Niacin Therapy Increases High-Density Lipoprotein Particles and Total Cholesterol Efflux Capacity But Not ABCA1-Specific Cholesterol Efflux in Statin-Treated Subjects

Abstract

Objective We investigated relationships between statin and niacin/statin combination therapy and the concentration of high density lipoprotein particles (HDL-P) and cholesterol efflux capacity, two HDL metrics that might better assess cardiovascular disease (CVD) risk than HDL-cholesterol (HDL-C) levels. Approach In the Carotid Plaque Composition Study, 126 subjects with a history of CVD were randomized to atorvastatin or combination therapy (atorvastatin/niacin). At baseline and after 1 year of treatment, the concentration of HDL and its three subclasses (small, medium, and large) were quantified by calibrated ion mobility analysis (HDL-PIMA). We also measured total cholesterol efflux from macrophages and ABCA1-specific cholesterol efflux capacity. Results Atorvastatin decreased low density lipoprotein cholesterol (LDL-C) by 39% and raised HDL-C by 11% (P=0.0001), but did not increase HDL-PIMA or macrophage cholesterol efflux. Combination therapy raised HDL-C by 39% (P<0.0001), but increased HDL-PIMA by only 14%. Triglyceride levels did not correlate with HDL-PIMA (P=0.39), in contrast to their strongly negative correlation with HDL-C (P<0.0001). Combination therapy increased macrophage cholesterol efflux capacity (16%, P<0.0001) but not ABCA1-specific efflux. ABCA1-specific cholesterol efflux capacity decreased significantly (P=0.013) in statin-treated subjects, with or without niacin therapy. Conclusions Statin therapy increased HDL-C levels but failed to increase HDL-PIMA. It also reduced ABCA1-specific cholesterol efflux capacity. Adding niacin to statin therapy increased HDL-C and macrophage efflux, but had much less effect on HDL-PIMA. It also failed to improve ABCA1-specific efflux, a key cholesterol exporter in macrophages. Our observations raise the possibility that niacin might not target the relevant atheroprotective population of HDL.

Inflammation, remodeling, and other factors affecting HDL cholesterol efflux

“…Key examples focusing on specific efflux pathways include baby kidney hamster (BHK) cells expressing inducible human ABCA1 or ABCG1 transporter under mifepristone control [25, 26]. Thus, ABCA1-BHK cells were used to show that atorvastatin specifically reduces ABCA1 mediated CEC to serum HDL [27] (Figure 2). Specific ABCA1-mediated efflux can also be estimated as the difference in CEC from J774 macrophages with and without cAMP stimulation, providing good agreement with ABCA1-specific CEC measured in ABCA1-BHK cells [22].…”

Translational and Therapeutic Approaches to the Understanding and Treatment of Dyslipidemia

“…The combination therapy also failed to improve ABCA1-specific cholesterol efflux. 42 Statin alone did not increase HDL particle concentration or macrophage cholesterol efflux capacity, even though it raised HDL-C. 42 In dyslipidemic patients on stable statin therapy, 12 weeks of extended-release niacin/laropiprant therapy reduced CETP activity, moderately improved plasma efflux capacity from macrophages, and increased the ability of HDL particles to deliver CE back to the liver during the postprandial phase. 43 These results suggest that specific subgroups of patients at high cardiovascular risk might benefit from combination therapy of statin and niacin for cardioprotection.…”

Time to ditch HDL-C as a measure of HDL function?

“…Thus, studies showed that niacin improved [37, 38] or did not change [39] HDL’s overall efflux capacity without improving ABCA1-specific efflux [37, 38]. Importantly, the improvement in total efflux correlated with the increase in HDL-C [38]. Treatment of patients with the CETP inhibitors torcetrapib and dalcetrapib also elevated total efflux capacity but not ABCA1-specific efflux [40, 41].…”

“…Pioneering proteomics studies demonstrate that HDL carries a rich cargo of proteins linked to inflammation, protease inhibition and complement regulation [51]. Moreover, aggressive lipid-lowering therapy favorably alters the protein composition and function of HDL of people with CVD [38, 52, 53] raising the possibility that quantifying the HDL proteome provides insights into the therapeutic efficacy of antiatherosclerotic interventions. In future studies, it will be important to use high-throughput methods [23, 26] to quantify the HDL proteome and to link specific proteins to CVD risk, HDL particle number and HDL function.…”