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

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00443755
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), Takeda Pharmaceuticals North America, Inc. (Industry), National Center for Research Resources (NCRR) (NIH)
• Enrollment: 28
• Location: 1
• Arms: 2
• Duration (Months): 60
• Patients Per Site Per Month: 0.5

Study Details

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
• 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: Aug 1, 2005
• Actual Primary Completion Date: Aug 1, 2010
• Actual Study Completion Date: Aug 1, 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 Names: 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) [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 [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) [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 [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 [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 [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) [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) [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) [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) [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 [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 [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 [Baseline, 3 months]

   Body fat is reported as a percentage of body weight.

3. Change From Baseline in Fat-Free Mass (FFM) [Baseline, 3 months]

   FFM was measured using dual energy x-ray absorptiometry (DEXA) scans and is reported in kilograms (kg).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

None provided.

• Responsible Party: K. Sreekumaran Nair, Professor of Medicine, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00443755
• Other Study ID Numbers: 05-004002; R01DK041973; KL2RR024151; UL1RR024150
• First Posted: Mar 6, 2007
• Last Update Posted: Oct 31, 2013
• Last Verified: Oct 1, 2013

• Keywords provided by K. Sreekumaran Nair, Professor of Medicine, Mayo Clinic: Inflammatory cytokine; Cardiovascular Disease; Thrombotic factors; Dyslipidemia
• Additional relevant MeSH terms: Metabolic Syndrome; Insulin Resistance; Metformin; Pioglitazone

Study Results

Participant Flow

Recruitment Details	The study was conducted between 8/19/2005 and 8/24/2010 at the Mayo Clinic in Rochester, Minnesota.
Pre-assignment Detail	48 Northern European Americans were assessed for eligibility and of those, 20 did not meet inclusion criteria.

Arm/Group Title	Insulin Sensitizer Therapy	Placebo
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	14	14
COMPLETED	12	13
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Insulin Sensitizer Therapy	Placebo	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	12	13	25
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.5 (15.6)	52.2 (18.2)	52.4 (16.6)
Sex: Female, Male (Count of Participants)
Female	7 58.3%	8 61.5%	15 60%
Male	5 41.7%	5 38.5%	10 40%
Region of Enrollment (participants) [Number]
United States	12 100%	13 100%	25 100%
Body Mass Index (kilograms/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms/m^2]	32.43 (5.65)	29.67 (3.34)	31.00 (4.71)
Fat-Free Mass (Kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kilograms]	48.81 (14.29)	46.67 (13.54)	47.70 (13.66)
Body Fat (Percentage of body weight) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of body weight]	46.49 (5.92)	43.26 (9.17)	44.81 (7.80)
Fasting Blood Glucose (milligrams per deciliter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milligrams per deciliter]	126.25 (21.87)	129.00 (26.32)	127.68 (23.82)
Glycosylated Hemoglobin (HbA1c) (Percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage]	5.97 (0.71)	6.25 (0.65)	6.11 (0.68)
Glucose Infusion Rate (GIR) (micromols/kilogram of FFM/minute) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [micromols/kilogram of FFM/minute]	22.28 (14.67)	23.40 (15.27)	22.86 (14.68)
Insulin level (micro International Units per milliliter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [micro International Units per milliliter]	15.68 (9.75)	10.18 (5.70)	12.82 (8.23)
Lipid Profile (milligrams per deciliter) [Mean (Standard Deviation) ]
Triglycerides	131.42 (54.76)	135.00 (51.36)	133.28 (51.93)
High Density Lipoprotein-Cholesterol (HDL-C)	43.33 (12.78)	39.23 (8.74)	41.20 (10.84)
Non-HDL-Cholesterol	135.58 (26.17)	132.46 (21.65)	133.96 (23.47)
Fibrinogen (milligrams per deciliter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milligrams per deciliter]	393.67 (78.63)	418.92 (100.23)	406.80 (89.57)
Plasminogen Activator Inhibitor 1 (PAI-1) (nanograms per milliliter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [nanograms per milliliter]	81.83 (22.01)	55.85 (33.70)	68.3 (31.1)
C-Reactive Protein (CRP) (milligrams per deciliter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milligrams per deciliter]	0.42 (0.43)	0.43 (0.49)	0.42 (0.45)
Interleukin-6 (IL-6) (picograms per milliliter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [picograms per milliliter]	2.46 (1.68)	3.28 (4.79)	2.88 (3.59)
Tumor Necrosis Factor-alpha (TNF-α) (picograms per milliliter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [picograms per milliliter]	1.39 (0.57)	2.98 (5.39)	2.22 (3.91)
Adiponectin (milligrams per milliliter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milligrams per milliliter]	6.08 (2.17)	5.22 (2.13)	5.63 (2.15)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Insulin Sensitivity as Measured by Glucose Infusion Rate (GIR)
Description	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.
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

Per-protocol analysis

Arm/Group Title	Insulin Sensitizer Therapy	Placebo
Arm/Group Description	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.	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.
Measure Participants	12	13
Mean (Standard Deviation) [micromols/kg of FFM/minute]	17.95 (8.60)	1.68 (7.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Sensitizer Therapy, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Change From Baseline in Fasting Blood Glucose Level
Description	Glucose (sugar) was measured in the blood and reported in milligrams per deciliter (mg/dL).
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

Per-protocol analysis

Arm/Group Title	Insulin Sensitizer Therapy	Placebo
Arm/Group Description	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.	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.
Measure Participants	12	13
Mean (Standard Deviation) [mg/dL]	-19.96 (14.02)	8.39 (22.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Sensitizer Therapy, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin (HbA1c)
Description	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.
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

Per-protocol analysis

Arm/Group Title	Insulin Sensitizer Therapy	Placebo
Arm/Group Description	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.	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.
Measure Participants	12	13
Mean (Standard Deviation) [percentage]	-0.35 (0.40)	0.19 (0.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Sensitizer Therapy, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	Change From Baseline in Insulin Levels
Description	Insulin levels in the blood were measured by immunoenzymatic assay and reported in micro International Units per milliliter (mcIU/mL).
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

Per-protocol analysis

Arm/Group Title	Insulin Sensitizer Therapy	Placebo
Arm/Group Description	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.	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.
Measure Participants	12	13
Mean (Standard Deviation) [microIU/mL]	-8.13 (7.47)	1.38 (3.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Sensitizer Therapy, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Change From Baseline in Lipid Profile
Description	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).
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Insulin Sensitizer Therapy	Placebo
Arm/Group Description	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.	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.
Measure Participants	12	13
Triglycerides	-15.58 (32.67)	17.77 (28.86)
HDL-C-Cholesterol	4.33 (6.75)	-0.31 (3.90)
Non-HDL-Cholesterol	-7.50 (15.29)	4.62 (17.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Sensitizer Therapy, Placebo
	Comments	P-value is for comparison between groups of the mean change in triglyceride levels.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Insulin Sensitizer Therapy, Placebo
	Comments	P-value is for comparison between groups of the mean change in HDL-C levels.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Insulin Sensitizer Therapy, Placebo
	Comments	P-value is for comparison between groups of mean change in non-HDL-C levels.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Change From Baseline in the Thrombotic Biomarker Fibrinogen
Description	Fibrinogen was measured by thrombin clotting rate assay (Beckman Coulter, Inc. Brea, California) and reported in milligrams/deciliter (mg/dL).
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

Per-protocol analysis

Arm/Group Title	Insulin Sensitizer Therapy	Placebo
Arm/Group Description	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.	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.
Measure Participants	12	13
Mean (Standard Deviation) [mg/dL]	14.00 (71.24)	-18.62 (62.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Sensitizer Therapy, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.23
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

7. Secondary Outcome

Title	Change From Baseline in the Thrombotic Biomarker Plasminogen Activator Inhibitor-1 (PAI-1)
Description	PAI-1 was measured by enzyme-linked immunosorbent assay (Diagnostica Stago Inc., Parsippany, New Jersey) and reported in nanograms per milliliter (ng/mL).
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

Per-protocol analysis

Arm/Group Title	Insulin Sensitizer Therapy	Placebo
Arm/Group Description	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.	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.
Measure Participants	12	13
Mean (Standard Deviation) [ng/mL]	-34.17 (25.35)	8.15 (30.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Sensitizer Therapy, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

8. Secondary Outcome

Title	Change From Baseline in the Inflammatory Biomarker Interleukin 6 (IL-6)
Description	IL-6 is an inflammatory cytokine and reported in picograms per deciliter (pg/dL).
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

Per protocol analysis

Arm/Group Title	Insulin Sensitizer Therapy	Placebo
Arm/Group Description	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.	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.
Measure Participants	12	13
Mean (Standard Deviation) [pg/mL]	-0.99 (1.44)	-1.42 (4.84)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Sensitizer Therapy, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

9. Secondary Outcome

Title	Change From Baseline in the Inflammatory Biomarker C-Reactive Protein (CRP)
Description	CRP is an inflammatory cytokine and is reported in milligrams per deciliter (mg/dL).
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

Per-protocol analysis

Arm/Group Title	Insulin Sensitizer Therapy	Placebo
Arm/Group Description	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.	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.
Measure Participants	12	13
Mean (Standard Deviation) [mg/dL]	-0.19 (0.22)	-0.15 (0.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Sensitizer Therapy, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

10. Secondary Outcome

Title	Change From Baseline in Inflammatory Biomarker Tumor Necrosis Factor-alpha (TNF-α)
Description	TNF-α is an inflammatory cytokine and is reported in picograms/milliliter (pg/mL).
Time Frame	Baseline, 3 month

Outcome Measure Data

Analysis Population Description

Per-protocol analysis

Arm/Group Title	Insulin Sensitizer Therapy	Placebo
Arm/Group Description	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.	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.
Measure Participants	12	13
Mean (Standard Deviation) [pg/mL]	-0.13 (0.21)	0.18 (0.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Sensitizer Therapy, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

11. Secondary Outcome

Title	Change From Baseline in the Inflammatory Biomarker Adiponectin
Description	Adiponectin is an anti-inflammatory cytokine and is reported in milligrams per milliliter (mg/mL).
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

Per-protocol analysis

Arm/Group Title	Insulin Sensitizer Therapy	Placebo
Arm/Group Description	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.	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.
Measure Participants	12	13
Mean (Standard Deviation) [mg/mL]	9.10 (5.22)	0.46 (0.92)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Sensitizer Therapy, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

12. Other Pre-specified Outcome

Title	Change From Baseline in Body Mass Index
Description	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.
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

Per-protocol population

Arm/Group Title	Insulin Sensitizer Therapy	Placebo
Arm/Group Description	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.	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.
Measure Participants	12	13
Mean (Standard Deviation) [kg/m^2]	0.37 (0.62)	-0.21 (0.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Sensitizer Therapy, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

13. Other Pre-specified Outcome

Title	Change From Baseline in Body Fat
Description	Body fat is reported as a percentage of body weight.
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

Per-protocol population

Arm/Group Title	Insulin Sensitizer Therapy	Placebo
Arm/Group Description	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.	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.
Measure Participants	12	13
Mean (Standard Deviation) [percentage of body weight]	1.73 (3.08)	-0.01 (1.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Sensitizer Therapy, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

14. Other Pre-specified Outcome

Title	Change From Baseline in Fat-Free Mass (FFM)
Description	FFM was measured using dual energy x-ray absorptiometry (DEXA) scans and is reported in kilograms (kg).
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

Per-protocol analysis

Arm/Group Title	Insulin Sensitizer Therapy	Placebo
Arm/Group Description	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.	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.
Measure Participants	12	13
Mean (Standard Deviation) [kilograms]	-1.13 (2.81)	-0.34 (1.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Sensitizer Therapy, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.76
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Arm/Group Title	Insulin Sensitizer Therapy		Placebo
Arm/Group Description	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.		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.
All Cause Mortality
	Insulin Sensitizer Therapy		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Insulin Sensitizer Therapy		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Insulin Sensitizer Therapy		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/13 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.