Trial Outcomes & Findings for Effect of Insulin Sensitizer Therapy on Atherothrombotic and Inflammatory Profiles Associated With Insulin Resistance (NCT NCT00443755)

Last Updated: 2013-10-31

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

28 participants

Primary outcome timeframe

Baseline, 3 months

Results posted on

2013-10-31

Participant Flow

The study was conducted between 8/19/2005 and 8/24/2010 at the Mayo Clinic in Rochester, Minnesota.

48 Northern European Americans were assessed for eligibility and of those, 20 did not meet inclusion criteria.

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	14	14
Overall Study COMPLETED	12	13
Overall Study NOT COMPLETED	2	1

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Overall Study Withdrawal by Subject	2	1

Baseline Characteristics

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

Baseline characteristics by cohort

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

PRIMARY outcome

Timeframe: Baseline, 3 months

Population: Per-protocol analysis

Outcome measures

Outcome measures
Measure	Insulin Sensitizer Therapy n=12 Participants 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 n=13 Participants 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.
Change From Baseline in Insulin Sensitivity as Measured by Glucose Infusion Rate (GIR)	17.95 micromols/kg of FFM/minute Standard Deviation 8.60	1.68 micromols/kg of FFM/minute Standard Deviation 7.56

SECONDARY outcome

Timeframe: Baseline, 3 months

Population: Per-protocol analysis

Glucose (sugar) was measured in the blood and reported in milligrams per deciliter (mg/dL).

Outcome measures

Outcome measures
Measure	Insulin Sensitizer Therapy n=12 Participants 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 n=13 Participants 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.
Change From Baseline in Fasting Blood Glucose Level	-19.96 mg/dL Standard Deviation 14.02	8.39 mg/dL Standard Deviation 22.51

SECONDARY outcome

Timeframe: Baseline, 3 months

Population: Per-protocol analysis

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.

Outcome measures

Outcome measures
Measure	Insulin Sensitizer Therapy n=12 Participants 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 n=13 Participants 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.
Change From Baseline in Glycosylated Hemoglobin (HbA1c)	-0.35 percentage Standard Deviation 0.40	0.19 percentage Standard Deviation 0.60

SECONDARY outcome

Timeframe: Baseline, 3 months

Population: Per-protocol analysis

Insulin levels in the blood were measured by immunoenzymatic assay and reported in micro International Units per milliliter (mcIU/mL).

Outcome measures

Outcome measures
Measure	Insulin Sensitizer Therapy n=12 Participants 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 n=13 Participants 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.
Change From Baseline in Insulin Levels	-8.13 microIU/mL Standard Deviation 7.47	1.38 microIU/mL Standard Deviation 3.29

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Insulin Sensitizer Therapy n=12 Participants 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 n=13 Participants 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.
Change From Baseline in Lipid Profile Triglycerides	-15.58 mg/dL Standard Deviation 32.67	17.77 mg/dL Standard Deviation 28.86
Change From Baseline in Lipid Profile HDL-C-Cholesterol	4.33 mg/dL Standard Deviation 6.75	-0.31 mg/dL Standard Deviation 3.90
Change From Baseline in Lipid Profile Non-HDL-Cholesterol	-7.50 mg/dL Standard Deviation 15.29	4.62 mg/dL Standard Deviation 17.76

SECONDARY outcome

Timeframe: Baseline, 3 months

Population: Per-protocol analysis

Fibrinogen was measured by thrombin clotting rate assay (Beckman Coulter, Inc. Brea, California) and reported in milligrams/deciliter (mg/dL).

Outcome measures

Outcome measures
Measure	Insulin Sensitizer Therapy n=12 Participants 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 n=13 Participants 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.
Change From Baseline in the Thrombotic Biomarker Fibrinogen	14.00 mg/dL Standard Deviation 71.24	-18.62 mg/dL Standard Deviation 62.91

SECONDARY outcome

Timeframe: Baseline, 3 months

Population: Per-protocol analysis

PAI-1 was measured by enzyme-linked immunosorbent assay (Diagnostica Stago Inc., Parsippany, New Jersey) and reported in nanograms per milliliter (ng/mL).

Outcome measures

Outcome measures
Measure	Insulin Sensitizer Therapy n=12 Participants 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 n=13 Participants 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.
Change From Baseline in the Thrombotic Biomarker Plasminogen Activator Inhibitor-1 (PAI-1)	-34.17 ng/mL Standard Deviation 25.35	8.15 ng/mL Standard Deviation 30.78

SECONDARY outcome

Timeframe: Baseline, 3 months

Population: Per protocol analysis

IL-6 is an inflammatory cytokine and reported in picograms per deciliter (pg/dL).

Outcome measures

Outcome measures
Measure	Insulin Sensitizer Therapy n=12 Participants 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 n=13 Participants 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.
Change From Baseline in the Inflammatory Biomarker Interleukin 6 (IL-6)	-0.99 pg/mL Standard Deviation 1.44	-1.42 pg/mL Standard Deviation 4.84

SECONDARY outcome

Timeframe: Baseline, 3 months

Population: Per-protocol analysis

CRP is an inflammatory cytokine and is reported in milligrams per deciliter (mg/dL).

Outcome measures

Outcome measures
Measure	Insulin Sensitizer Therapy n=12 Participants 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 n=13 Participants 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.
Change From Baseline in the Inflammatory Biomarker C-Reactive Protein (CRP)	-0.19 mg/dL Standard Deviation 0.22	-0.15 mg/dL Standard Deviation 0.53

SECONDARY outcome

Timeframe: Baseline, 3 month

Population: Per-protocol analysis

TNF-α is an inflammatory cytokine and is reported in picograms/milliliter (pg/mL).

Outcome measures

Outcome measures
Measure	Insulin Sensitizer Therapy n=12 Participants 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 n=13 Participants 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.
Change From Baseline in Inflammatory Biomarker Tumor Necrosis Factor-alpha (TNF-α)	-0.13 pg/mL Standard Deviation 0.21	0.18 pg/mL Standard Deviation 0.37

SECONDARY outcome

Timeframe: Baseline, 3 months

Population: Per-protocol analysis

Adiponectin is an anti-inflammatory cytokine and is reported in milligrams per milliliter (mg/mL).

Outcome measures

Outcome measures
Measure	Insulin Sensitizer Therapy n=12 Participants 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 n=13 Participants 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.
Change From Baseline in the Inflammatory Biomarker Adiponectin	9.10 mg/mL Standard Deviation 5.22	0.46 mg/mL Standard Deviation 0.92

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, 3 months

Population: Per-protocol population

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.

Outcome measures

Outcome measures
Measure	Insulin Sensitizer Therapy n=12 Participants 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 n=13 Participants 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.
Change From Baseline in Body Mass Index	0.37 kg/m^2 Standard Deviation 0.62	-0.21 kg/m^2 Standard Deviation 0.40

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, 3 months

Population: Per-protocol population

Body fat is reported as a percentage of body weight.

Outcome measures

Outcome measures
Measure	Insulin Sensitizer Therapy n=12 Participants 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 n=13 Participants 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.
Change From Baseline in Body Fat	1.73 percentage of body weight Standard Deviation 3.08	-0.01 percentage of body weight Standard Deviation 1.44

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, 3 months

Population: Per-protocol analysis

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

Outcome measures

Outcome measures
Measure	Insulin Sensitizer Therapy n=12 Participants 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 n=13 Participants 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.
Change From Baseline in Fat-Free Mass (FFM)	-1.13 kilograms Standard Deviation 2.81	-0.34 kilograms Standard Deviation 1.28

Adverse Events

Insulin Sensitizer Therapy

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

K. Sreekumaran Nair, MD, Ph.D.

Mayo Clinic

Phone: 507-255-3605

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place