
measure: Change From Baseline in Insulin Levels
timeFrame: Baseline, 3 months
measure: Change From Baseline in Lipid Profile
timeFrame: Baseline, 3 months
measure: Change From Baseline in the Thrombotic Biomarker Fibrinogen
timeFrame: Baseline, 3 months
measure: Change From Baseline in the Thrombotic Biomarker Plasminogen Activator Inhibitor-1 (PAI-1)
timeFrame: Baseline, 3 months
measure: Change From Baseline in the Inflammatory Biomarker Interleukin 6 (IL-6)
timeFrame: Baseline, 3 months
measure: Change From Baseline in the Inflammatory Biomarker C-Reactive Protein (CRP)
timeFrame: Baseline, 3 months
measure: Change From Baseline in Inflammatory Biomarker Tumor Necrosis Factor-alpha (TNF-α)
timeFrame: Baseline, 3 month
measure: Change From Baseline in the Inflammatory Biomarker Adiponectin
timeFrame: Baseline, 3 months
Other outcomes:
measure: Change From Baseline in Body Mass Index
timeFrame: Baseline, 3 months
measure: Change From Baseline in Body Fat
timeFrame: Baseline, 3 months
measure: Change From Baseline in Fat-Free Mass (FFM)
timeFrame: Baseline, 3 months
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: K. Sreekumaran Nair, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.