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. Author manuscript; available in PMC: 2012 May 1.
Published in final edited form as: Curr Opin Cardiol. 2011 Jan;26(1):66–70. doi: 10.1097/HCO.0b013e3283410c16

Effects of niacin on atherosclerosis and vascular function

Neil Ruparelia 1, Janet E Digby 1, Robin P Choudhury 1
PMCID: PMC3145140  EMSID: UKMS35177  PMID: 21045681

Abstract

Purpose of Review

Niacin has been used for over fifty years in the management of atherosclerosis and is associated with improved patient outcomes. The routine use of niacin has been superseded in recent years with the advent of newer lipid-modulating interventions. Recently however, there has been a renewed interest in its use due to the appreciation of its many beneficial effects on atherosclerosis and endothelial function both ‘lipid-targeted’ and ‘pleiotropic’. This review will consider the effects of niacin in the setting of clinical trials and will critically evaluate proposed mechanisms of action.

Recent Findings

The identification of the GPR109A receptor has promoted a greater insight into niacin’s mechanism of action, with demonstrated beneficial effects on endothelial function and inflammation, in addition to its lipid modulation role.

Summary

Whether niacin itself is used routinely in the future will depend on the outcomes of two large outcome trials (AIM-HIGH and HPS2-THRIVE). In the future however, with even better understanding of niacin pharmacology, new drugs may be able to be engineered to capture aspects of niacin that capitalise on the benefits more specifically and also more selectively, to avoid troublesome side effects.

Keywords: Niacin, nicotinic acid, atherosclerosis, endothelial function

Introduction

The use and effects of niacin on plasma lipoproteins were first described over fifty years ago1. In pharmacological doses, niacin reduces low-density lipoprotein-cholesterols (LDL-c), very low-density lipoprotein-cholesterols (VLDL-c) and lipoprotein(a) (Lp[a]). In addition, it is the most effective currently-available drug for raising high-density lipoprotein-cholesterol (HDL-c) (by between 20-25%).

Niacin was the first drug to show efficacy in reduction of both major cardiovascular events and mortality in patients with prior myocardial infarction2. However, the routine use of early preparations of niacin was limited by the side effect profile (most notably cutaneous flushing). Its use was largely superseded due to the advent of better tolerated therapies for dyslipidaemia and particularly by high efficacious and well-tolerated ‘statins’. For a number of reasons, there has been a recent renewal of interest in the use of niacin. Firstly, there is an appreciation that despite effective LDL-c reduction, there remains substantial ‘residual risk’ in patients with established atherosclerosis 3. Based on epidemiology 4, 5, historic trial data2, 6and study of animal models7-9, HDL-c elevation is a rational next target. Secondly, contemporary niacin preparations have a superior tolerability profile, compared to earlier versions and thirdly, there is emerging interest in several potentially beneficial non-lipid mediated effects of niacin e.g. anti-inflammatory effects.

Recent studies have illustrated that the use of niacin in combination with contemporary statin treatment can slow or reverse the progression of atherosclerosis in patients with dyslipidaemia and established atherosclerosis 10**, 11*. Whether or not this is translated into clinical benefit will be determined by two large, ongoing outcome trials, AIM-HIGH12 (Atherothrombosis Intervention in Metabolic syndrome with Low HDL/High Triglycerides and Impact on global health outcomes) and HPS2-THRIVE13 (Heart Protection Study 2 treatment on HDL to reduce the incidence of vascular events).

This review will consider the effects of niacin on atherosclerosis and vascular function in the setting of clinical trials and will critically evaluate proposed mechanisms of action, focusing on both ‘lipid-targeted’ and ‘pleiotropic’ effects.

Clinical Effects of Niacin

The Coronary Drug Project 2 was the first clinical study to show the benefits of niacin in patients with a history of myocardial infarction. It reduced the incidence of non-fatal re-infarction by 27% in the initial five year follow up period and was associated with a significant decrease of 9% in all cause mortality at fifteen year follow up 2.

Subsequent clinical trials have investigated the effects of niacin in combination with other lipid-altering agents currently in routine clinical use. The FATS (Familial Atherosclerosis Treatment Study) 14 study was a double-blind trial assessing the efficacy of niacin in combination with colestipol, a bile-acid sequestrant in comparison to lovastatin (20mg twice a day) or conventional therapy (placebo or colestipol if baseline LDL-c was elevated) in 146 male patients (younger than 62 years of age) with documented coronary artery disease and a family history of coronary artery disease. HDL-c increased by 43% and was associated with angiographic atherosclerotic regression in 39% in the niacin and colestipol group with an associated significant outcome benefit with a 73% reduction in clinical events (death, myocardial infarction, or revascularization for worsening symptoms) over a 2.5 year follow up period.

The CLAS (The cholesterol lowering atherosclerosis study) 15 confirmed the benefits of niacin in combination with colestipol in coronary artery bypass patients where an increase in HDL-c was associated with angiographic regression of atherosclerosis at two and four year follow up.

The combination of niacin with fibrate in the Stockholm Ischaemic Heart Disease Secondary prevention study 16 in comparison to placebo resulted in a 26% reduction in all cause mortality and a 36% reduction in coronary heart disease mortality in patient surviving myocardial infarction at 5 years.

Patients treated with extended-release niacin in combination with simvastatin in the HATS (HDL-atherosclerosis treatment study) trial 17 compared to dual-placebo benefited with regression of coronary atheroma and a 90% reduction in end-points (arteriographic evidence of a change in coronary stenosis and the occurrence of a first cardiovascular event (death, myocardial infarction, stroke, or revascularization)) albeit with the limitation that it was impossible to ascertain what proportion of the beneficial impact was attributable to niacin or statin.

The currently most pressing question is whether or not there is additional benefit from niacin treatment in patients who are treated with statins to reach contemporary LDL-c targets. Clinical trials that use non-invasive imaging techniques have been employed to further investigate the effects of niacin in combination with other agents. The ARBITER 2 (Arterial biology for the investigation of treatment effects of reducing cholesterol 2) trial 18 investigated the additive effect of extended release niacin to patients already receiving statin therapy. This combination therapy was associated with no change in carotid intima-media thickness (IMT), whereas there was progression in the placebo group (statin therapy alone). After a further 12 months open-label treatment, a regression in IMT was described 19. The first demonstration of a benefit of niacin (vs placebo) when added to statin treatment, came from a recent magnetic resonance imaging study where high dose (2g daily) niacin reduced carotid wall area over 12 months 10**. A similar study, ARBITER 6 11* assessed the effects of niacin vs ezetimibe in statin-treated patients. The study was designed to compare the strategies of further LDL-c lowering (with ezetimibe) versus HDL-c elevation (with niacin). This trial, was controversially stopped early following the observation that patients receiving niacin had a significant reduction in carotid IMT at both 8 months and 14 months 20-22.

While the imaging studies underpin a rationale for addition of niacin to current treatment, clearly the evidence of alterations in outcome needs to be demonstrated and there are currently two large outcome trials underway. The first AIM-HIGH12, is a multicentre double-blind placebo-controlled clinical trial aiming to recruit 3300 patients who are older than 45 years of age and at high risk of cardiovascular by virtue of having established cardiovascular disease together with the two dyslipidaemic elements of metabolic syndrome – low HDL-c (<40mg/dl) and high triglycerides (TG) (>150mg/dl). It is designed to test whether the combination of extended release niacin and simvastatin is superior to simvastatin therapy alone at comparable levels of LDL-c over a median follow up period of 4 years. Primary end-points comprise cardiovascular death, nonfatal myocardial infarction, non-haemorrhagic stroke, or hospitalization for high-risk acute coronary syndrome with objective evidence of ischaemia (troponin-positive or ST-segment deviation). The trial is specifically designed to assess the additive benefit of treating HDL-c and triglycerides in comparison to current standard lipid treatment in patients with atherogenic dyslipidaemia.

The second large clinical trial is HPS2-THRIVE13 - a multicentre randomized double-blind placebo controlled trial again aiming to further define the additional benefits of HDL-c and TG treatment in patients treated with statin therapy, at high risk of cardiovascular events. Investigators have recruited 25,673 patients to date with a previous history of myocardial infarction or cerebrovascular atherosclerotic disease or peripheral arterial disease of diabetes mellitus. LDL-c levels will be optimized with statin therapy (with the addition of ezetemibe if required) prior to randomization to either placebo or niacin and laropiprant (a selective prostaglandin D2 inhibitor to reduce flushing and therefore improve the tolerability of the drug). Patients are to be followed up for a minimum of four years with primary end-points including: cardiovascular death, non-fatal myocardial infarction, non-fatal or fatal stroke or requirement of revascularization. The trial is aiming to report its findings in 2013.

If these clinical outcome trials do show additional benefit associated with HDL-c and TG modification it would fundamentally change our approach to lipid-modulation of high risk patients.

Effects of Niacin on Lipids and Lipoproteins

Niacin has multiple beneficial lipid-altering effects 23, which have long been observed although the exact mechanisms are still not completely understood.

The identification of GPR109A, a G-protein coupled receptor (HM74A, NIACR1), in humans and PUMA-G (protein up-regulated in macrophages by interferon-gamma) in mice for which niacin is a high affinity ligand 24-26 has advanced understanding of the actions of niacin on adipocyte triacylglyceride (TAG) lipolysis. GPR109A is distributed predominantly on adipocytes and also macrophages27. Activation of GPR109A in adipocytes occurs through the Gi-mediated inhibition of adenylyl cyclase resulting in decreased activity of hormone-sensitive lipase and reduced hydrolysis of triglycerides to free fatty acids (FFA). A subsequent reduction in FFA flux to the liver limits substrate availability for hepatic VLDL-c synthesis 28. It has been proposed that alterations in VLDL-c production by the liver limits plasma enzyme cholesteryl ester transfer protein (CETP) activity which exchanges TGs in VLDL-c and LDL-c particles for cholesteryl esters in HDL particles 29; thus a reduction in FFA could explain, at least in some part, the effects of niacin on VLDL-c, HDL-c and LDL-c and this interpretation is consistent with the findings of Van der Hoorn et al in transgenic mice 30. Mice do not usually express CETP: therefore by making APOE3 Leiden mice transgenic for human CETP, it is possible to examine the effects of niacin in the presence and absence of that enzyme. Niacin, in a dose dependent fashion, reduced plasma TG and total cholesterol whilst simultaneously increasing the levels of HDL-c, plasma apolipoprotein-AI and HDL-c particle size. However, in mice without the human CETP (wild type mice) there was a reduction in VLDL-c and LDL-c in response to niacin but no increase in HDL-c. Therefore, nicotinic acid, by reducing TG to VLDL-c, seems to favor the carriage of cholesteryl esters in HDL particles. In addition, CETP expression, mass and activity were all reduced by nicotinic acid treatment in these mice.

The liver also plays a major role in lipid modulation and is involved in the production and secretion of apolipoprotein B (apoB) which is integral to regulating apo-B-containing lipoprotein secretion. Using human hepatocyte cell lines (Hep G2 cells), niacin has been shown to increase apo B intracellular degradation and decrease secretion of apo B into the culture media of Hep G2 cells 31. In addition, niacin has been shown to noncompetitively inhibit hepatocyte microsomal diacylglycerol acyltransferase-2 (DGAT-2) activity, which catalyses the final reaction in TG synthesis 32. As well as removing cholesteryl ester from HDL -c particles leaving apoAI for ‘recycling’, HDL-c whole particle uptake is achieved by ATP synthase β-chain endocytosis. Niacin has been shown to have further hepatic action by inhibiting cell surface expression of the ATP synthase β-chains in HepG2 cells, leading to reduced hepatic removal of apoAI 28. This would therefore implicate an additional potential cellular target for niacin action in raising HDL-c.

In summary, the mechanisms by which niacin exerts its effects on plasma lipoproteins are not clearly elucidated. There are several potential mechanisms (both GPR-109A dependent and independent) that may work synergistically to explain the lipid modifying actions of niacin.

Effects of Niacin on inflammation

Atherosclerosis involves complex inflammatory processes that are manifest both locally and systemically 33. As well as its favorable effects on lipid profile and metabolism, it has been proposed that niacin therapy can also make a contribution to inflammation amelioration via mechanisms unrelated to its effect on lipid and lipoprotein profiles. This ‘pleiotropic’ role may well play a significant role in the beneficial effect of niacin on cardiovascular outcomes both systemically and at a local/cellular level.

Elevated baseline levels of the inflammatory marker C-reactive protein (CRP) have been associated with an increased risk of future myocardial infarction, stroke, peripheral vascular disease and cardiovascular death in otherwise asymptomatic individuals 34-36 and also patients who have suffered an acute coronary syndrome 37-39 . Niacin reduced the levels of CRP and lipoprotein-associated phospholipase A2 (an independent risk factor for cardiovascular disease) after three months administration 40.

By virtue of high GPR109A expression levels in adipose tissue it is not surprising that niacin exerts many of its effects here. Adipose tissue functions as an active endocrine organ, secreting a wide variety of pro-inflammatory adipokines, such as leptin, TNF-α, IL-6, IL-10, and monocyte chemoattractant protein-1 (MCP-1); and the anti-inflammatory adipokine, adiponectin. Adipose tissue excess and dysfunction influences both local and distant inflammatory processes which are involved in the progression of vascular inflammatory disease and atherosclerosis 41.

High plasma levels of adiponectin, have also been shown to be associated with a lower risk of myocardial infarction in men 42 and moderately decreased risk of coronary heart disease in male diabetic patients43. Adiponectin levels are also reported to rapidly decline following acute myocardial infarction44. Recent human studies have shown that treatment with niacin leads to a marked increase in plasma adiponectin 10**, 45 which have been demonstrated in rat models to likely be mediated by the action of niacin on GPR109A 46 in a dose-dependent fashion 47.

Pro-atherogenic chemokines (e.g. MCP-1, RANTES (‘regulated upon activation, normal T cell expressed and secreted’) and fractalkine) secreted by adipose tissue contribute significantly to the recruitment of inflammatory T cells and macrophages into atherosclerotic lesions 48. Niacin administration has been illustrated to suppress TNF-α induced expression and release of these chemokines 47 and thus exerts a significant anti-inflammatory function either through modulation of peri-vascular fat that might drive atherosclerosis 49 or through another indirect mechanism.

Niacin, therefore in addition to its lipid modulation role has many anti-inflammatory effects and in animal models have been shown to be lipid-independent 50*. These athero-protective qualities therefore do seem contribute to the improved cardiovascular outcomes demonstrated in patients treated with niacin.

Conclusion - Future Directions

In recent years, increased understanding of the pathophysiology of atherosclerosis has highlighted different targets for therapy. It is now appreciated that lipid modulation is only one aspect of treatment of patients with atherosclerosis and even intensive management with statins and aggressive strategies to lower LDL-c prevents only a minority of cardiovascular events. There is increasing evidence of the pivotal role that HDL-c plays in atherosclerosis 51 and to date niacin is the most effective clinical agent at increasing HDL-c levels in addition to its other beneficial lipid-modulatory effects.

The identification of the GPR109A receptor has promoted a greater insight into niacin’s mechanism of action and also those of the associated toxic effects. The use of laropiprant (a selective D2 inhibitor) in the HPS2-THRIVE13 trial is an example of how our improved understanding has attempted to overcome some of these limitations.

Whether niacin itself is used routinely in the future will depend on the outcomes of the two large outcome trials: AIM-HIGH12 and HPS2-THRIVE13 that are due to report within the next 2-3 years. In the future however, with even better understanding of niacin pharmacology, new drugs may be able to be engineered to capture aspects of niacin that capitalise on the benefits more specifically and also more selectively, to avoid troublesome side effects.

Acknowledgements

Dr Choudhury’s laboratory is funded by the Wellcome Trust and The British Heart Foundation and supported by the NIHR Biomedical Research Centre, Oxford. Dr Ruparelia is a British Heart Foundation funded clinical research fellow.

Funding: The Wellcome Trust The British Heart Foundation National Institute for Health Research (NIHR) Biomedical Research Centre, Oxford

Footnotes

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