Primary Outcome Measures:
- The apolipoprotein AI rate of catabolism and rate of production. [ Time Frame: Experimental visits ] [ Designated as safety issue: No ]
- The incremental area under the curve for triglycerides and high-density lipoprotein cholesterol. [ Time Frame: Experimental visits ] [ Designated as safety issue: No ]
- Other 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. [ Time Frame: experimental visits ] [ Designated as safety issue: No ]
Objectives Summary
* 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.
Major Efficacy Aims
- 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.
- Objective 2 is to test the hypothesis that the fibrate ABT335 and ER niacin 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.
- Objective 3 is to test the hypothesis that the fibrate ABT335 and ER niacin 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.
Additional Aims
* 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.
Study Design:
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.