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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Niaspan® in the management of dyslipidaemia: the evidence

B. Greg Brown

Division of Cardiology, University of Washington, A-509 Health Sciences Center, Seattle, WA 98195-6422, USA

Corresponding author. Tel: +1 425 454 6403; fax: +1 206 616 4302. E-mail address: bgbrown{at}u.washington.edu


   Abstract
Top
 Abstract
Introduction
 Anti-atherogenic effects of...
 Combination therapy based on...
 Discussion
 Conclusions
 References
 
Simultaneous correction of hyperlipidaemia and low HDL-cholesterol may provide superior cardiovascular protection than a single pharmacological lipid-modifying strategy. Combinations of nicotinic acid (the most effective HDL-raising agent currently available) and a statin have been especially well studied. The HDL Atherosclerosis Treatment Study (HATS) demonstrated regression of atherosclerosis and a 60–90% reduction in cardiovascular event rates in patients with cardiovascular disease and low HDL-cholesterol who were randomized to receive a combination of immediate-release nicotinic acid and a statin when compared with patients randomized to placebo. Niaspan®, a prolonged-release formulation of nicotinic acid with superior tolerability to the immediate-release version also reduced the progression of atherosclerosis, in the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER 2) study, although this trial was not powered to evaluate outcomes. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-C/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study will test the hypothesis that treatment with Niaspan® plus a statin will provide superior cardiovascular outcomes to a statin given alone in a population of >3000 patients with vascular disease and atherogenic dyslipidaemia (low HDL-cholesterol and hypertriglyceridaemia). The results of AIM-HIGH will be available in 2010. However, the current clinical evidence base supports intensive intervention to correct low HDL-cholesterol today.

Key Words: HDL-cholesterol • Nicotinic acid • Niacin • HMG-CoA reductase inhibitors • Statins • Cardiovascular events


   Introduction
Top
 Abstract
 Introduction
Anti-atherogenic effects of...
 Combination therapy based on...
 Discussion
 Conclusions
 References
 
In recent years, the design of strategies to reduce the risk of morbid cardiovascular events has focussed strongly on control of LDL-cholesterol. This strategy has undoubtedly been successful: many randomized evaluations of statins have demonstrated significant reductions in cardiovascular event rates,1 and meta-analyses attest further to the efficacy of these agents in improving prognosis in patients at high coronary risk.2–4 Figure 1 shows the effects of the statin intervention on cardiovascular event rates in several of these trials, namely the Scandinavian Simvastatin Survival Study (4S),5 the Heart Protection Study (HPS),6 the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study,7 the Cholesterol and Recurrent Events (CARE) study,8 the West of Scotland Coronary Prevention Study (WOSCOPS),9 and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).10 The effects of the statin intervention on cardiovascular event rates was remarkably similar, and typical of the results of such trials in that event rate reductions of between ~20 and 40% were observed.1 Recent evaluations of intensive vs. moderate statin therapy have yielded only incremental additional outcome benefits.11–13


Figure 0431
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  		Figure 1 Relative and absolute risk reductions, and numbers needed to treat (NNT) in order to prevent a major cardiovascular event, in the 4S Study,5 the Heart Protection Study (HPS),6 the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study,7 the Cholesterol and Recurrent Events (CARE) study,8 the West of Scotland Coronary Prevention Study (WOSCOPS),9 and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).10 Major coronary events were defined as follows—4S: death from coronary heart disease, myocardial infarction, or cardiac arrest requiring resuscitation; HPS: death from coronary heart disease, myocardial infarction, stroke, or revascularization; CARE, LIPID, WOSCOPS: death from coronary heart disease or myocardial infarction; AFCAPS/TexCAPS: myocardial infarction, unstable angina, or sudden cardiac death. Absolute risk reduction (ARR) was differences between event rates in placebo and intervention groups. Number needed to treat was calculated as 100/ARR.

 
However, it is also important to consider effects on absolute risk in addition to relative risk reduction. The latter may provide a more meaningful estimate of the impact of an intervention on the burden of disease in a given patient population. Absolute risk reductions (the absolute difference in event rates between control and intervention arms of the studies) in the trials shown in Figure 1 ranged from almost 10% in the high-risk 4S population, which demonstrated a cardiovascular event rate of 29% in its placebo group, to only 2% in the lower-risk, primary prevention AFCAPS/TexCAPS population (placebo cardiovascular event rate 6%). The number of patients needed to treat to prevent a single major cardiovascular event ranged from 12 in 4S to 49 in AFCAPS/TexCAPS.

Intervention with a statin is therefore necessary, but not necessarily sufficient to normalize elevated cardiovascular risk. This review focuses on the potential for cardiovascular protection of simultaneous correction of hypercholesterolaemia and low HDL-cholesterol, an additional independent risk factor for cardiovascular disease.14 Nicotinic acid (niacin) is the most effective agent currently available for increasing levels of HDL-cholesterol.15 This agent has been well studied in combination with lipid-lowering agents, and particular emphasis will be placed on the effects of such combinations on atherosclerosis and clinical outcomes.


   Anti-atherogenic effects of nicotinic acid-based therapy
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 Abstract
 Introduction
 Anti-atherogenic effects of...
Combination therapy based on...
 Discussion
 Conclusions
 References
 
Description of studies
Table 1 summarizes the designs and principal outcomes of trials that have evaluated the effects of nicotinic acid-based combination therapy on indices relating to the progression of atherosclerosis.16–24 In general, these were randomized trials in substantial patient populations, with a sufficient duration of follow-up to gain meaningful measurements of atherosclerosis progression. Patients in all trials had pre-existing coronary artery disease (CAD), except for the University of California San Francisco Arteriosclerosis Specialized Center of Research Intervention Trial (UCSF-SCOR), which recruited a population at high risk of atherosclerosis through familial hypercholesterolaemia.19 The HDL-Atherosclerosis Treatment Study (HATS),21 the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER 2) study,22 and the Armed Forces Regression Study (AFREGS)24 recruited patients with low HDL-cholesterol. The cut-off values used for this parameter were <35 mg/dL (0.9 mmol/L) in men and <40 mg/dL (1.0 mmol/L) in women in HATS, and <45 mg/dL (1.2 mmol/L) and <40 mg/dL (1.0 mmol/L) for the male populations of ARBITER 2 and AFREGS, respectively.


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  		Table 1 Overview of evaluations of the effects of combination therapy with IRNA or Niaspan® and a lipid-lowering agent on atherosclerosis progression

 
Treatment with nicotinic acid exerted the expected effects on lipid profile, largely characterized by markedly increased HDL-cholesterol and reductions in triglycerides. These effects have been reviewed previously.25 Most of the trials evaluated an immediate-release formulation of nicotinic acid (IRNA). However, the ARBITER trials evaluated a prolonged-release formulation of nicotinic acid, Niaspan®. This formulation is as effective as the immediate-release formulation in terms of its effects on the lipid profile.26 A randomized trial has demonstrated dose-related effects on lipids typical of nicotinic acid when Niaspan® is given as monotherapy (Figure 2), with a marked increase in HDL-cholesterol, a marked decrease in triglycerides, with additional reductions in LDL-cholesterol and the atherogenic lipoprotein, Lp(a).27,28 Co-administration of Niaspan® with a statin in a further randomized trial yielded similar effects on HDL-cholesterol as monotherapy, with somewhat larger effects on triglycerides and a markedly larger effect on LDL-cholesterol, as would be expected (Figure 2).28,29 The incidence of flushing, the principal side-effect associated with nicotinic acid, is lower with Niaspan® than with IRNA (Figure 3), which may help to maximize compliance with therapy.27–29


Figure 0432
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  		Figure 2 Effect of Niaspan® alone and combined with a statin on the lipid profile. Data presented are from a 16-week dose ranging evaluation of Niaspan® monotherapy27,28 and from the first 16 weeks of a long-term evaluation of a combination tablet containing Niaspan® and lovastatin.28,29 The doses of lovastatin accompanying Niaspan® in the combination therapy study were 10 mg for Niaspan® 500 mg, 20 mg for Niaspan® 1000 mg, and 40 mg for Niaspan® 2000 mg.

 

Figure 0433
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  		Figure 3 Incidence of flushing with IRNA and with Niaspan® during short-term and long-term clinical studies.28,29 Adapted with permission from McGovern ME. Niaspan®: creating a new concept for raising HDL-cholesterol. Eur Heart J 2005;7(Suppl. F):F41–F47 (by permission of Oxford University Press).

 
Nicotinic acid plus bile acid sequestrants
Three angiographic studies evaluated the effects of IRNA in combination with the bile acid sequestrant, colestipol. The Cholesterol-Lowering Atherosclerosis Study (CLAS) was conducted in 188 middle-aged men (40–59 years) who had previously undergone coronary bypass surgery.16–18 Angiographic measurements were made in 162 subjects at 2 years, and in 103 subjects at 4 years. Clinical benefits were apparent from treatment based on nicotinic acid at 2 years. Examination of native arteries demonstrated a significant improvement in the nicotinic acid–colestipol group, with a lower global atherosclerosis score (P=0.001 vs. placebo), fewer patients with new lesions (10 vs. 22% on placebo, P=0.03), and fewer progressing lesions per patient (1.0 vs. 1.4 on placebo, P=0.03). Comparable benefits were observed in bypass grafts. Benefits were maintained at 4 years (P=0.001): findings in native arteries showed that more patients randomized to nicotinic acid-based treatments did not have atherosclerosis progression (52 vs. 15% on placebo), more patients demonstrated atherosclerosis regression (18 vs. 6% on placebo) and fewer developed new lesions (14 vs. 40% on placebo).

UCSF-SCOR initially randomized patients to receive either IRNA plus colestipol or to diet treatment.19 Emerging data on the clinical benefits of lipid-lowering prompted the study investigators to offer colestipol to the control group, as this was considered to represent an updated standard for usual cardiovascular care. Mean percent coronary stenosis, the primary outcome measure in this trial, progressed by 0.8% in the control group and regressed by 1.5% in the nicotinic acid–colestipol group (P=0.039). Similar benefits were seen in women and men, although effects were no longer statistically significant because of the reduced number of patients in each group.

IRNA and colestipol in combination were also evaluated in comparison with usual care (placebo plus colestipol if required to control elevated LDL-cholesterol) in the Familial Atherosclerosis Treatment Study (FATS).20 This trial also included a third arm, in which patients were randomized to receive lovastatin in combination with colestipol. Definite progression of atherosclerosis in at least one proximal coronary segment (with no evidence of regression) was observed in 46% of control subjects, 25% of patients receiving nicotinic acid with colestipol, and in 21% of patients receiving lovastatin+colestipol. Conversely, regression of atherosclerosis (observed as the only change on angiography) was more common in patients receiving nicotinic acid-based therapy (39%) or lovastatin-based therapy (32%), compared with control (11%). These changes were statistically significant (P-value for trend=0.005). Effects in percent area stenosis were consistent with these observations: this parameter increased by 2.1% in the control group and decreased by 0.9% and 0.7% in the nicotinic acid-based and lovastatin-based combination therapy groups, respectively. Changes in both HDL-cholesterol and LDL-cholesterol were independent and significant predictors of atherosclerosis regression on multivariate analysis (P<0.001 and P<0.01, respectively).

Nicotinic acid plus statins
Two randomized, double-blind trials evaluated this combination in patients with established coronary disease and low HDL-cholesterol at baseline: HATS21 and ARBITER 2.22 HATS was an angiographic study that measured atherosclerotic changes in the coronary arteries of patients randomized to receive placebo, IRNA plus simvastatin, antioxidant vitamins, or a triple combination of nicotinic acid, simvastatin, or antioxidant vitamins. Atherosclerosis (mean percent stenosis in nine proximal coronary artery segments) progressed in the placebo and antioxidant vitamin groups, by 3.9% and by 1.8%, respectively. In contrast, regression of atherosclerosis was observed in the nicotinic acid–simvastatin group, with a mean reduction in stenosis of 0.4% (P<0.001 vs. placebo). The combination of lipid-modifying treatment with antioxidant vitamins attenuated the anti-atherosclerotic effect, with an outcome intermediate between nicotinic acid-simvastatin and placebo (mean change in stenosis of +0.7%, P<0.005 vs. placebo). Improvements in the minimum lumen diameter of coronary arteries paralleled the observed changes in coronary artery stenosis.

ARBITER 2 used ultrasound to measure carotid intima-media thickness (CIMT), a surrogate measure of coronary atherosclerosis. Patients had pre-existing coronary disease and were randomized to receive additional once-daily Niaspan® (1000 mg) or placebo in addition to pre-existing statin treatment. Significant progression of CIMT occurred during treatment with placebo (mean change 0.044 mm, P<0.001) but no significant change occurred during treatment with Niaspan®. A 1-year extension to this study, ARBITER 3, demonstrated regression of atherosclerosis, on average, in a subset of patients who either received Niaspan® in ARBITER 2, or who switched from placebo to Niaspan® at the end of ARBITER 2.23 A more detailed description of this trial is given in the accompanying paper by Dr Allen Taylor, the principal investigator for this trial.

Triple combination therapy
The effects of this treatment strategy on coronary atherosclerosis were explored in 143 men with low HDL-cholesterol and pre-existing coronary disease in AFREGS.24 Cardiovascular risk factors were prevalent in the AFREGS population: the majority of patients in this trial had a history of hypertension (71%), angina (65%), and/smoking (85%), and almost half (43%) had a prior myocardial infarction. Patients were randomized to receive a combination of IRNA, gemfibrozil, and cholestyramine or matching placebos for a double-blind treatment period of 30 months. No patient in the study received a statin as this trial was initiated before the availability of outcomes data with the statins. Once again, focal coronary stenosis increased in the placebo group by 1.4%, and decreased in the active therapy group by 0.8%, with a significant mean difference between treatments of –2.2% (95% CI –4.2 to –0.1) (P=0.04).


   Combination therapy based on nicotinic acid and clinical outcomes
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 Abstract
 Introduction
 Anti-atherogenic effects of...
 Combination therapy based on...
Discussion
 Conclusions
 References
 
Several of the trials described earlier included measurement of clinical outcomes. The principal results of these evaluations are shown in Table 2.


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  		Table 2 Clinical outcomes with nicotinic acid-based combination therapy

 
The FATS trial, followed patients for the occurrence of a composite of death, myocardial infarction, or revascularization for ischaemia in patients randomized to receive IRNA plus colestipol or usual care (diet plus colestipol if required).20 The incidence of this endpoint was markedly lower in either of the intensive therapy arms, relative to the usual care arm. Taken together, the incidence of the primary endpoint was significantly lower in patients randomized to either intensive therapy, compared with usual care [relative risk 0.27 (95% CI 0.10–0.77)]. The benefit of intensive lipid-modifying combination therapy persisted throughout the 8–10 years of open label follow-up in a subset of patients after the double-blind phase of the FATS trial came to an end.30 The incidence of cardiovascular or myocardial infarction continued to diverge throughout this period between patients receiving triple therapy (nicotinic acid, colestipol, and lovastatin) and patients who returned to the usual care of the time as described earlier. At the end of the long-term follow-up, clinical cardiovascular event rates were similar to those previously observed in the double-blind phase of the study.

The placebo-controlled AFREGS trial also evaluated intensive lipid management with a combination including nicotinic acid and colestipol, but with the further addition of gemfibrozil to the regimen, in men with low HDL-cholesterol.24 This trial employed a composite cardiovascular endpoint including hospitalization for angina, myocardial infarction, transient ischaemic attack and stroke, death, and cardiovascular procedures. The incidence of this endpoint in the active therapy group was half that observed in the placebo group (P=0.04). While these data are consistent with those from FATS and other studies described below, they should be interpreted with some caution, because of the broad definition of the composite primary cardiovascular endpoint, and the lack of power to detect differences in event rates between the placebo and active therapy groups.

The studies with nicotinic acid-colestipol combinations described earlier are suitable for testing the hypothesis that simultaneous reduction of LDL-cholesterol and elevation of HDL-cholesterol is a rational and effective clinical strategy. However, most patients at elevated cardiovascular risk are indicated for statin therapy according to current guidelines,15,31 and outcome studies evaluating combination regimens containing a statin are thus particularly relevant to current clinical practice. The HATS trial evaluated two such combinations: IRNA plus simvastatin with or without additional antioxidant vitamins, whereas additional arms involved randomization to antioxidants alone or to placebo. The primary cardiovascular outcome was a composite of cardiovascular death, myocardial infarction, revascularization, or hospitalization for confirmed ischaemia. This endpoint occurred in only a single patient of the 38 patients randomized to receive this treatment (3%), compared with 12/38 patients receiving placebo (32%), with this difference achieving statistical significance (P=0.003) in the intent-to-treat analysis.

The Kaplan–Meier relative risk reduction in the nicotinic acid–simvastatin group, compared with placebo was 90% (P=0.03) (Figure 4). The addition of antioxidant vitamins attenuated the protective effect of simvastatin-nicotinic acid therapy on cardiovascular events, as with the anti-atherogenic effects described earlier. However, a comparison of event rates between all patients who received nicotinic acid-simvastatin and all patients who did not (irrespective of the addition of antioxidant vitamins in each case) also revealed a significant relative risk reduction of 60% (P=0.02) (Figure 4). Antioxidant vitamins given alone did not influence cardiovascular event rates.


Figure 0434
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  		Figure 4 Cardiovascular outcomes (Kaplan–Meier survival curves for patients free of the primary composite cardiovascular event) in patients randomized to receive nicotinic acid plus simvastatin in the HDL Atherosclerosis Treatment Study. (Reproduced with permission from Brown et al.21© 2001 Massachusetts Medical Society. All rights reserved.) (A) Nicotinic acid plus simvastatin vs. placebo. (B) All patients who received nicotinic acid-simvastatin (nicotinic acid–simvastatin and nicotinic acid–simvastatin–antioxidant vitamin groups combined) vs. patients who did not receive nicotinic acid-simvastatin (placebo and antioxidant vitamin groups combined).

 
A composite cardiovascular event of hospitalization for acute coronary syndrome, stroke, arterial revascularization, or sudden cardiac death was measured in ARBITER 2.22 A trend towards a lower incidence of this event was observed in the Niaspan®–statin group of ARBITER 2, but this study was not powered to detect differences in event rates between groups.


   Discussion
Top
 Abstract
 Introduction
 Anti-atherogenic effects of...
 Combination therapy based on...
 Discussion
Conclusions
 References
 
Current database for increasing HDL-cholesterol as a strategy for reducing cardiovascular event rates
Well designed and carefully conducted studies have demonstrated that combining lipid-lowering therapy with nicotinic acid has the potential to induce regression of atherosclerosis and improvements in clinical outcomes. The demonstration of significant reductions in cardiovascular events rates with nicotinic acid-based therapy in FATS, HATS, and AFREGS are consistent with earlier demonstrations of improved cardiovascular outcomes in earlier studies in which nicotinic acid was given as monotherapy, in the Coronary Drug Project,32,33 or in combination with a fibrate, in the Stockholm Ischaemic Heart disease Study.34 Treatment with fibrates has also been associated with improved clinical outcomes in patients with low HDL-cholesterol, notably in the Veterans Administration HDL Intervention Trial (VA-HIT),35 in which the improvements in event rates observed were statistically related principally to increased HDL-cholesterol.36 In contrast, the recently published Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study did not demonstrate a significant effect of fibrate therapy on cardiovascular events in patients with type 2 diabetes and atherogenic dyslipidaemia.37 However, the study treatment did not raise HDL-cholesterol to a clinically significant extent during long-term treatment, so that this study adds little to the debate concerning HDL-cholesterol raising and cardiovascular protection.

While a correlation is evident between reductions in the extent of coronary stenosis or event rates and the level of LDL-cholesterol achieved during treatment, the correlation is better when the sum of changes in LDL-cholesterol and HDL-cholesterol are used in such analyses. Taken together, these trials provide a compelling evidence base for intervention to correct low HDL-cholesterol as a strategy for improving cardiovascular event rates, especially in patients with already well-controlled LDL-cholesterol. Nevertheless, while current guidelines for the management of cardiovascular disease set diagnostic criteria for low HDL-cholesterol [<40 mg/dL (1.03 mmol/L) in men and <50 mg/dL (1.29 mmol/L) in women], they stop short of defining these cut-off values as a basis for initiating HDL-raising therapy.15,31

Future trials
FIELD, like AFREGS, was initiated before treatment with a statin became usual care for most patients at high coronary risk, and a high rate of statin use may also have confounded its results to some extent. Future trials will add to the database of clinical evidence concerning combinations of HDL-cholesterol-raising agents and statins. Niaspan® is of particular interest in this regard, with its equivalent efficacy and superior tolerability compared with IRNA. ARBITER 2 defined the potential of a combination of Niaspan® with a statin to inhibit progression of atherosclerosis, with a suggestion of improved cardiovascular outcomes. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-C/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study will extend this hypothesis to an evaluation of the effect of Niaspan®-statin combination therapy on clinical outcomes.

AIM-HIGH will recruit a large population (target 3300 patients) with evidence of vascular disease and atherogenic dyslipidaemia characterized by low HDL-cholesterol and hypertriglyceridaemia. These lipid abnormalities will be defined in a manner consistent with diagnostic criteria presented in US guidelines,15 with criteria for HDL-cholesterol as described earlier and triglycerides >150 mg/dL (1.7 mmol/L). The trial will compare nicotinic acid plus simvastatin with simvastatin given alone (Figure 5) over a double-blind follow-up period of 3–5 years. The primary cardiovascular endpoint will be a composite of coronary heart disease death, myocardial infarction, non-haemorrhagic stroke, or hospitalization for high-risk acute coronary syndrome. The study, jointly sponsored by the National Institutes of Health and Kos Pharmaceuticals Inc., is scheduled to complete in the second half of 2010.


Figure 0435
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  		Figure 5 Design of the AIM-HIGH Study.

 
Other trials are also evaluating comparable therapeutic strategies. For example, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, evaluating fenofibrate with a statin vs. statin monotherapy will report in late 2009. ILLUMINATE (Investigation of Lipid Level management to Understand its iMpact IN ATherosclerotic Events) is evaluating a combination of atorvastatin and the cholesteryl ester transfer protein inhibitor, torcetrapib, vs. atorvastatin alone, and is due to report in early 2010. These trials will define fully the potential contribution of HDL-cholesterol raising to improved cardiovascular care. However, we have a growing body of trial evidence today supporting the use of intensive intervention to correct low HDL-cholesterol.


   Conclusions
Top
 Abstract
 Introduction
 Anti-atherogenic effects of...
 Combination therapy based on...
 Discussion
 Conclusions
References
 
Well-designed trials have defined the potential of combinations of nicotinic acid and a statin to induce regression of atherosclerosis and improve cardiovascular outcomes in patients with cardiovascular disease and low HDL-cholesterol. While large outcome trials evaluating combinations of statins with HDL-raising agents in comparison with statin monotherapy will report early in the next decade, the current evidence base supports use of this therapeutic strategy now. Nicotinic acid is currently the most effective agent available for increasing HDL-cholesterol, and a prolonged-release formulation (Niaspan®) has equivalent efficacy and better tolerability than the immediate-release formulation. The combination of Niaspan® with a statin represents an evidence-based intervention for the reduction of cardiovascular risk in patients with low HDL-cholesterol.

Conflict of interest: none declared.


   References
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 Abstract
 Introduction
 Anti-atherogenic effects of...
 Combination therapy based on...
 Discussion
 Conclusions
 References
 

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