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

Linda Brookes, MSc

Disclosures

June 12, 2007

In This Article

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.[9,10,11]

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) ( Table 6 ), 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.

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]

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