Metabolic Syndrome
Conditions
Keywords
HDL cholesterol, Metabolic syndrome
Brief summary
We will test our primary hypothesis that combining niacin extended release (niacin-ER), at a daily dosage of up to 2.0 g with pioglitazone, at a daily dosage of 45 mg will result in a 12% greater increase in HDL-C when compared to niacin-ER monotherapy over 12 weeks in non-diabetic patients with the metabolic syndrome (see Table 1).
Detailed description
This is a two-arm, parallel, double-blind randomized prospective clinical trial. The subjects will be asked to provide informed consent, and then undergo screening for enrollment criteria at the first visit (-5 weeks). The subjects who are eligible, and provide informed consent will return for Visit 2 baseline data (-4 weeks), and then begin the unblinded niacin-ER titration. Specifically, subjects will receive a starting dose of niacin-ER of 500 mg per day, which will be increased in 500 mg increments every week up to a dose of 2000 mg per day. Subjects will need to tolerate at least 1500 mg per day of niacin-ER in order to remain in the study and be randomized. Thus subjects who are unable to tolerate the 2000 mg daily dose of niacin-ER will be taken back to 1500 mg per day for one week and then randomized. Subjects who develop prohibitive side effects at doses less than 1500 mg per day will be discontinued from the study. All subjects who are able to take the target dose of niacin-ER will continue that dose of niacin-ER and come to the General Clinical Research Center (GCRC) to be randomized in a 1:1 fashion to either niacin-ER plus pioglitazone or niacin-ER plus matching placebo for 12 weeks. Pioglitazone will be started at 30 mg and then increased to 45 mg at week 6. This entry design is designed to minimize the differences in mean dose of niacin-ER and dropout rate between study groups.
Interventions
DRUGPioglitazone
Pioglitazone, initially 30 mg, then titrated to 45 mg/day
OTHERPlacebo
Pioglitazone placebo
DRUGNiacin ER
Niacin ER 2.0 g/day
DRUGAspirin
asprin 325 mg/day
Sponsors
Kos Pharmaceuticals
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Pioglitazone and placebo were overencapsulated
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Men and women between the ages of 18 and 75 2. HDL-C ≤ 40 mg/dL for Men and HDL-C \< 50 mg/dl for Women\* 3. At least two of the following criteria (a, b, c, or d) listed below: 1. Abdominal obesity (waist circumference: men 40 inches and women 35 inches)\*\* 2. Blood pressure \> 130/\>85 mmHg in untreated patients OR use of any antihypertensive agent. 3. Fasting glucose \> 100 mg/dL but \< 126 mg/dL 4. Fasting triglycerides \> 150 mg/dL
Exclusion criteria
1. Diabetes or use of anti-hyperglycemic medication in the last 3 months (subjects with a fasting blood glucose of \> 110 mg/dL will have an oral glucose tolerance test (OGTT) to rule out diabetes mellitus). 2. Subjects on statin therapy may be enrolled, but only if they have been on a stable dose for at least 3 months, and are not expected to require titration of statin therapy during the course of the study. 3. Uncontrolled hypertension (defined as systolic bp \> 180, diastolic BP \> 100). 4. Triglycerides \> 400 mg/dL 5. LDL-cholesterol level \> 190 mg/dl 6. History of chronic renal insufficiency (serum creatinine \>2.0 mg/dl). 7. History of liver disease or abnormal liver function tests (LFTs) (\>2x upper limit normal) 8. Hemoglobin \< 10 mg/dL 9. History of congestive heart failure (NYHA Class III or IV) 10. Women who are pregnant or lactating 11. History of a non-skin malignancy within the previous 5 years 12. Any major active rheumatologic, pulmonary, or dermatologic disease or other chronic inflammatory condition 13. Surgery in the last 90 days 14. History of HIV positive 15. Active alcohol or drug abuse 16. Active peptic ulcer disease 17. Gout attack within the past 6 months 18. Participation in an investigational drug study within 6 weeks 19. Serious or unstable medical or psychological conditions that, in the opinion of the investigator, would compromise the subject's safety or successful study participation 20. Subjects on warfarin may be enrolled, but they will be excluded from the optional adipose biopsy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Increase in High Density Lipoprotein Cholesterol (HDL-C) at Baseline and 12 Weeks | Baseline, after 12 weeks of pioglitazone vs placebo | Mean increase in HDL-C from baseline (week -4) to 12 weeks post randomization in non-diabetic subjects with low HDL-C and metabolic syndrome. After baseline, all subjects titrated niacin extended release (ER) to 2 grams (g) daily over 4 weeks. Subjects were also given 325 mg aspirin to take 30 minutes before the niacin ER. After 4 weeks, half of the subjects added blinded pioglitazone 30mg/day (milligrams/day) for 6 weeks followed by 45 mg/day for 6 weeks; the other half added placebo. HDL-C was was assessed at baseline and 12 weeks post randomization |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited and participated in the study from December 2005 and July 2007. Subjects were recruited from the University of Pennsylvania and the Philadelphia Veterans Affairs Medical Center.
Pre-assignment details
4 weeks prior to randomization, subjects titrated to 2.0 g/day of niacin extended release. Subjects who could not tolerate niacin were excluded from the study.
Participants by arm
| Arm | Count |
|---|---|
| Pioglitazone Placebo + Open-Label Niacin + Aspirin Subjects receiving pioglitazone placebo in combination with niacin ER 2.0 g/daily and 325 mg aspirin | 38 |
| Active Pioglitazone + Open-Label Niacin + Asprin Subjects receiving 45 mg/day active pioglitazone in combination with niacin ER 2.0 g/daily and 325 mg aspirin. Subjects received 30mg/day pioglitazone for 6 weeks, followed by 45 mg/day for another 6 weeks | 40 |
| Total | 78 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Pioglitazone Placebo + Open-Label Niacin + Aspirin | Active Pioglitazone + Open-Label Niacin + Asprin | Total |
|---|---|---|---|
| Age, Continuous | 52.0 years STANDARD_DEVIATION 12.1 | 49.3 years STANDARD_DEVIATION 12.2 | 50.6 years STANDARD_DEVIATION 12.2 |
| Race/Ethnicity, Customized African American | 10 participants | 10 participants | 20 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian | 26 participants | 26 participants | 52 participants |
| Race/Ethnicity, Customized Hispanic | 2 participants | 3 participants | 5 participants |
| Sex: Female, Male Female | 11 Participants | 10 Participants | 21 Participants |
| Sex: Female, Male Male | 27 Participants | 30 Participants | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 38 | 15 / 40 |
| serious Total, serious adverse events | 3 / 38 | 2 / 40 |
Outcome results
Primary
Mean Increase in High Density Lipoprotein Cholesterol (HDL-C) at Baseline and 12 Weeks
Mean increase in HDL-C from baseline (week -4) to 12 weeks post randomization in non-diabetic subjects with low HDL-C and metabolic syndrome. After baseline, all subjects titrated niacin extended release (ER) to 2 grams (g) daily over 4 weeks. Subjects were also given 325 mg aspirin to take 30 minutes before the niacin ER. After 4 weeks, half of the subjects added blinded pioglitazone 30mg/day (milligrams/day) for 6 weeks followed by 45 mg/day for 6 weeks; the other half added placebo. HDL-C was was assessed at baseline and 12 weeks post randomization
Time frame: Baseline, after 12 weeks of pioglitazone vs placebo
Population: All subjects for whom HDL-C measurements were recorded at baseline (week -4) and 12 weeks post randomization to placebo, niacin ER, and aspirin or pioglitazone, niacin ER, and aspirin
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Pioglitazone Placebo + Open-Label Niacin + Aspirin | Mean Increase in High Density Lipoprotein Cholesterol (HDL-C) at Baseline and 12 Weeks | Baseline HDL-C | 37.4 mg/dL |
| Pioglitazone Placebo + Open-Label Niacin + Aspirin | Mean Increase in High Density Lipoprotein Cholesterol (HDL-C) at Baseline and 12 Weeks | HDL-C 12 weeks Post Randomization | 40.6 mg/dL |
| Active Pioglitazone + Open-Label Niacin + Asprin | Mean Increase in High Density Lipoprotein Cholesterol (HDL-C) at Baseline and 12 Weeks | Baseline HDL-C | 36.2 mg/dL |
| Active Pioglitazone + Open-Label Niacin + Asprin | Mean Increase in High Density Lipoprotein Cholesterol (HDL-C) at Baseline and 12 Weeks | HDL-C 12 weeks Post Randomization | 44.2 mg/dL |
p-value: <0.0001Mixed Models Analysis