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| ID | Type | Description | Link |
|---|---|---|---|
| R01DK041973 | U.S. NIH Grant/Contract | View source | |
| KL2RR024151 | U.S. NIH Grant/Contract | View source | |
| UL1RR024150 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
| Takeda Pharmaceuticals North America, Inc. | INDUSTRY |
| National Center for Research Resources (NCRR) | NIH |
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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| Placebo | Placebo Comparator | Placebo tablets were used to match the active comparator drugs and dosing regimen. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Fasting Blood Glucose Level | Glucose (sugar) was measured in the blood and reported in milligrams per deciliter (mg/dL). | Baseline, 3 months |
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Body Mass Index | 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. | Baseline, 3 months |
Inclusion criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| K. Sreekumaran Nair, M.D., Ph.D. | Mayo Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic | Rochester | Minnesota | 55905 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22677076 | Result | 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. | |
| 25733201 | Derived | 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. |
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48 Northern European Americans were assessed for eligibility and of those, 20 did not meet inclusion criteria.
The study was conducted between 8/19/2005 and 8/24/2010 at the Mayo Clinic in Rochester, Minnesota.
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| ID | Title | Description |
|---|---|---|
| FG000 | Insulin Sensitizer Therapy | Two insulin sensitizing drugs will be taken together for 3 months; metformin 1000 mg twice daily plus pioglitazone 45 mg daily. The number of subjects analyzed for baseline measures and outcome measures were the 12 subjects who completed the study. |
| FG001 | Placebo | Placebo tablets were used to match the active comparator drugs and dosing regimen. The number of subjects analyzed for baseline measures and outcome measures were the 13 subjects who completed the study. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
The baseline characteristics are reported for the subjects who completed the study.
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| ID | Title | Description |
|---|---|---|
| BG000 | Insulin Sensitizer Therapy | Two insulin sensitizing drugs will be taken together for 3 months; metformin 1000 mg twice daily plus pioglitazone 45 mg daily. The number of subjects analyzed for baseline measures and outcome measures were the 12 subjects who completed the study. |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Per-protocol analysis | Posted | Mean | Standard Deviation | micromols/kg of FFM/minute | Baseline, 3 months |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Insulin Sensitizer Therapy | Two insulin sensitizing drugs will be taken together for 3 months; metformin 1000 mg twice daily plus pioglitazone 45 mg daily. The number of subjects analyzed for baseline measures and outcome measures were the 12 subjects who completed the study. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| K. Sreekumaran Nair, MD, Ph.D. | Mayo Clinic | 507-255-3605 | nair@mayo.edu |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D007333 | Insulin Resistance |
| D024821 | Metabolic Syndrome |
| D002318 | Cardiovascular Diseases |
| D050171 | Dyslipidemias |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| D000077205 | Pioglitazone |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
| D045162 |
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|
| 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. |
|
|
| Placebo | Drug | Placebo tablets matching the metformin and pioglitazone tablets are given in the same regimen as the active drug arm for 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.
| Baseline, 3 months |
| Change From Baseline in Insulin Levels | Insulin levels in the blood were measured by immunoenzymatic assay and reported in micro International Units per milliliter (mcIU/mL). | Baseline, 3 months |
| Change From Baseline in Lipid Profile | 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). | Baseline, 3 months |
| Change From Baseline in the Thrombotic Biomarker Fibrinogen | Fibrinogen was measured by thrombin clotting rate assay (Beckman Coulter, Inc. Brea, California) and reported in milligrams/deciliter (mg/dL). | Baseline, 3 months |
| Change From Baseline in the Thrombotic Biomarker Plasminogen Activator Inhibitor-1 (PAI-1) | PAI-1 was measured by enzyme-linked immunosorbent assay (Diagnostica Stago Inc., Parsippany, New Jersey) and reported in nanograms per milliliter (ng/mL). | Baseline, 3 months |
| Change From Baseline in the Inflammatory Biomarker Interleukin 6 (IL-6) | IL-6 is an inflammatory cytokine and reported in picograms per deciliter (pg/dL). | Baseline, 3 months |
| Change From Baseline in the Inflammatory Biomarker C-Reactive Protein (CRP) | CRP is an inflammatory cytokine and is reported in milligrams per deciliter (mg/dL). | Baseline, 3 months |
| Change From Baseline in Inflammatory Biomarker Tumor Necrosis Factor-alpha (TNF-α) | TNF-α is an inflammatory cytokine and is reported in picograms/milliliter (pg/mL). | Baseline, 3 month |
| Change From Baseline in the Inflammatory Biomarker Adiponectin | Adiponectin is an anti-inflammatory cytokine and is reported in milligrams per milliliter (mg/mL). | Baseline, 3 months |
| Change From Baseline in Body Fat |
Body fat is reported as a percentage of body weight. |
| Baseline, 3 months |
| Change From Baseline in Fat-Free Mass (FFM) | FFM was measured using dual energy x-ray absorptiometry (DEXA) scans and is reported in kilograms (kg). | Baseline, 3 months |
Placebo tablets were used to match the active comparator drugs and dosing regimen. The number of subjects analyzed for baseline measures and outcome measures were the 13 subjects who completed the study. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Body Mass Index | 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. | Mean | Standard Deviation | kilograms/m^2 |
|
| Fat-Free Mass | Mean | Standard Deviation | Kilograms |
|
| Body Fat | Mean | Standard Deviation | Percentage of body weight |
|
| Fasting Blood Glucose | Mean | Standard Deviation | milligrams per deciliter |
|
| Glycosylated Hemoglobin (HbA1c) | The HbA1c level reflects the average glucose (blood sugar) concentration over the previous 3 month period. | Mean | Standard Deviation | Percentage |
|
| Glucose Infusion Rate (GIR) | FFM is Fat Free Mass | Mean | Standard Deviation | micromols/kilogram of FFM/minute |
|
| Insulin level | Mean | Standard Deviation | micro International Units per milliliter |
|
| Lipid Profile | Mean | Standard Deviation | milligrams per deciliter |
|
| Fibrinogen | Mean | Standard Deviation | milligrams per deciliter |
|
| Plasminogen Activator Inhibitor 1 (PAI-1) | Mean | Standard Deviation | nanograms per milliliter |
|
| C-Reactive Protein (CRP) | Mean | Standard Deviation | milligrams per deciliter |
|
| Interleukin-6 (IL-6) | Mean | Standard Deviation | picograms per milliliter |
|
| Tumor Necrosis Factor-alpha (TNF-α) | Mean | Standard Deviation | picograms per milliliter |
|
| Adiponectin | Mean | Standard Deviation | milligrams per milliliter |
|
| OG000 | Insulin Sensitizer Therapy | Two insulin sensitizing drugs will be taken together for 3 months; metformin 1000 mg twice daily plus pioglitazone 45 mg daily. The number of subjects analyzed for baseline measures and outcome measures were the 12 subjects who completed the study. |
| OG001 | Placebo | Placebo tablets were used to match the active comparator drugs and dosing regimen. The number of subjects analyzed for baseline measures and outcome measures were the 13 subjects who completed the study. |
|
|
|
| Secondary | Change From Baseline in Fasting Blood Glucose Level | Glucose (sugar) was measured in the blood and reported in milligrams per deciliter (mg/dL). | Per-protocol analysis | Posted | Mean | Standard Deviation | mg/dL | Baseline, 3 months |
|
|
|
|
| Secondary | Change From Baseline in Glycosylated Hemoglobin (HbA1c) | 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. | Per-protocol analysis | Posted | Mean | Standard Deviation | percentage | Baseline, 3 months |
|
|
|
|
| Secondary | Change From Baseline in Insulin Levels | Insulin levels in the blood were measured by immunoenzymatic assay and reported in micro International Units per milliliter (mcIU/mL). | Per-protocol analysis | Posted | Mean | Standard Deviation | microIU/mL | Baseline, 3 months |
|
|
|
|
| Secondary | Change From Baseline in Lipid Profile | 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). | Posted | Mean | Standard Deviation | mg/dL | Baseline, 3 months |
|
|
|
|
| Secondary | Change From Baseline in the Thrombotic Biomarker Fibrinogen | Fibrinogen was measured by thrombin clotting rate assay (Beckman Coulter, Inc. Brea, California) and reported in milligrams/deciliter (mg/dL). | Per-protocol analysis | Posted | Mean | Standard Deviation | mg/dL | Baseline, 3 months |
|
|
|
|
| Secondary | Change From Baseline in the Thrombotic Biomarker Plasminogen Activator Inhibitor-1 (PAI-1) | PAI-1 was measured by enzyme-linked immunosorbent assay (Diagnostica Stago Inc., Parsippany, New Jersey) and reported in nanograms per milliliter (ng/mL). | Per-protocol analysis | Posted | Mean | Standard Deviation | ng/mL | Baseline, 3 months |
|
|
|
|
| Secondary | Change From Baseline in the Inflammatory Biomarker Interleukin 6 (IL-6) | IL-6 is an inflammatory cytokine and reported in picograms per deciliter (pg/dL). | Per protocol analysis | Posted | Mean | Standard Deviation | pg/mL | Baseline, 3 months |
|
|
|
|
| Secondary | Change From Baseline in the Inflammatory Biomarker C-Reactive Protein (CRP) | CRP is an inflammatory cytokine and is reported in milligrams per deciliter (mg/dL). | Per-protocol analysis | Posted | Mean | Standard Deviation | mg/dL | Baseline, 3 months |
|
|
|
|
| Secondary | Change From Baseline in Inflammatory Biomarker Tumor Necrosis Factor-alpha (TNF-α) | TNF-α is an inflammatory cytokine and is reported in picograms/milliliter (pg/mL). | Per-protocol analysis | Posted | Mean | Standard Deviation | pg/mL | Baseline, 3 month |
|
|
|
|
| Secondary | Change From Baseline in the Inflammatory Biomarker Adiponectin | Adiponectin is an anti-inflammatory cytokine and is reported in milligrams per milliliter (mg/mL). | Per-protocol analysis | Posted | Mean | Standard Deviation | mg/mL | Baseline, 3 months |
|
|
|
|
| Other Pre-specified | Change From Baseline in Body Mass Index | 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. | Per-protocol population | Posted | Mean | Standard Deviation | kg/m^2 | Baseline, 3 months |
|
|
|
|
| Other Pre-specified | Change From Baseline in Body Fat | Body fat is reported as a percentage of body weight. | Per-protocol population | Posted | Mean | Standard Deviation | percentage of body weight | Baseline, 3 months |
|
|
|
|
| Other Pre-specified | Change From Baseline in Fat-Free Mass (FFM) | FFM was measured using dual energy x-ray absorptiometry (DEXA) scans and is reported in kilograms (kg). | Per-protocol analysis | Posted | Mean | Standard Deviation | kilograms | Baseline, 3 months |
|
|
|
|
| 0 |
| 12 |
| 0 |
| 12 |
| EG001 | Placebo | Placebo tablets were used to match the active comparator drugs and dosing regimen. The number of subjects analyzed for baseline measures and outcome measures were the 13 subjects who completed the study. | 0 | 13 | 0 | 13 |
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| D004700 | Endocrine System Diseases |
| D006946 | Hyperinsulinism |
| D052439 | Lipid Metabolism Disorders |
| Thiazolidinediones |
| D013844 | Thiazoles |
| D013457 | Sulfur Compounds |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| Non-HDL-Cholesterol |
|
| Wilcoxon (Mann-Whitney) |
| 0.06 |
| 95 |
| No |
| Superiority or Other |
| P-value is for comparison between groups of mean change in non-HDL-C levels. | Wilcoxon (Mann-Whitney) | 0.06 | 95 | No | Superiority or Other |