The investigators propose to investigate if using a combination of medications that may
improve cholesterol give additional benefit to that gained from the statin medication,
Lipitor. It is recommended that patients who meet certain criteria for risk of heart
disease take a statin medication to improve cholesterol and hopefully reduce risk of heart
disease. The combination therapy will include Lipitor, Niaspan, and investigational
medication (known as ABT335) in a class of drugs called fibrates. We are looking to see if
and how these three medications together might improve risk factors for atherosclerosis and
influence HDL cholesterol. The study will also look at the safety and any side effects that
might be associated with this combination of medications.
* To investigate whether the progressive addition of a fibrate and niacin to baseline statin
therapy will improve apolipoprotein A-I kinetics, postprandial lipidemia, and postabsorptive
lipoproteins and metabolism in adult men and women with atherogenic dyslipidemia.
- Objective 1 is to test the hypothesis that the fibrate ABT335 and extended release (ER)
niacin progressively improve apolipoprotein A-I kinetics when added sequentially to
baseline therapy with atorvastatin. The key outcomes include the apolipoprotein AI rate
of catabolism and rate of production.
progressively improve postprandial lipidemia by oral fat challenge when added
sequentially to baseline therapy with atorvastatin. Key outcomes include the
incremental area under the curve for triglycerides and high-density lipoprotein
cholesterol.
progressively improve markers of postabsorptive lipoproteins and metabolism when added
sequentially to baseline therapy with atorvastatin. Key outcomes include a. fasting
cholesterol efflux, b. HDL cholesterol, apolipoprotein A-I, and enzymes that remodel
HDL, c. atherogenic lipoproteins, and d. markers of energy metabolism and e. markers of
inflammation.
* Objective 4 is to assess tolerability and adverse events when ABT335 and ER niacin are
added sequentially to atorvastatin. Specifically, we will assess changes in hepatobiliary
laboratory tests (including incidence of elevation), incidence of symptomatic myalgia, and
incidence of flushing. On an exploratory basis, we will enhance the flushing evaluation with
objective and subjective measurements of flushing during inpatient visits.
This is an open-label feasibility study of fixed-sequence addition of lipid-altering
medications, in which comparisons are made to the baseline for each subject. Subjects begin
a lead-in phase in which they start the study statin (atorvastatin) or switch from previous
statin therapy to the study statin. Subjects will wash off other excluded lipid-altering
drugs during the lead-in. Subjects return for the first inpatient visit, where they have
baseline studies on statin monotherapy. At the end of this visit, subjects are started on
fibrate therapy (ABT335). They repeat the studies on dual therapy with statin and fibrate,
and then add niacin (ER niacin). To minimize flushing during chronic treatment, they start
aspirin 325 mg daily, or titrate to 325 mg if they are taking a lower dose of aspirin (e. g.
81 mg). Finally, they repeat the studies on triple therapy with statin, fibrate, and
niacin/aspirin.
Inclusion Criteria:
1. Men and women from the age of 18 to 80 inclusive.
2. Low HDL cholesterol, adjusted for baseline use of statin drugs
1. Not on statin: Men with HDL <= 40 or women with HDL <= 50 mg/dL
2. On statin: Men with HDL <= 42 or women with HDL <= 52 mg/dL
3. Triglyceride / HDL ration >= 3. 5
4. Ability to understand and agree to informed consent
5. Women of child-bearing potential, that is, women not surgically sterilized and
between menarche and 1 year post menopause, must test negative for pregnancy based on
a urine pregnancy test and agree to use a reliable method of birth control during the
study and for one month following the last dose of the study drugs. Reliable methods
include oral contraceptives, a reliable barrier method (diaphragms with contraceptive
jelly, cervical caps with contraceptive jelly, condoms with contraceptive foam,
intrauterine device), partner with vasectomy, or abstinence.
6. Are reliable and willing to make themselves available for the duration of the study
and are willing to follow study procedures
Exclusion Criteria:
1. Subjects with the following lipoprotein disorders:
1. Patients on a high-potency lipid-lowering regimen are excluded, as defined as
chronic therapy with two or more prescription lipid-altering medications
(excluding fish oils) where one is a high-dose statin (40 mg/day of
rosuvastatin, 80 mg/day of other approved statins). Those on combination
therapy with a lower dose of statin may participate, as can those taking
high-dose statin monotherapy (excluding fish oils). In that case, patients will
switch to atorvastatin 10 mg and/or wash off of other lipid medications to
participate
2. LDL > 190 mg/dL
3. History of substantial triglyceridemia (TG > 750 mg/dL) or pancreatitis from
triglyceridemia, regardless of whether TG is currently controlled
4. Dysbetalipoproteinemia (VLDL/TG > 0. 3 - AND- TG > 200 mg/dL).
2. Use of daily non-statin lipid-altering therapy prior to the initiation of study
medication is exclusionary under the following circumstances (n. b. washout of
non-statins is permitted):
1. Niacin > 250 mg/ day within 6 weeks: Advicor, Niaspan, Niacor, Simcor,
Slo-Niacin, or supplemental niacin
2. Fibrates within 12 weeks: fenofibrate (Antara, Lofibra, Tricor, Triglide),
gemfibrozil (Lopid), or clofibrate
3. Enterically active drugs within 4 weeks: colestipol (Colestid), cholestyramine
(Questran), colesevelam (Welchol), ezetimibe (Zetia, Vytorin), orlistat
(Xenical, Alli)
4. Red yeast rice during the treatment phase of the study (i. e. must be switched to
study statin)
5. Fish oil > 2 g/day within 4 weeks: Lovaza (née Omacor), numerous supplements
6. Altered dose of a selective estrogen receptor modulator (SERM) within 4 weeks
3. History of intolerance of a statin, fibrate, aspirin, deuterated leucine, or niacin
4. Contraindications to medications, including chronic muscular disease, history of
rhabdomyolysis, moderate to severe gout, severe peptic ulcer disease, bleeding
disorders, and aspirin-sensitive asthma.
5. History of Type 1 or Type 2 diabetes, or fasting glucose > 110 mg/dL on two different
days obtained for screening purposes, or use of medications indicated for the
treatment of diabetes within 6 weeks of the screening visit
6. History of chronic renal insufficiency, nephrotic syndrome, or current serum
creatinine > 2. 5 mg/dL, or GFR < 60 mL/min/1. 73m2 by the MDRD Study equation.
7. Aspartate aminitransferase (AST), alanine aminotransferase (ALT), alkaline
phosphatase (ALP), total bilirubin > 2 X the upper limit of normal (ULN), albumin of
< 2. 5 mg/dL, prothrombin time (PT) > 1. 5 X ULN, partial thromboplastin time (PTT) >
1. 5 X ULN, or current active hepatobiliary disease
8. Hemoglobin (Hgb) < 10 mg/dL
9. Weight < 110 pounds
10. Administration of an investigational drug within 6 weeks prior to the screening visit
11. Major surgery within the previous 6 weeks, or anticipated major surgery during the
course of the study, or any history of organ transplant
12. History of a non-skin malignancy within the previous 5 years
13. History of drug abuse within the past 3 years, or regular alcohol use of greater than
14 drinks per week
14. Women who are pregnant, plan to conceive, or breast-feed
15. Serious or unstable medical or psychological conditions that, in the opinion of the
investigator, would compromise the subject's safety or successful participation in
the study.
16. Currently adhering to or planning to adhere to or having used within 3 months prior
to screening supplements intended for weight loss or adopt diets with aggressive
carbohydrate restrictions for weight loss, such as but not limited to Atkins or South
Beach diets.
17. Currently taking Vitamin A supplements (multivitamins allowed)(washouts will be
permitted)
18. Excluded concomitant medications
1. Immunosuppressive therapy within 2 months prior to screening or are likely to
require such treatment during the course of the study
2. Warfarin (coumadin)
19. Significant disinclination to dairy products (e. g. inviolable dietary restrictions or
lactose intolerance to an 8 ounce glass of milk despite lactase supplementation)
Lactase supplementation is allowed during the study.
20. Regular consumers of grapefruit juice, or currently taking medications known to be
metabolized by CYP 3A4 (cyclosporine, itraconazole, ketoconazole, erythromycin,
clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone)
21. History of pancreatitis or gallbladder disease
22. History of coronary heart disease
23. Subjects who have a history of intolerance/adverse reaction to heparin or women who
have dysfunctional uterine bleeding
24. Thrombocytopenia identified at screening
25. History of intracerebral hemorrhage or significant GI bleed
26. Subjects who engage in regular strenuous activity or who have a CK > 3x ULN at
screening
