Pioglitazone Vs Placebo in Combination With Niacin Extended Release on Low HDL

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 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.

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 a 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 blood pressure > 180, diastolic blood
pressure > 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 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.