EDITORIAL COMMENT
Assessing Niacin as an Atherosclerosis Therapeutic AgentValuable Insights Provided by High-Resolution Vascular Magnetic Resonance Imaging*
Farouc A. Jaffer, MD, PhD*
Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts
* Reprint requests and correspondence: Dr. Farouc A. Jaffer, MGH CVRC, Simches Research Building, Room 3206, 185 Cambridge Street, Boston, Massachusetts 02114 (Email: fjaffer{at}mgh.harvard.edu).
Key Words: niacin • atherosclerosis • magnetic resonance imaging • high-density lipoprotein • carotid
Despite the substantial clinical benefit offered by potent low-density lipoprotein (LDL)-reducing therapeutics such as statins, a majority of patients will still experience major cardiovascular events (1). Accordingly, there exists a large, unmet need for new atherosclerosis therapeutic strategies that will further reduce cardiovascular disease (CVD) events.
Nicotinic acid (NA), or niacin, is an intriguing candidate therapy for CVD, and in fact has been investigated as an atherosclerosis therapy for over 40 years. A number of clinical outcome studies and, notably, imaging studies have demonstrated consistent benefits of niacin (2). Yet, remarkably only a few trials have studied niacin in combination with statin therapy, with limitations of the lack of a statin monotherapy arm (3) or the use of modest dosages of niacin (4,5). So, does high-dose niacin (2 g/day) provide antiatherosclerotic benefits when administered to statin-treated patients with vascular disease?
In this issue of the Journal, Lee et al. (6) utilize high-resolution vascular magnetic resonance imaging (MRI) to provide valuable insights into the effects of niacin on carotid atherosclerosis. The authors performed a placebo-controlled, double-blind, single-center, randomized study of high-dose niacin (2 g/day) in 71 patients with established atherosclerotic vascular disease and a low high-density lipoprotein cholesterol (HDL-C) level (<40 mg/dl). All patients received effective statin therapy on entry, with a baseline low-density lipoprotein cholesterol (LDL-C) level of 85 mg/dl, at target for high-risk patients (7). Patients were randomized to receive modified release NA or placebo for 1 year. NA was initiated at 375 mg daily and titrated up to 2,000 mg daily over approximately 3 months.
The primary end point of the study was the absolute change in carotid artery wall area as determined by MRI. Patients underwent electrocardiogram-gated 1.5-T vascular MRI at baseline, 6 months, and 12 months. A multiterritory, multifunctional MRI study was performed to assess carotid wall area, aortic wall area, aortic distensibility, and brachial artery vascular response to flow-mediated dilation or glyceryl trinitrate, based on protocols developed in the investigators' and others' laboratories (8–10).
A total of 59 of 71 patients completed the study, with greater dropout in the NA arm (63% study completion) compared with the placebo group (81% study completion). Differences in the dropout rates reflected the known side-effect profile of niacin such as flushing, itching, and gastrointestinal symptoms. Encouragingly, the authors did not report NA withdrawal for more serious side-effects such as elevated liver function tests or elevated creatine kinase levels. Withdrawal due to claustrophobia during MRI was a minor component (<10% in both arms).
After 12 months, the primary end point was met, with evidence of carotid wall area regression in the NA group (–1.1 ± 2.6 mm2) compared with progression in the placebo group (+1.2 ± 3.0 mm2, p = 0.03). In the aorta, there was a significant reduction in vessel wall area at 6 months of NA therapy, but this result was not significant at 12 months, possibly due to an insufficient sample size. Flow-mediated dilation of the brachial artery showed a favorable trend with NA therapy. Aortic distensibility and glyceryl-trinitrate–mediated brachial reactivity did not change significantly with NA therapy.
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Lipid Effects
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The effects of niacin on the lipid parameters were as expected with high-dose niacin—a 23% increase in HDL-C levels and 19% reduction in LDL-C levels. Study limitations included the lack of information on diet and exercise, factors that affect lipid levels. Given the multiple lipid effects of niacin, what mechanisms might explain the observed benefit of NA on carotid plaque area? To address this question, the authors analyzed scatterplots of the change in carotid wall area versus the change in the HDL-C and LDL-C levels. Analyses revealed an inverse relationship between the HDL-C level and wall area, and no evident relationship between the LDL-C level and wall area. These results further strengthen the concept that niacin-based increases in HDL-C may be beneficial, despite recent experiences with other HDL-C–augmenting agents (2). However, it is important to recognize that niacin also reduces triglyceride, lipoprotein (a), and apolipoprotein B levels, as observed here and in other studies. Potential benefits of niacin may therefore be due to multiple factors.
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Comparison With Other Imaging Studies
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Two prior randomized NA trials incorporated a monotherapy statin control arm and investigated moderate dose NA therapy (1 g/day) or placebo for 12 months in 167 patients (4,5). These studies also employed imaging to provide a surrogate end point, namely B-mode ultrasound carotid intima-media thickness (IMT). In the ARBITER-2 (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 2) study, the primary end point of reduced change in the common carotid IMT did not reach statistical significance (p = 0.08), although significance was reached at 24 months in the cross-over, open-label extension study (5). As carotid MRI may offer improved sensitivity compared with carotid IMT (11), future atherosclerosis imaging trials may benefit from employing both modalities.
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Alternative Imaging End Points
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MRI offers the added ability to evaluate plaque composition. While not investigated in the current study due to stated low prevalence, it may be important to ascertain whether NA therapy reduces carotid plaque lipid-rich/necrotic cores, a risk factor for cerebrovascular ischemic events (12). In addition, inflammation, a major driving force of plaque complications, is an important molecular imaging target for many atherosclerosis therapeutic agents (13). Indeed, clinical molecular MRI and positron emission tomography imaging studies show that statins significantly reduce plaque inflammation. Will niacin further reduce plaque inflammation in statin-treated patients?
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Imaging as a Surrogate End Point for Atherosclerosis Therapeutics
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Atherosclerosis imaging can provide surrogate end points for therapeutic efficacy, namely plaque regression. While imaging end points are unlikely to result in a candidate drug approval by the Food and Drug Administration, atheroma imaging studies can provide direct evidence of atheroma therapies on the vessel wall, and therefore rationally motivate larger outcome trials. In the case of niacin, such studies are well underway (14,15).
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Conclusions
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This important study by Lee et al. (6) provides direct MRI evidence that niacin reduces carotid atherosclerosis in statin-treated patients with low HDL-C levels. These results strengthen the hypothesis that combination niacin + statin therapy will reduce CVD events compared with statin monotherapy. We eagerly await the results of these ongoing pivotal trials (14,15).
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction J Am Coll Cardiol 2005;46:1225-1228.[Abstract/Free Full Text]2. Singh IM, Shishehbor MH, Ansell BJ. High-density lipoprotein as a therapeutic target: a systematic review JAMA 2007;298:786-798.[Abstract/Free Full Text] 3. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease N Engl J Med 2001;345:1583-1592.[CrossRef][Web of Science][Medline] 4. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins Circulation 2004;110:3512-3517.[Abstract/Free Full Text] 5. Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3 Curr Med Res Opin 2006;22:2243-2250.[Medline] 6. Lee JMS, Robson, MD, Yu L-M, et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study J Am Coll Cardiol 2009;54:1787-1794.[Abstract/Free Full Text] 7. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines J Am Coll Cardiol 2004;44:720-732.[Abstract/Free Full Text] 8. Yuan C, Beach KW, Smith Jr. LH, Hatsukami TS. Measurement of atherosclerotic carotid plaque size in vivo using high resolution magnetic resonance imaging Circulation 1998;98:2666-2671.[Abstract/Free Full Text] 9. Corti R, Fayad ZA, Fuster V, et al. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging Circulation 2001;104:249-252.[Abstract/Free Full Text] 10. Jaffer FA, O'Donnell CJ, Larson MG, et al. Age and sex distribution of subclinical aortic atherosclerosis: a magnetic resonance imaging examination of the Framingham Heart study Arterioscler Thromb Vasc Biol 2002;22:849-854.[Abstract/Free Full Text] 11. Duivenvoorden R, de Groot E, Elsen BM, et al. In vivo quantification of carotid artery wall dimensions: 3.0-Tesla MRI versus B-mode ultrasound imaging Circ Cardiovasc Imaging 2009;2:235-242.[Abstract/Free Full Text] 12. Takaya N, Yuan C, Chu B, et al. Association between carotid plaque characteristics and subsequent ischemic cerebrovascular events: a prospective assessment with MRI—initial results Stroke 2006;37:818-823.[Abstract/Free Full Text] 13. Jaffer FA, Libby P, Weissleder R. Molecular imaging of cardiovascular disease Circulation 2007;116:1052-1061.[Free Full Text] 14. Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) trial http://clinicaltrials.gov/ct2/show/NCT00880178 2007Accessed July 6, 2009. 15. Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial http://clinicaltrials.gov/ct2/show/NCT00461630 2007Accessed July 6, 2009.
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Lipid Effects
Comparison With Other Imaging...