- WHATS NEW?
- Suppression of chemokines by HDL
- HDL cholesterol linked to oestrogen levels
- New gene loci regulating HDL cholesterol identified
- Abnormal lipids when young predicts atherosclerosis in later life
- JUPITER: Is HDL cholesterol relevant to residual risk in low-risk patients on potent statin therapy?
- EAS Workshop: How does HDL protect against atherosclerosis?
Niacin and HDL cholesterol: new insights
Niacin (nicotinic acid) is the most effective agent currently available for raising plasma levels of high-density lipoprotein (HDL) cholesterol. However, to date little is known about the mechanism of its effect in people with dyslipidemia, ideal targets for therapy. Data from a study by researchers at
Lamon-Fava S, Diffenderfer MR, Barrett PHR et al. Extended-release niacin alters the metabolism of plasma apolipoprotein (
This randomized, double-blind, cross-over study was conducted in 5 male subjects with combined dyslipidemia (HDL cholesterol £40 mg/dL, low-density lipoprotein (LDL) cholesterol ³130 mg/dL and triglycerides ³150 mg/dL). None of the subjects had diabetes, previous myocardial infarction or stroke, or were receiving medication known to affect lipid metabolism.
The study had 3 treatment phases, each lasting 12 weeks, placebo, extended-release (ER) niacin, and ER niacin plus lovastatin. Each of the treatment phases was separated by a 4-week washout period. During each of the active phases ER niacin dosage was titrated from 500 mg during weeks 1-4 to 1,000 mg during weeks 5-8 and 2,000 mg during weeks 9 to 12. Lovastatin was titrated to a dose of 40 mg/day during weeks 9 to 12. Subjects also followed a therapeutic lifestyle diet (<30% of calories as total fat, <7% saturated fat and <200 mg/day cholesterol) during the study.
The authors measured plasma levels of HDL, LDL and total cholesterol, triglycerides, and apolipoproteins (apo) A-I and A-II, apoB-100 and triglyceride-rich lipoprotein (TRL) apoB-48 using standard procedures. Levels were measured in samples obtained after a 12-hour fast (at weeks 11 and 12) and in non-fasting samples obtained during a 15-hour infusion with a leucine radioligand (5,5,5-2H3-L-leucine) (at 0, 3 and 6 hours). Plasma HDL subpopulations were evaluated by 2-dimensional gel electrophoresis.
Kinetic analysis was used to evaluate the fractional catabolic rate (FCR) of each lipoprotein and production rates (PR) were also determined.
HDL cholesterol, apoA-I and apoA-II
Niacin monotherapy led to significant increases in HDL cholesterol (by 35%) and apoA-I by 15% (Figure 1), and these changes were associated with a 24% increase (p=0.04) in the PR of apoA-I, relative to placebo. There was no additional significant effect on apoA-I PR with the combination of ER niacin plus lovastatin (Figure 2). Niacin (alone or in combination with lovastatin) had no significant effect on the apoA-I FCR (change from baseline 6% and 7%) (Figure 2). Plasma apoA-II levels, PR or FCR were not affected by niacin treatment.
The authors showed that niacin treatment led to a significant increase in large HDL particle concentrations, specifically a1, a2, prea1 and prea2. However, the addition of lovastatin had no significant effect on the HDL subpopulation profile. These findings indicate that niacin promotes the maturation of HDL into large particles and their corresponding prea particles.
TRL apoB
Niacin treatment led to a 28% decrease (p=0.01) in TRL apoB-100 levels, with a trend towards an increases in FCR (+94%, p=0.06), relative to placebo. There was also a 44% increase (p=0.04) in TRL apo-48 FCR, compared with placebo. Niacin had no significant effect on either TRL apoB-100 or apoB-48 PR, or on intermediate-density lipopoprotein (IDL) apoB-100 or LDL apoB-100.
Based on these results, the authors concluded that in subjects with mixed dyslipidemia, increases in HDL cholesterol are mediated in part by increased secretion of apoA-I. In contrast, reduction in plasma triglycerides is mainly mediated by increased clearance of TRL apoB-100 and apoB-48. While the mechanism for the faster clearance of TRL is not clear, the researchers emphasised that it is unlikely to involve increased expression of the LDL receptor as niacin had no effect on the clearance of IDL apoB-100 or LDL apoB-100. The study findings highlight the overall beneficial effect of niacin on HDL-triglyceride metabolism.
The authors note that their findings differ from those previously reported in subjects with normal lipid levels, in which slower catabolism of HDL particles,1 or no significant effects on apoA-I kinetics (either FCR or PR)2 were reported. However, they emphasised that the apparent discrepancy in these results may be explained on the basis of the study population. This suggests that the effects of ER niacin on the metabolism of HDL and TRL may differ in subjects with mixed dyslipidemia including low HDL cholesterol, compared with those with normal lipid levels.
Finally, this is the first time that any pharmacological agent has been shown to induce a major increase in apoAI production. It is essential now to define the molecular and cellular mechanisms involved.
References
1. Blum CB,
2. Shepherd J, Packard CJ, Patsch JR et al. Effects of nicotinic acid therapy on plasma high density lipoprotein subfraction distribution and composition and on apolipoprotein A metabolism. J Clin Invest 1979;63:858-67.
Corporate sponsor
