Differential effects of nicotinic acid in subjects with different LDL subclass patterns

doi:10.1016/0021-9150(92)90177-I

Atherosclerosis

Volume 95, Issue 1, July 1992, Pages 69-76

https://doi.org/10.1016/0021-9150(92)90177-I Get rights and content

Abstract

Twenty-six subjects (20 male, 6 female) at high risk for CAD events were treated with moderate doses of nicotinic acid to investigate whether there was a differential lipoprotein response in patients with different LDL subclass patterns. Subjects were selected to have either pattern A (predominance of large LDL, peak particle diameter > 262 Å, n = 9) or pattern B (predominance of small LDL, peak particle diameter < 255 Å, n = 17) as assessed by 2–16% gradient gel electrophoresis of plasma. Nicotinic acid dose was similar in pattern A (2111 ± 651 mg/day) and pattern B subjects (1875 ± 698 mg/day). Total cholesterol and LDL cholesterol decreased by similar amounts in pattern A (-41 ± 26 mg/dl and −37 ± 18 mg/dl) and pattern B (−51 ± 44 mg/dl and −44 ± 45 mg/dl) subjects. Triglycerides tended to be reduced more in pattern B subjects (−100 ± 175 mg/dl) compared to pattern A subjects (−23 ± 34 mg/dl) although this difference was not statistically significant (P = 0.08 for triglycerides log transformed). HDL cholesterol increased significantly more in the pattern B group (11.9 ± 14.2 mg/dl) compared to pattern A subjects (0.7 ± 8.5 mg/dl), (P < 0.04). Similarly, LDL particle diameter increased significantly more in the pattern B subjects (9.8 ± 6.9 Å) compared to the pattern A subjects (3.6 ± 3.0 Å), (P < 0.02). All pattern B subjects who achieved a plasma triglyceride < 140 mg/dl converted to pattern A. The differential effect of nicotinic acid in individuals with differing LDL subclass profiles may contribute to intraindividual variation in response to this drug and its effect on coronary atherosclerosis.

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Niacin (nicotinic acid) has been used for primary and secondary coronary heart disease prevention for over 40 years. Until recently clinical trials incorporating niacin as part of an intervention strategy consistently demonstrated reduction in clinical events and lesion improvement, including ≥6% absolute mortality reduction. Two large clinical event trials in 2011 (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes) and 2014 (Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events) concluded that niacin added to statin therapy did not provide clinical event benefit over statin alone. This has prompted some individuals to call for an end to the use of niacin in statin-treated patients and the US Food and Drug Administration to halt marketing of statin/niacin combination tablets. There are significant differences between the earlier clinical trials that revealed cardiovascular benefit of niacin and the 2 trials that failed to demonstrate a benefit. These differences include dyslipidemia types, niacin formulation, dosing, and timing. In general, the patient population that benefits the most from incorporating niacin in their treatment regimen can be defined by elevations in low-density lipoprotein cholesterol and triglycerides, and reduced high-density lipoprotein cholesterol. The niacin formulation and dose should be capable of achieving adequate lipoprotein change. Mealtime dosing of niacin, as opposed to bedtime dosing, may avoid a counter-regulatory hormone response, including catecholamines, because of altered fuel supply potentially leading to unexpected cardiovascular outcomes.
Regression of atherosclerosis: Insights from animal and clinical studies
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As expected, when niacin was part of the treatment, HDL-C levels were increased (by 18.4%), and the authors attributed the improvement in carotid intimal-medial thickness particularly to this change. It is important to note that niacin does more than just raise HDL-C levels; it also decreases plasma triglyceride levels, makes LDL size increase, and possesses anti-inflammatory properties, all of which have the potential to limit plaque progression.99-101 These pleiotropic effects obviously confound the interpretation of both the ARBITER and another statin-niacin clinical trial: the HDL-Atherosclerosis Treatment Study (HATS). 102
Based on studies that date back to the 1920s, regression and stabilization of atherosclerosis in humans has gone from just a dream to one that is achievable. Review of the literature indicates that the successful attempts at regression generally applied robust measures to improve plasma lipoprotein profiles. Examples include extensive lowering of plasma concentrations of atherogenic apolipoprotein B and enhancement of reverse cholesterol transport from atheromata to the liver.
Possible mechanisms responsible for lesion shrinkage include decreased retention of atherogenic apolipoprotein B within the arterial wall, efflux of cholesterol and other toxic lipids from plaques, emigration of lesional foam cells out of the arterial wall, and influx of healthy phagocytes that remove necrotic debris as well as other components of the plaque. This review will highlight the role key players such as LXR, HDL and CCR7 have in mediating regression.
Although much progress has been made, there are many unanswered questions. There is, therefore, a clear need for preclinical and clinical testing of new agents expected to facilitate atherosclerosis regression with the hope that additional mechanistic insights will allow further progress.
Extended-release niacin reduces LDL particle number without changing total LDL cholesterol in patients with stable CAD
2009, Journal of Clinical Lipidology
Citation Excerpt :
The present study demonstrates that, in addition to these effects, in patients with stable CAD and LDL levels <100 mg/dL, the addition of ERN to their baseline statin significantly decreased the number of total LDL particles as well as the number of medium and small LDL particles in the absence of changes in total serum LDL cholesterol. Several studies have described the augmented risk of CAD associated with increased numbers of small, dense LDL particle subtypes.9,13,14 In the present study, ERN also altered the number of circulating particles of subtypes of HDL, and changes in HDL subtypes have been associated with reduced cardiovascular risk.15,16
The importance of the number of circulating low-density lipoprotein (LDL) cholesterol particles, in addition to total LDL level, has been increasingly recognized. The effects of extended-release niacin (ERN) on LDL particle numbers have not been studied.
To evaluate ERN's effects on LDL particle numbers.
Fifty-four patients with stable coronary artery disease (CAD) and well-controlled LDL levels were randomly assigned to 3 months of ERN (1 g/day) or placebo in addition to their baseline medications. Lipoprotein particle number was analyzed by proton nuclear magnetic resonance spectroscopy at baseline and after 3 months.
Compared to baseline, the addition of ERN had no significant effect on total LDL cholesterol levels; however, ERN decreased the number of medium and small LDL particles (P < .005). After 3 months, ERN decreased the number of medium and small LDL particles compared to placebo-treated patients (P < .05). ERN raised HDL cholesterol levels by 2.7%, significantly increased the number of large HDL particles (P < .001), and decreased the number of small HDL particles (P = .027) compared to placebo. There were no significant changes in lipid values or particle numbers in the placebo-treated patients. In patients with stable coronary artery disease and well-controlled LDL cholesterol levels, ERN reduced the number of circulating particles of the more atherogenic subtypes of LDL, despite having no effect on total LDL cholesterol levels. ERN also favorably altered the number of HDL particles.
ERN-induced alterations in lipoprotein particle numbers may contribute to its anti-atherosclerotic effects, and these effects may not be evident from the standard lipid profile.
Effect of Combination Nicotinic Acid and Gemfibrozil Treatment on Intermediate Density Lipoprotein, and Subclasses of Low Density Lipoprotein and High Density Lipoprotein in Patients With Combined Hyperlipidemia
2009, American Journal of Cardiology
Citation Excerpt :
In the present investigation, nicotinic acid alone (1,500 mg/day) added to placebo significantly reduced triglycerides, total cholesterol, IDL, and dense LDL-II mass and significantly increased the reputably antiatherogenic HDL2 mass by 147%. This effect of nicotinic acid on reducing dense LDL is consistent with previous studies.6,25 The differential effect of nicotinic acid on increasing HDL2 (147%) substantially more than total HDL cholesterol (26%) is a relevant clinical finding, because similar changes in HDL subclass distribution, using different laboratory methods, have been associated with clinical benefit in the Familial Atherosclerosis Treatment Study (FATS) and the HDL Atherosclerosis Treatment Study (HATS) and appear to be a powerful characteristic of nicotinic acid, particularly when compared with statins.7,26
The goal of this study was to determine, using analytic ultracentrifugation, the effect of nicotinic acid alone or nicotinic acid added to gemfibrozil on lipoprotein subclass distribution, including intermediate-density lipoprotein (IDL; low-density to very low density flotation rate [S_f] 12 to 20); low-density lipoprotein (LDL) subfractions LDL-I (S_f 7 to 12), LDL-II (S_f 5 to 7), LDL-III (S_f 3 to 5), and LDL-IV (S_f 0 to 3); and high-density lipoprotein (HDL) subfractions HDL₂ (high-density flotation rate 3.5 to 9.0) and HDL₃ (high-density flotation rate 0 to 3.5). Patients with combined hyperlipidemia were randomized to nicotinic acid (1,500 mg/day) plus placebo or nicotinic acid plus gemfibrozil (1,200 mg/d) for 12 weeks. Baseline characteristics were similar between the 2 groups, and mean LDL cholesterol (180 ± 33 mg/dl) and triglycerides (310 ± 126 mg/dl) were typical for patients with combined hyperlipidemia. Treatment with nicotinic acid resulted in a reduction in dense LDL (S_f 5 to 7; p = 0.02), which was counterbalanced by an increase in buoyant LDL (S_f 7 to 12; p = 0.03) that resulted in no significant LDL mass or LDL cholesterol change. IDL was reduced (p = 0.005) and HDL₂ increased by 143% (p = 0.004). The combination of nicotinic acid and gemfibrozil resulted in a further 17.8% reduction in apolipoprotein B (p = 0.06), a further 33.8% reduction in IDL (p = 0.06), and a greater reduction in the apolipoprotein B/apolipoprotein A-I ratio (p = 0.02). The combination of nicotinic acid and gemfibrozil reduced atherogenic by IDL 71%, dense LDL-III by 52%, and apolipoprotein B by 37% and increased protective HDL₂ by 90%. In conclusion, this investigation revealed that a combination of a fibric acid derivative and nicotinic acid offers greater improvement in detailed lipoprotein subclass distribution and apolipoprotein ratios than monotherapy.
Anti-inflammatory effect is an important property of niacin on atherosclerosis beyond its lipid-altering effects
2007, Medical Hypotheses
Niacin has been used for decades to lower the plasma concentrations of cholesterol, free fatty acids, and triglycerides in humans, and in addition it raises more than any other drug the levels of the protective high density lipoprotein. These effects have been used to treat dyslipidemic states. Trials have shown that treatment with niacin reduces progression of atherosclerosis, and clinical events and mortality from coronary heart disease. The beneficial clinical efficacy of niacin appropriately emphasizes the prominent role of its lipid-altering effects; however, high expression of niacin receptor in a variety of immune cell types, lowering of inflammatory markers, and beneficial impact on adipokines expression could provide rational to the hypothesis that anti-inflammatory effect is also an important property of niacin on atherosclerosis beyond its lipid-altering effects.
Polyacrylamide Gradient Gel Electrophoresis of Lipoprotein Subclasses
2006, Clinics in Laboratory Medicine
Citation Excerpt :
Electrophoresis is at 150 V for 3 hours after a 15-minute prerun at 75 V. Gels are stained with 0.07% Sudan black for 1 hour and stored in a 0.81% acetic acid, 4% methanol solution until scanned [121,122]. Alternatively, the gels may be stained with Oil red O [123,124], which is relatively specific for neutral lipids, specifically cholesteryl ester and triglycerides, and poorly stains the more polar lipids, such as unesterified cholesterol and phospholipids [125]. The assignment of particle size proceeds much as described for the HDL subclasses, using a calibration curve created from the migration distances of serum or plasma standards with known molecular weights and particle diameters.

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Research paperDifferential effects of nicotinic acid in subjects with different LDL subclass patterns

Abstract

Lancet

J. Lipid. Res.

Methods Enzymol.

Lancet

Metabolism

Low density lipoprotein subclass patterns and risk of myocardial infarction

J. Am. Med. Assoc.

Linkage of atherogenic lipoprotein phenotype to the low-density lipoprotein receptor locus on the short arm of chromosome 19

Inheritance of low density lipoprotein subclass patterns in familial combined hyperlipidemia

Arteriosclerosis

Hyperapo B: a pleiotropic phenotype characterized by dense low-density lipoprotein and associated with coronary artery disease

Clin. Chem.

Influence of obesity, impaired glucose tolerance and NIDDM on LDL structure and composition

Diabetes

Changes in lipoprotein subfractions during dietinduced and exercise-induced weight loss in moderately overweight men

Circulation

Research paper
Differential effects of nicotinic acid in subjects with different LDL subclass patterns