New study shows plaque regression with nicotinic acid on top of statin therapy

Results of a new imaging study have provided the first direct evidence that treatmnt with modified-release nicotinic acid (niacin) reduced carotid atherosclerosis within 12 months vs. placebo in statin-treated patients with low plasma levels of high-density lipoprotein (HDL) cholesterol and clinical evidence of atherosclerotic disease. According to senior author Dr Robin P. Choudhury, ‘This is the first study to show regression in patients taking established best contemporary treatment. The data feed into a bigger understanding of how nicotinic acid (niacin) works.’

 The findings were reviewed by HDL Forum Editor Professor Philip Barter.

 Lee JMS, Robson MD, Yu L-M et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function. J Am Coll Cardiol 2009;54:1787-94.

 Background to the study: HATS and ARBITER

 Previous studies such as HATS (HDL-Atherosclerosis Treatment Study) (1) and ARBITER 2 and 3 (ARterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol study) (2,3) have suggested that adding nicotinic acid to statin therapy reduces coronary atheroma.  HATS showed that nicotinic acid combination therapy produced up to 90% reduction in major coronary events compared with placebo together with significant angiographic regression of stenosis. However, implications from HATS were limited by relatively small numbers of patients, low simvastatin dosage (mean 13 mg/day) and the absence of a statin monotherapy group for comparison (1).

 ARBITER 2, which included a statin monotherapy group, showed no change in carotid intima-media thickness (IMT) at 12 months in coronary heart disease (CHD) patients also receiving nicotinic acid 1 g daily whereas there was significant progression in the group receiving statin alone. The difference between the two groups was not statistically significant (2). However, in an open-label follow-up study (ARBITER 3) continuation of combination nicotinic acid-statin therapy for a further 12 months therapy did induce regression of carotid IMT (3) . 

 Magnetic Resonance Imaging Study

 This double-blind placebo-controlled study randomized 71 statin-treated patients with low HDL cholesterol (<40 mg/dL) and either type 2 diabetes with CHD or clinical evidence of carotid or peripheral atherosclerosis.  Modified-release nicotinic acid (niacin) was up-titrated from a starting dose of 375 mg over 8 weeks to 2 g daily.  Magnetic resonance imaging was performed at baseline and 6 and 12 months. Fasting blood samples were also taken at these visits for measurement of blood lipids, lipoproteins, CRP, adiponectin and laboratory safety tests.  The primary endpoint was the absolute change in carotid artery wall area at 12 months.

 Baseline characteristics of the two groups were similar; patients were generally obese (mean BMI 30-31 kg/m2) and 65% had diabetes.

Treatment with nicotinic acid for 12 months led to a 23% increase in HDL cholesterol (from 39 mg/dL to 48 mg/dL, p<0.001), 19% decrease in low-density lipoprotein (LDL) cholesterol, as well as significant decreases in triglycerides and Lp(a) (Table 1).

 

In the nicotinic acid treatment group there was significant regression of the carotid artery wall area compared with progression in the group receiving statin monotherapy (-1.1 ± 2.6 mm2 vs. +1.2 ± 3.0 mm2, adjusted treatment difference -1.64 mm2, 95% CI -3.12 to ‑0.16, p=0.03) (Table 2). There was also significant reduction in the aortic wall area at 6 months associated with nicotinic acid vs. placebo (estimated treatment difference ‑6.40 mm2, 95% CI  -12.27 to -0.54, p=0.03), although this was not significant at 12 months, possibly due to the small patient numbers in the study.

 

Overall, 20% of patients in the niacin group withdrew due to side effects (gastrointestinal effects, skin flushing or itching, or hyperglycaemia in one patient) associated with nicotinic acid therapy.

 In the discussion, the authors suggested that the incremental benefit of nicotinic acid observed is likely to be due to HDL cholesterol elevation and enhanced cholesterol transport. Anti-inflammatory effects may also be implicated. A number of limitations of the study were acknowledged, including small sample size and no evaluation of plaque composition. Dr Choudhury commented that while the magnitude of the change is not clinically relevant in terms of relieving a stenosis, the direction of the change observed is important. He concluded that the study findings underpin the rationale for ongoing clinical outcomes studies, AIM-HIGH and HPS2-THRIVE. These are due to report in 2011 and 2013, respectively.

 In an accompanying editorial Dr. Farouc A. Jaffer, Assistant Professor of Medicine, Harvard Medical School and Director, Cardiovascular Molecular Imaging Program, Massachusetts General Hospital, highlighted the clinical relevance of the study. Dr Jaffer indicated that the potential benefits of nicotinic acid may be due to multiple factors, given its profile of lipid-modifying activity. However, he also underlined the importance of investigating alternative imaging endpoints, including treatment effects on the volume and composition of carotid plaque lipid-rich necrotic cores, as well as plaque inflammation, to gain further understanding of the mechanism(s) of nicotinic acid. 

Editorial Comment. Jaffer FA. Assessing niacin as an atherosclerosis therapeutic agent. J Am Coll Cardiol 2009;54:1795-6.

 This study sets the scene for reporting of the full results of ARBITER-6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: HDL and LDL Treatment Strategies in Atherosclerosis) at the American Heart Association Scientific Sessions, November 16, 2009 – see HDL Forum for reporting and comment. 

 ARBITER-6 HALTS study is an imaging study that compared changes in carotid IMT in patients treated with ezetimibe or extended-release niacin. The study was stopped early by the independent steering committee based on "results of a prespecified, blinded interim analysis," according to information posted on a National Institutes of Health (NIH) website. The study was not stopped due to safety concerns (4).

 

References

1. 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;345:1583-92.

2. 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;110:3512-7.

3. 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;22:2243-50.

4. ClinicalTrials.gov. Comparative study of the effect of ezetimibe versus extended-release niacin on atherosclerosis. June 16, 2009. http://clinicaltrials.gov/ct2/show/NCT00397657

 


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