Pharmacological Intervention to Modulate HDL: What Do We Target?

Abstract

The cholesterol concentrations of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) have traditionally served as risk factors for cardiovascular disease. As such, novel therapeutic interventions aiming to raise HDL cholesterol have been tested in the clinical setting. However, most trials led to a significant increase in HDL cholesterol with no improvement in cardiovascular events. The complexity of the HDL particle, which exerts multiple physiological functions and is comprised of a number of subclasses, has raised the question as to whether there should be more focus on HDL subclass and function rather than cholesterol quantity. We review current data regarding HDL subclasses and subclass-specific functionality and highlight how current lipid modifying drugs such as statins, cholesteryl ester transfer protein inhibitors, fibrates and niacin often increase cholesterol concentrations of specific HDL subclasses. In addition this review sets out arguments suggesting that the HDL3 subclass may provide better protective effects than HDL2.

Exercise intervention alters HDL subclass distribution and function in obese women

“…Much of the existing literature describes two principal HDL subclasses, the larger, HDL2 and smaller HDL3 [ 38 , 39 ]. Whilst epidemiological studies describe lower HDL2 levels as an inverse predictor for cardiovascular disease, pre-clinical studies describe the benefits of increased HDL3 owing to a higher association with cardioprotective proteins and lipids, as reviewed by [ 10 ]. Therefore, while the results from this study are consistent with other studies in the literature, it is difficult at this stage to affirm whether the decrease in small HDL subclasses is of benefit to overall risk of CVD.…”

“…Non-normally distributed data are presented as medians ± interquartile range (IQR). Sample size determination was based on previous studies regarding exercise training interventions in obese individuals [ 10 , 30 ], using a significance level of p < 0.05 and power of 80%, as described in detail previously [ 24 ]. Two-way repeated measures analysis of variance was used to compare changes in anthropometry, VO 2peak , lipids, cholesterol efflux capacity, anti-inflammatory function, paraoxonase activity, PAF-AH activity and HDL subclass distribution between groups over the 12-week period, followed by Fischer post-hoc testing.…”

“…As little as 30 min of exercise per day can increase the concentration of HDL-C in diabetic patients [ 8 ]. Although HDL-C concentrations are inversely associated with risk for cardiovascular disease [ 9 ], the recent outcomes of clinical trials aimed at reducing the risk of cardiovascular disease (CVD) by increasing HDL-C levels have been unsuccessful (reviewed by [ 10 ]). Accordingly, there has been a significant shift in focus from studying the quantity of HDL to studying the quality [ 11 – 15 ].…”

Lipoprotein(a) the Insurgent: A New Insight into the Structure, Function, Metabolism, Pathogenicity, and Medications Affecting Lipoprotein(a) Molecule

“…It has an antilipolytic effect, reducing the mobilization of free fatty acids from the adipose tissue to the liver and reducing the trafficking of free fatty acids, which significantly decreases the concentrations of all apo-B-containing lipoproteins from chylomicrons to Lp(a) [206,232]. Niacin also stimulates the degradation of apoB-containing lipoproteins and decreases TG synthesis by inhibiting diacylglycerol acyltransferase-2 [23], an enzyme that catalyzes the final reaction involved in TG production as well as selective inhibition of apoA-I uptake without affecting de novo production [205], which eventually increases HDL-C concentrations [205,231]. A therapeutic dose of niacin is associated with LDL-C and Lp(a) reduction by approximately 45% [205] and 20-30%, respectively, as shown in a meta-analysis of 14 randomized placebo-controlled clinical trials including 9,013 subjects [206], but with detrimental adverse effects.…”

“…Niacin also stimulates the degradation of apoB-containing lipoproteins and decreases TG synthesis by inhibiting diacylglycerol acyltransferase-2 [23], an enzyme that catalyzes the final reaction involved in TG production as well as selective inhibition of apoA-I uptake without affecting de novo production [205], which eventually increases HDL-C concentrations [205,231]. A therapeutic dose of niacin is associated with LDL-C and Lp(a) reduction by approximately 45% [205] and 20-30%, respectively, as shown in a meta-analysis of 14 randomized placebo-controlled clinical trials including 9,013 subjects [206], but with detrimental adverse effects. Unfortunately, niacin intervention has not been shown to reduce cardiovascular risk in recent clinical trials [233].…”