The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3

Cardiology Service, Walter Reed Army Medical Center, Washington, DC 20307-5001, USA.
Current Medical Research and Opinion (Impact Factor: 2.65). 11/2006; 22(11):2243-50. DOI: 10.1185/030079906X148508
Source: PubMed


The ARBITER 2 trial showed that extended-release niacin (ERN) when added to statin monotherapy slowed the progression of carotid atherosclerosis over 12 months. Whether longer treatment with ERN would have a greater effect on carotid intima-media thickness (CIMT) is unknown.
We examined the long-term effects of ERN on high density lipoprotein (HDL-C) cholesterol and CIMT during 12-24 months treatment with ERN in ARBITER 2 participants who were either continued or were crossed over (from placebo) to ERN 1000 mg daily.
Among 149 subjects completing ARBITER 2, 130 (88%) enrolled in ARBITER 3. The prespecified primary endpoints were the within-group change in CIMT and HDL-C in patients receiving placebo for 12 months (n = 71), ERN for 12 months (comprised of subjects from ERN treatment during ARBITER 2 (n = 78) and those crossed over to ERN from placebo after ARBITER 2 (n = 47)), and ERN for 24 months spanning ARBITER 2 and 3 (n = 57). Five subjects discontinued the study due to flushing side effects. The study was completed by 104 subjects (47 crossed over from placebo; 57 with ERN continued from ARBITER 2).
HDL-C increased in the ERN group from 39.5 +/- 6.7 to 48.6 +/- 13.3 mg/dl (p < 0.001) along with modest reductions in LDL-C and TG. Among 125 participants treated with ERN for 12 months, there was a net regression of CIMT of -0.027 +/- 0.011 mm (p < 0.001 vs. placebo). Among 57 participants treated with ERN for 24 months, there was additional significant regression of CIMT of -0.041 +/- 0.021 mm (p = 0.001 vs. placebo). Controlling for changes in LDL and triglycerides, only changes in HDL-C were independently associated with regression of CIMT (beta = -0.25; p = 0.001).
When added to statin therapy, ERN significantly increases HDL-C and induces atherosclerosis regression measured by CIMT over 24 months. Limitations to this study include its open-label design and the inability to relate CIMT effects to clinical outcomes.

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    • "The HDL Atherosclerosis Treatment Study (HATS) showed that the combination of simvastatin and niacin reduced the risk of the composite primary endpoint (coronary mortality, MI, stroke, and revascularization) and prevented atherosclerotic plaque progression in a population of patients with CHD and low HDL-C (mean baseline 34 mg/dL) [84]. A number of studies show niacin reduces carotid atherosclerosis in high-risk patients with low HDL-C who were on statin therapy [85] [86]. The ARBITER 6-HALTS trial compared extended-release niacin and ezetimibe as add-ons to statin monotherapy in patients with CHD or CHD risk equivalents [87]. "
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    ABSTRACT: The first observations linking a low serum level of HDL-C to increased risk for cardiovascular disease were made over 50 years ago. High serum levels of HDL-C appear to protect against the development of atherosclerotic disease, while low serum levels of this lipoprotein are among the most important predictors of atherosclerotic disease in both men and women and people of all racial and ethnic groups throughout the world. It has long been assumed that therapeutic interventions targeted at raising HDL-C levels would lower risk for such cardiovascular events as myocardial infarction, ischemic stroke, and death. Even after five decades of intensive investigation, evidence to support this assumption has been fleeting. A number of post hoc analyses of randomized controlled trials and meta-analyses suggest that HDL-C raising, particularly when coupled with aggressive LDL-C reduction, impacts risk for cardiovascular events and rates of progression of atherosclerotic disease. Unfortunately, four recent prospective trials performed with the intent of testing the "HDL hypothesis" (ILLUMINATE, dal-OUTCOMES, AIM-HIGH, and HPS2-THRIVE) failed to meet their primary composite endpoints. These results have lead many clinicians and investigators to question the validity of the assumption that HDL-C raising reduces risk for cardiovascular events. Additional trials with other drugs are underway. In the meantime, HDL-C cannot be considered a target of therapy. Given the complexity of the HDL proteome and lipidome, there is biological plausibility for how HDL particles might exert atheroprotection. We explore the evidence supporting the inverse relationship between HDL-C and cardiovascular disease risk, documented mechanisms by which HDL particles may exert atheroprotection, and the findings either supporting or negating specific therapeutic interventions in patients afflicted with low HDL-C.
    Best Practice & Research: Clinical Endocrinology & Metabolism 06/2014; 28(3):353-368. DOI:10.1016/j.beem.2013.11.002 · 4.60 Impact Factor
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    • "Although initial clinical studies showed that niacin reduced atherosclerosis development in combination with statins [3]–[5] and reduced the relative risk of cardiovascular events [6], results from the large outcome trials AIM-HIGH and HPS2-THRIVE did not confirm earlier findings [8], [44], [45]. In order to test the HDL hypothesis, the AIM-HIGH investigators minimized the differences in LDL levels between the groups. "
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    ABSTRACT: Niacin potently lowers triglycerides, mildly decreases LDL-cholesterol, and largely increases HDL-cholesterol. Despite evidence for an atheroprotective effect of niacin from previous small clinical studies, the large outcome trials, AIM-HIGH and HPS2-THRIVE did not reveal additional beneficial effects of niacin (alone or in combination with laropiprant) on top of statin treatment. We aimed to address this apparent discrepancy by investigating the effects of niacin without and with simvastatin on atherosclerosis development and determine the underlying mechanisms, in APOE*3Leiden.CETP mice, a model for familial dysbetalipoproteinemia (FD). Mice were fed a western-type diet containing cholesterol without or with niacin (120 mg/kg/day), simvastatin (36 mg/kg/day) or their combination for 18 weeks. Similarly as in FD patients, niacin reduced total cholesterol by -39% and triglycerides by -50%, (both P<0.001). Simvastatin and the combination reduced total cholesterol (-30%; -55%, P<0.001) where the combination revealed a greater reduction compared to simvastatin (-36%, P<0.001). Niacin decreased total cholesterol and triglycerides primarily by increasing VLDL clearance. Niacin increased HDL-cholesterol (+28%, P<0.01) and mildly increased reverse cholesterol transport. All treatments reduced monocyte adhesion to the endothelium (-46%; -47%, P<0.01; -53%, P<0.001), atherosclerotic lesion area (-78%; -49%, P<0.01; -87%, P<0.001) and severity. Compared to simvastatin, the combination increased plaque stability index [(SMC+collagen)/macrophages] (3-fold, P<0.01). Niacin and the combination reduced T cells in the aortic root (-71%, P<0.01; -81%, P<0.001). Lesion area was strongly predicted by nonHDL-cholesterol (R(2) = 0.69, P<0.001) and to a much lesser extent by HDL-cholesterol (R(2) = 0.20, P<0.001). Niacin decreases atherosclerosis development mainly by reducing nonHDL-cholesterol with modest HDL-cholesterol-raising and additional anti-inflammatory effects. The additive effect of niacin on top of simvastatin is mostly dependent on its nonHDL-cholesterol-lowering capacities. These data suggest that clinical beneficial effects of niacin are largely dependent on its ability to lower LDL-cholesterol on top of concomitant lipid-lowering therapy.
    PLoS ONE 06/2013; 8(6):e66467. DOI:10.1371/journal.pone.0066467 · 3.23 Impact Factor
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    • "Low HDLC levels, defined as below 40 mg/dL for men and 50 mg/dL for women, remain prevalent [15] [16] [17]. Numerous prospective cohort studies support a powerful inverse correlation between circulating HDLC levels and coronary risk [18] [19] [20] [21] [22] [23] [24] [25]. Earlier studies supported an inverse correlation between circulating HDLC and coronary risk in patients with normal or elevated LDLC. "
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    ABSTRACT: Circulating level of low HDLC (high-density lipoprotein cholesterol) represents a common critical risk factor for IHD (ischemic heart disease) and may further aggravate the condition in anemic subjects, as the presence of anemia itself is a threat to cardiovascular consequences. To investigate the relationship of circulating HDLC with anemia, first we determined the levels of total hemoglobin (Hb) in a total of 301 subjects (male, n = 158; female, n = 143) randomly, and then examined the circulating levels of HDLC in fasting condition. Age of the study subjects was 47.9 ± 16.6 (mean ± SD) years. Both the male and female subjects were divided into three groups according to their levels of Hb. The relationship of circulating levels of HDLC with the levels of total Hb was statistically analyzed. In case of the male subjects, we found that the levels of HDLC differed significantly among the three groups with different levels of Hb (P = 0.0233) and decrease in the levels of HDLC correlated significantly with the gradual decrease of total Hb level (r = 0.2504; P = 0.0015). In female subjects, we observed a similar trend of difference among the three groups (P = 0.0685). However, decrease in the levels of HDLC correlated significantly with the gradual decrease of Hb level (r = 0.2199; P = 0.0083). Altogether, this study demonstrates that decrease in the circulating HDLC is related to the gradual decrease of Hb level. This study also indicates that circulating level of HDLC may be influenced by the level of total Hb and reveals the cardiovascular risks in anemia as well.
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