Niacin (Nicotinic Acid) -- The Old Drug Is Making a Comeback With A New Act

Linda Brookes, MSc

June 12, 2007

Introduction

Niacin (nicotinic acid) is well known as the most effective drug currently available for raising levels of high-density lipoprotein (HDL) cholesterol, raising it by 25% to 35% at the highest doses. The extended-release (ER) formulation of niacin is safe and as effective as the immediate-release version, but it is better tolerated. However, despite the availability of the ER form, niacin is still not optimally utilized because of the cutaneous flushing and the patient resistance and nonadherence that are associated with its use.

Because of the importance of addressing low levels of HDL cholesterol in patients at risk, and because the flushing side effect is such an impediment to acceptance of niacin, a great deal of research has been targeted at addressing or ameliorating this effect. A series of reports on this topic were presented at the 2007 American College of Cardiology (ACC) 56th Annual Scientific Session meeting held in New Orleans, Louisiana. The first assessed to what extent flushing leads to patient nonadherence or discontinuation of niacin therapy. The second study used measurement of carotid artery intima media thickness (CIMT) to assess progression of atherosclerosis in patients with metabolic syndrome. Lastly, the third report used magnetic resonance imaging (MRI) to compare the effects of a niacin-plus-simvastatin combination vs high-dose simvastatin as protection against clinical end points.

Discontinuing Niacin Due to Flushing

Sachin J. Kamal-Bahl, PhD, and other researchers at Merck & Co., (West Point, Pennsylvania) have been exploring the extent to which the flushing that occurs even with ER niacin can be associated with patient discontinuation and nonadherence in clinical practice. These researchers recently presented an analysis showing that ER niacin has the second highest discontinuation rate of all lipid-modifying drug classes (after bile acid sequestrants). At the 2006 Scientific Sessions of the American Heart Association, Dr. Kamal-Bahl reported that in more than 14,000 patients, the mean time to discontinuation of ER niacin was 12.0 months vs 27.5 months in statins (in over 161,000 patients), and that the respective 1-year discontinuation rates were 55.4% vs 28.9%.[1]

In their latest study, Dr. Kamal-Bahl and colleagues reported that about half of new ER niacin users experience flushing in the first week and over one third flushed during all 7 days of that week.[2] Flushing severity was found to be a strong predictor of discontinuation in new ER niacin users and a strong predictor of skipping or delaying niacin in patients who remained on ER niacin who experienced some flushing. However, other side effects were not found to be useful as significant predictors of flushing.

These findings were based on telephone interviews with 500 patients identified from administrative claims data to have newly initiated ER niacin (mean time between initiation and interview: 9.26 months). A pilot-tested questionnaire was used to obtain information on the patients' experiences with the drug. About 27% of the sample (136 subjects) reported having discontinued taking niacin at the time of interview, after a mean duration of use of 3.2 months.

Overall, 57.6% of patients reported flushing in the first week on ER niacin, and 35.2% reported that they flushed at some point during all 7 days of that week. Whereas 54% of patients who continued on ER niacin (continuers) reported flushing in the first week, 69% of those who discontinued the drug (discontinuers) had the same experience ( ). Overall, 91% of the discontinuers reported ever experiencing flushing symptoms, of which 55% were rated as "severe" or "extreme" (on a scale of mild, moderate, severe, or extreme), whereas a slightly smaller 82% of the 364 continuers reported experiencing flushing symptoms, with 21% reporting it as "severe" to "extreme" flushing.

  Flushing Experience Among New Niacin Users

Flushing Severity First Week of Therapy Overall
Continuers Discontinuers Continuers Discontinuers
None 46% 31% 18% 9%
Mild 13% 22% 29% 20%
Moderate 22% 16% 32% 17%
Severe 15% 20% 17% 32%
Extreme 4% 11% 4% 23%

Multivariate analysis showed that regardless of age, gender, type of niacin product, time of day the drug was taken, or any other side effects, experiencing "severe" or "extreme" flushing with ER niacin was a strong prediction of discontinuation ( ).

  Severity of Ever Flushing as Predictor of Discontinuation of ER Niacin

Flushing Severity Adjusted Odds Ratio 95% CI P Value
None Reference    
Mild 1.25 0.56-2.80 .592
Moderate 1.08 0.47-2.47 .862
Severe 3.19 1.43-7.15 .005
Extreme 11.29 4.20-30.39 .000

CI = confidence interval

Among the 299 continuers who had flushing, 21% (1 in 5) reported skipping or delaying doses, and 19% reported stopping ER niacin for > 7 days and then restarting. Flushing severity ("moderate," "severe," and "extreme") was a strong predictor of discontinuation of ER niacin ( ).

  Severity of Ever Flushing as Predictor for Skipping/Delaying ER Niacin Among Continuers Experiencing Flushing

Flushing Severity Adjusted Odds Ratio 95% CI P Value
Mild Reference    
Moderate 2.44 1.01-5.94 .049
Severe 9.39 3.57-24.72 .000
Extreme 8.04 1.93-33.52 .004

CI = confidence interval

The investigators did not identify why continuers who had severe to extreme flushing were still taking ER niacin, nor did they discover whether patients defined as continuers at the time of the study discontinued or were adherent later. Nonetheless, they pointed out that "since long-term continuous treatment is generally necessary in persons with dyslipidemia, flushing side effects with ER niacin appear to limit the acceptability of this otherwise highly effective therapy."

Currently, Merck has a drug in development to counteract niacin-associated flushing, laropiprant (MK-0524), a prostaglandin D2 receptor-1 (DP1) antagonist. Compared with niacin alone, this agent has been shown to significantly reduce flushing when coadministered with niacin. There are currently 2 ongoing trials of an investigational fixed-dose combination (formerly known as MK-0524A) that combines ER niacin with laropiprant.

The first study, Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), is a phase 3 clinical trial to determine whether the combination of ER niacin/laropiprant can further reduce the risk of heart attacks, strokes, and revascularization procedures in up to 20,000 patients already being treated to lower their low-density lipoprotein (LDL) cholesterol levels. The second study, An Assessment of Coronary Health Using an Intima-Media Thickness Endpoint for Vascular Effects (ACHIEVE), will assess the effect of ER niacin/laropiprant on the change in CIMT in patients with heterozygous familial hypercholesterolemia.

Niacin as Treatment for the Metabolic Syndrome

Niacin has been proposed as a viable alternative to statin treatment in patients with the metabolic syndrome, but this has not been studied extensively.[3,4] Martin Thoenes, MD (Technical University, Dresden, Germany) and coinvestigators at Emory University School of Medicine (Atlanta, Georgia) presented the results of a study that demonstrated the beneficial effects of ER niacin on CIMT and endothelial function in patients with metabolic syndrome.[5] The metabolic syndrome is characterized by raised triglycerides and low serum HDL cholesterol and impaired endothelial function in a proinflammatory vascular environment, which is a hallmark of progression of the syndrome. The results of this study also suggested that niacin has anti-inflammatory effects and confirmed previous studies as to the effects of niacin on HDL cholesterol, triglycerides, and adiponectin. Finally, there was no significant increase in fasting glucose levels with niacin, a potential concern raised by previous investigators.

Dr. Thoenes and his colleagues recruited 50 subjects aged ≥ 18 years who had the metabolic syndrome according to the National Cholesterol Education Program (NCEP)/Adult Treatment Panel III (ATP III) criteria[6,7] and were unable or unwilling to take a statin. The subjects were randomized in a double-blind manner and in a 1:2 ratio to either placebo or 1 g daily of ER niacin (Slow-niacin, Upsher-Smith Laboratories, Minneapolis, Minnesota) for 52 weeks. The ER niacin dose was selected on the basis of previous studies. Five subjects withdrew from the study, 3 in the niacin group due to flushing and 2 in the placebo group due to nausea. Measurements were obtained at baseline and 52 weeks. Pill counts were obtained to determine compliance with the protocol.

At 52 weeks, compared with placebo, treatment with ER niacin was associated with a significant 17% decrease in LDL cholesterol and a significant 24% increase in HDL cholesterol ( ). Triglycerides were also significantly decreased with ER niacin vs placebo. There was no significant effect of ER niacin on adiponectin, an adipokine negatively associated with risk of atherosclerosis. Dr. Thoenes noted that, contrary to reports that have suggested niacin may increase insulin resistance, fasting glucose did not change significantly over 52 weeks with either placebo or niacin treatment in this study.

  Effects on Lipids and Blood Glucose Between Baseline and 52 Weeks

Serum Factor (mg/dL) Agent Baseline 52 Weeks P Value
LDL cholesterol Placebo 128.75 ± 7.8 127.8 ± 7.2 .647
Niacin 125.7 ± 11.3 108.0 ± 15.4 < .001
HDL cholesterol Placebo 39.5 ± 4.7 38.5 ± 3.3 .452
Niacin 39.0 ± 5.7 48.5 ± 6.6 < .001
Triglycerides Placebo 177.6 ± 29.2 178.9 ± 32.4 .908
Niacin 183.2 ± 32.8 141.0 ± 27.8 < .001
Blood glucose Placebo 102.2 ± 13.0 105.6 ± 13.5 .457
Niacin 106.0 ± 12.4 104.0 ± 8.1 .447

HDL = high-density lipoprotein; LDL = low-density lipoprotein

In the ER niacin group, there was a reduction in high-sensitivity C-reactive protein (hsCRP), compared with no change in the placebo group ( ). Flow-mediated dilation (FMD) increased significantly from 4.58 ± 0.57% to 5.47 ± 0.79% with niacin. CIMT, the primary end point of the study, was increased in the placebo group, whereas it decreased in the ER niacin group (from 0.700 mm ± 0.018 to 0.695 ± 0.16 mm).

  Changes in hsCRP, CIMT, and FMD Over 52 Weeks

  Placebo Niacin P Value
Niacin vs placebo
CRP (mg/dL) 0.035 -0.361 < .001
CIMT (mm) 0.009 -0.005 < .001
FMD (%) 0.171 0.888 .007

hsCRP = high-sensitivity C-reactive protein; CIMT = carotid intima medial thickness; FMD = flow mediated dilation

Copresenter Bobby V. Khan, MD, PhD (Emory University School of Medicine) concluded that treatment with ER niacin appears to have a sustained effect in reducing the progression of atherosclerosis, as measured by CIMT, and there is also a concomitant improvement in endothelial function with improvements in FMD. In a word, "Niacin really hits on metabolic syndrome."

Niacin/Simvastatin Combination More Effective Than High-Dose Simvastatin

Preliminary data from the first trial to examine the long-term effects of a niacin plus simvastatin combination vs high-dose simvastatin on lipids, apolipoproteins, lipoprotein particles, and inflammatory markers in patients with carotid atherosclerosis were presented by Subha L. Airan-Javia, MD (University of Pennsylvania, Philadelphia).[8] The combination of ER niacin with simvastatin has been investigated in a number of clinical studies, and a large clinical trial is underway to investigate its effects on cardiovascular events.[9-11]

The data reported by Dr. Airan-Javia came from a trial that investigators at the University of Pennsylvania, led by Muredach P. Reilly, MB, MSCE, completed in 2005 and is currently under analysis. The trial was sponsored by Merck (Whitehouse Station, New Jersey), manufacturer of Zocor (simvastatin) and Kos, now part of Abbott (Abbott Park, Illinois), manufacturer of Niaspan (ER niacin). The primary objective of the trial was to determine whether therapies aimed at lowering LDL cholesterol or increasing HDL cholesterol would induce regression of carotid atherosclerotic plaque in vivo using MRI techniques. Secondary objectives included the effects of combination therapy on lipoproteins and their subfractions.

Investigators showed that compared with high-dose simvastatin, the ER niacin/simvastatin combination produced similar LDL-cholesterol lowering, reduced the LDL particle population and increased average particle size, and markedly increased HDL cholesterol and mature HDL levels.

The patients entered into this study were required to be aged 18-90 years, with ≥ 1 carotid stenosis of > 30% by ultrasound criteria, and LDL cholesterol > 100 mg/dL or LDL cholesterol > 80 mg/dL and HDL cholesterol < 40 mg/dL. Patients were excluded from the trial if they had recent (< 3 months) stroke, transient ischemic attack, history of myocardial infarction, unstable angina, critical limb ischemia, poorly controlled diabetes mellitus, or severe hyperlipidemia requiring combination therapy. A sample size of 69 patients was needed for the MRI analysis. Patients enrolled in the trial were randomized to 1 of 3 treatments for 1 year:

  1. Simvastatin 20 mg daily and placebo niacin (low dose statin; n = 25)

  2. Simvastatin 80 mg daily and placebo niacin (high dose statin; n = 24)

  3. Simvastatin 20 mg daily and active niacin (combination therapy; n = 26)

The 2-g dose of niacin in treatment group 3 was used so that groups 2 and 3 would have approximately equivalent LDL lowering because of the synergistic LDL lowering effect of the combination of simvastatin and niacin.

Plasma samples taken at baseline and at return visits 1, 3, 6, and 12 months later were tested for lipoproteins, lipids, and apolipoproteins; lipoprotein particle size and number; and plasma hsCRP and other inflammatory markers. Baseline characteristics were similar in all 3 treatment groups: average age was 70 years; 70% were male; 62% were on a statin at enrollment; baseline LDL cholesterol was 110 mg/dL; and HDL was 42 mg/dL. Effects of treatment on fasting plasma lipoproteins, lipoprotein particles (assessed by nuclear magnetic resonance [NMR]), and inflammatory markers were examined. Analysis of variance was performed on the between-group differences in change in lipids and biomarkers at 12 months.

Over 1 year, combination therapy and high-dose statin both led to similar large reductions in LDL cholesterol, in the range 25% to 40%, compared with low-dose statin. A similar pattern of reduction was seen in non-HDL cholesterol, triglycerides, and very low density lipoprotein particles. Of note, combination therapy led to gradual incremental reductions in most parameters, whereas statin alone tended to cause a more immediate effect, Dr. Airan-Javia noted. Although combination therapy tended to produce greater effects than high-dose statin, the difference between combination therapy and high-dose statin was not statistically significant.

Combination therapy reduced lipoprotein(a) by 18%, which was highly significant compared with low- and high-dose statin (P < .001). A large reduction in apolipoprotein B seen with combination therapy was significantly greater than the effect of high-dose statin (P < .05). Combination therapy also led to greater reductions in the total number of small LDL particles than high-dose statin (P = .05). This was further demonstrated by a marked and incremental reduction with combination therapy in the percentage of patients with pattern "B" LDL (average diameter of LDL particles ≤ 20.5 nm on NMR spectroscopy), which is associated with the metabolic syndrome and insulin resistance, compared with no change with low- and high-dose simvastatin, but combination therapy led to marked and incremental reductions in the percentage of patients with this slightly more atherogenic profile (P = .001).

The combination produces a gradual 20% increase in HDL cholesterol (P = .001 vs high-dose statin monotherapy). Notably, there were no changes in apoA-I or apoA-II levels or in total number of HDL particles with any of the 3 treatments. However, the combination therapy led to increases in content and size and a shift of HDL particles toward more mature forms compared with monotherapy. The number of large (mature) HDL particles increased by an average of 80% with combination therapy, compared with no significant change with statin monotherapy. A small but significant increase in average HDL particle size was seen with combination therapy compared with statin monotherapy (P = .01 vs high dose).

Exploratory analysis of inflammatory markers showed a small but significant decrease in plasminogen activator 1 (PAI-1) with combination therapy compared with high-dose statin (P = .04) ( ), although this analysis was limited by small sample size, Dr. Airan-Javia noted. There was no effect of combination therapy on hsCRP, and levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), matrix metalloproteinase 9, myeloperoxidase, and E-selectin did not differ significantly among the 3 treatment groups over time.

  Inflammatory Markers

  Baseline 6 Months 12 Months
hsCRP (mg/dL)
   Simvastatin 20 mg 1.35 1.83 (35.6%) 1.56 (15.6%)
   Simvastatin 80 mg 0.91 0.99 (8.8%) 0.79 (-13.2%)
   Simvastatin 20 mg + ER niacin 2 g 1.30 1.84 (41.7%) 1.19 (-8.1%)
PAI-1 (ng/dL)
   Simvastatin 20 mg 15.97 15.93 (-0.34%) 15.55 (-2.62%)
   Simvastatin 80 mg 15.67 13.17 (-15.96%) 16.68 (6.46%)
   Simvastatin 20 mg + ER niacin 2 g 13.68 10.54 (-23.00%) 10.35 (-24.35%)

hsCRP = high-sensitivity C-reactive protein; PAI-1 = plasminogen activator 1; ER = extended release

Analysis of metabolic markers showed that combination therapy increased plasma free fatty acids (FFA) by 60% in contrast to no significant changes with statin monotherapy. This effect may contribute to insulin resistance effects of niacin, Dr. Airan-Javia suggested. Despite this increase in FFA, however, there was no significant change in fasting glucose levels in any of the treatment groups.

These results show that the effects of simvastatin/niacin combination therapy are at least as significant as simvastatin 80 mg on LDL cholesterol, and the effects are greater than simvastatin 80 mg on apolipoprotein B and apolipoprotein particles, and HDL cholesterol and particle size. Dr. Airan-Javia and her colleagues believe that further studies are warranted to evaluate the effect of this combination, compared with high-dose statins, on atherosclerotic cardiovascular disease. Dr. Airan-Javia speculated that increasing mature HDL particle levels in this way may be a valid therapeutic HDL target and lead to increased cellular cholesterol efflux via the ATP binding cassette transporter G1 (ABCG1), ultimately improving reverse cholesterol transport. She and her colleagues are currently analyzing the primary end point of this study, which they hope will give more insight into clinical significance of these findings. "Total HDL levels may not be as clinically significant as previously thought, and perhaps we need to focus on more specific and physiologically valid biomarkers," she said.

The large clinical trial comparing the effects of ER niacin and simvastatin in the prevention of coronary heart disease (CHD) is the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH). This US-Canadian multicenter, randomized, double-blind, parallel-group, controlled clinical trial will enroll about 3300 patients aged > 45 years with established vascular disease and atherogenic dyslipidemia. The primary end point of AIM-HIGH is a composite of CHD death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for high-risk acute coronary syndrome with objective evidence of ischemia. A secondary end point is the composite of CHD death, nonfatal myocardial infarction, or ischemic stroke. Follow-up will extend through 2010.

AIM-HIGH is sponsored by the National Heart, Lung, and Blood Institute with additional support from Abbott. Abbott filed a New Drug Application for combination Niaspan/simvastatin in April 2007.[12]

References

  1. Kamal-Bahl S, Burke T, Watson D, et al. Discontinuation of newly-initiated extended-release niacin versus other lipid-modifying drug classes in clinical practice. Circulation. 2006;1113:e790-e791. Abstract P21.

  2. Kamal-Bahl SJ, Watson DJ, Kremer B, et al. Flushing experience and discontinuation with niacin in clinical practice. J Am Coll Cardiol. 2007;49(9 suppl A):273A. Abstract 1006-149.

  3. Taylor AJ, Sullenberger LE, Lee HJ, et al. 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

  4. Al-Shaer MH, Jerome WP. The appropriateness of nicotinic acid derivative use in patients with the metabolic syndrome: insights from the ARBITER 2 study. Am J Cardiol. 2006;98:275-276.

  5. Thoenes M, Oguchi A, Vaccari CS, et al. The effects of extended release niacin on carotid intimal media thickness, endothelial function, and inflammatory markers in patients with the metabolic syndrome. J Am Coll Cardiol. 2007;49(9 suppl A):409A. Abstract 1026-125.

  6. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421. Abstract

  7. Grundy SM, Brewer HB Jr, Cleeman JI, et al. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Arterioscler Thromb Vasc Biol. 2004;24:e13-e18. Abstract

  8. Airan-Javia SL, Wolfe ML, Wolf RL, et al. Long-term effects of niacin-simvastatin combination compared to high-dose simvastatin on lipids, apolipoproteins, lipoprotein particles and inflammatory markers in patients with carotid atherosclerosis. J Am Coll Cardiol. 2007;49(9 suppl A):394A. Abstract 820-7.

  9. 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. Abstract

  10. 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. Abstract

  11. McKenney JM, Jones PH, Bays HE, et al. Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). Atherosclerosis. 2007 Jan 18; [Epub ahead of print].

  12. Abbott submits New Drug Application for combination Niaspan[R]/simvastatin tablet. April, 23, 2007. Available at: http://www.abbott.com/global/url/pressRelease/en_US/60.5:5/Press_
    Release_0447.htm. Accessed May 31, 2007.