Effects on HDL Subclass Distribution
Plasma HDL is highly heterogeneous and can be separated in several subclasses according to density, size, shape, and lipid and protein composition (Calabresi et al. 2010). According to density, two HDL subclasses can be identiﬁed, the less dense HDL2 and the more dense HDL3 (De Lalla and Gofman 1954). HDL2 and HDL3 could be further fractionated in ﬁve distinct subclasses on the basis of particle size (from large to small: HDL2b, HDL2a, HDL3a, HDL3b, and HDL3c) (Nichols et al. 1986). According to surface charge, HDL could be separated into α-HDL and preβ-HDL. The separation by charge and size, using a two-dimensional (2-D) gel electrophoresis, allow the identiﬁcation of up to 12 distinct apoA-Icontaining HDL subclasses (Asztalos and Schaefer 2003). Finally, according to the protein component, HDL can be separated into particles containing only apoA-I (LpA-I) or containing also apoA-II (LpA-I:A-II).
The reported effects of statins on HDL subclass distribution are not consistent, likely depending on the technique used for the analysis. Some studies showed no effect of statins on HDL subclasses (Alaupovic et al. 1994; Bard et al. 1989; Franceschini et al. 2007; Tomas et al. 2000), and on HDL particle size distribution (Franceschini et al. 1989; Homma et al. 1995). On the contrary, studies evaluating HDL subclasses by 2-D gel electrophoresis showed that all statins, although with different potency, increase the levels of the large HDL particles and decrease the levels of small particles (Asztalos et al. 2002a, b, 2007).
A number of studies have shown that treatment with ﬁbrates causes a shift of HDL from large to small particles in low HDL (Franceschini et al. 2007; Otvos et al. 2006), hypertriglyceridemic (Miida et al. 2000; Sasaki et al. 2002), and hypercholesterolemic (Franceschini et al. 1989) patients. These effects could be explained by the ﬁbrate-induced increase in hepatic lipase activity (Miida et al. 2000; Patsch et al. 1984). In addition, bezaﬁbrate has been shown to increase small discoidal preβ1-HDL particles in hypertriglyceridemic patients (Miida et al. 2000). The analysis of HDL subclasses by 2-D electrophoresis in the large cohort of the VA-HIT trial conﬁrmed that gemﬁbrozil treatment is associated with a decrease in large (α-1 and α-2) HDL and with an increase in the small, lipid-poor HDL particles (Asztalos et al. 2008).
Sheperd et al. were the ﬁrst to demonstrate in the late 1970s that niacin (3 g/day) in healthy volunteers signiﬁcantly increases the large HDL2 particles, associated with a parallel reduction of the small HDL3 (Shepherd et al. 1979). Several studies have conﬁrmed this observation in patients with different types of dyslipidemia treated with 2, 3, or 4 g/day of regular or ER niacin (Johansson and Carlson 1990; Knopp et al. 1998; Morgan et al. 2003; Wahlberg et al. 1990) and in patients with coronary artery disease (Kuvin et al. 2006). A very recent study showed that also 1 g/day of ER niacin increases large HDL particles in dyslipidemic patients, with a concomitant signiﬁcant increase in mean HDL size (Franceschini et al. 2013). The analysis of HDL subclasses by 2-D gel electrophoresis recently conﬁrmed the observation that niacin promotes the maturation of HDL into large particles (Lamon-Fava et al. 2008), likely explained by a reduction in CETP activity. In addition, Sakai et al. reported that niacin selectively increases LpA-I particles in patients with low HDL-C, due to a prolongation of apoA-I residence time (Sakai et al. 2001).