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Achieving the therapeutic benefits of Niaspan^® in daily practice

Charles A. Reasner

Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78282-7877, USA

Corresponding author. Tel: +1 210 358 7402; fax: +1 210 358 7406. E-mail address: charles.reasner{at}uhs-sa.com

	Abstract

Top Abstract Introduction Myth 1: 'statins are... Myth 2: 'diabetic patients... Myth 3: flushing renders... Myth 4: the clinical... Conclusions References

 
Aims The purpose of this aricle is to discuss the use of niacin to reduce cardiovascular events in patients with diabetes.

Methods and Results Five common misconceptions regarding the use of niacin are discussed and practical suggestions to decrease flushing with niacin are outlined. Evidence that combining niacin with statin therapy is presented.

Conclusions That simultaneous lowering of LDL-cholesterol with statins and raising HDL-cholesterol with niacin is a rational and effective strategy for preventing cardiovascular disease in patients with diabetes.

Key Words: Type 2 diabetes • Dyslipidaemia • HDL-cholesterol • Nicotinic acid • Niacin

	Introduction

Top Abstract Introduction Myth 1: 'statins are... Myth 2: 'diabetic patients... Myth 3: flushing renders... Myth 4: the clinical... Conclusions References

 
Cardiovascular disease remains the leading cause of death in the developed world, despite the many advances in cardiovascular care that we have seen in recent years. Sedentary habits and rapidly increasing rates of obesity (especially abdominal obesity) are driving an increased incidence of the metabolic syndrome, pre-diabetic dysglycaemia, and type 2 diabetes.^1–3 The net result of these developments will inevitably be a continuing burden of cardiovascular disease, unless we can intervene effectively to control cardiovascular risk. This is especially true when viewed in the context of the ageing populations of Western countries, but increasing sedentariness of populations of developing nations, often associated with urbanization of populations, and increased access to energy-rich diets are also driving similar adverse changes in these countries.^4–7

The practising cardiologists have more therapeutic options at their disposal than ever before in designing therapeutic regimens for the management of cardiovascular risk. At present, guidelines for the management of cardiovascular risk focus firmly on the control of individual cardiovascular risk factors, such as dyslipidaemia, hypertension, and obesity.^8,9 With regard to dyslipidaemia, these guidelines focus firmly on the control of LDL-cholesterol, first and foremost, with the control of other lipid components viewed as a secondary objective. However, the pattern of dyslipidaemia commonly found in insulin-resistant patients, such as those with the metabolic syndrome or type 2 diabetes, often does not involve increased overall levels of LDL-cholesterol. Rather, these patients often display an atherogenic dyslipidaemia phenotype featuring low HDL-cholesterol, hypertriglyceridaemia, and a preponderance of small, dense LDL particles.¹⁰

The clinical benefits of statin-based therapy are proved by many well-designed intervention trials.¹¹ However, the presentation of dyslipidaemic phenotypes is heterogeneous, as described earlier, and combination therapy with agents to reduce LDL-cholesterol (statins) together with agents that correct low HDL-cholesterol and hypertriglyceridaemia provides a rational strategy for addressing cardiovascular risk arising from these multiple sources. Nicotinic acid (NA) (niacin in some countries) is the most effective agent available to increase levels of HDL-cholesterol,⁸ and this agent also induces substantial reductions in triglycerides and shifts the LDL subclass profile towards larger, less atherogenic particles.¹²

A once-daily prolonged release formulation of NA, Niaspan^®, is now available, which is better tolerated than the immediate-release (IR) version. The objective of this article is to review practical considerations in the use of this agent in the management of atherogenic dyslipidaemia. In particular, I have set out to dispel several common misconceptions (‘myths’) surrounding the use of NA in general, and of Niaspan in particular, in the management of dyslipidaemia.

	Myth 1: ‘statins are all my patients need’

Top Abstract Introduction Myth 1: 'statins are... Myth 2: 'diabetic patients... Myth 3: flushing renders... Myth 4: the clinical... Conclusions References

 
Intervening with a statin is effective in controlling cardiovascular risk in patients likely to display the atherogenic dyslipidaemia phenotype. For example, the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) demonstrated a reduction of 37% in the primary endpoint of this trial [fatal or non-fatal myocardial infarction (MI), sudden cardiac death, or unstable angina] in a patient population with low HDL-cholesterol according to the inclusion criteria of the study [HDL-cholesterol <1.16 mmol/L (45 mg/dL) in men and <1.21 mmol/L (47 mg/dL) in women].¹³ More recently, the Collaborative Atorvastatin Diabetes Study (CARDS) evaluated the effectiveness of intensive control of LDL-cholesterol with atorvastatin in a patient population with a diagnosis of type 2 diabetes and demonstrated an identical risk reduction (37%) in its primary endpoint of acute coronary heart disease (CHD) events, coronary revascularization, or stroke.¹⁴

A number of other large studies recruited sufficient numbers of diabetic patients to permit meaningful subgroup analyses in these patients, including the Cholesterol and Recurrent Events (CARE) Study,^15,16 the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study,^16,17 the West of Scotland Coronary Prevention Study,^16,18 the MRC/BHF Study,¹⁹ and the Scandinavian Simvastatin Survival study (4S).²⁰ Without exception, these analyses demonstrated that patients with type 2 diabetes benefited from statin treatment. For example, Figure 1A shows Kaplan–Meier curves for all-cause mortality (the primary endpoint) in the 4S trial.²⁰ The relative risk reduction in patients with diabetes at baseline (43%) was larger than that observed in the non-diabetic subgroup (29%). Recent studies evaluating the effects of intensive control of LDL-cholesterol provide similar results. The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial (TIMI-22) demonstrated lower primary event rates (death, MI, revascularization, or hospitalization for unstable angina) in its overall population and in its diabetic subgroup (Figure 1B).²¹

View larger version (25K): [in this window] [in a new window]   Figure 1 Substantial burden of residual cardiovascular risk following intervention with a statin in patients at high risk of cardiovascular events. (A) All-cause mortality according to diabetes status in the Scandinavian Simvastatin Survival Study (4S) (from Pyorala et al.,20 with permission; ©1997 American Diabetes Association). (B) 2-year event rates in the PROVE-IT Study.21

 
As a result of intervention trials with statins, most patients with diabetes are now considered to be candidates for treatment with a statin. However, the trials illustrated in Figure 1 provide an example of the substantial risk of adverse outcomes that remains after statin treatment. Overall of the statin trials, observed risk reductions for primary events generally lie in the range 20–40%. Thus, 60–80% of coronary events are not prevented by statin treatment. Intensive management of LDL-cholesterol in trials such as PROVE-IT [where median LDL-cholesterol was reduced to 1.6 mmol/L (62 mg/dL) in the intensive therapy group] or subsequent similar studies such as Treating To New Targets (TNT)²² or the Incremental Decrease in End Points Through Aggressive Lipid lowering (IDEAL) study²³ has not demonstrated clear potential to reduce cardiovascular risk further. Until such additional risk reduction is demonstrated, statins, although important, are not all that is required to control cardiovascular risk associated with dyslipidaemia.

	Myth 2: ‘diabetic patients should not be prescribed NA because of the potential for adverse effects on insulin resistance and glycaemia’

Top Abstract Introduction Myth 1: 'statins are... Myth 2: 'diabetic patients... Myth 3: flushing renders... Myth 4: the clinical... Conclusions References

 
Niaspan and glycaemia
Concerns over a risk of hyperglycaemia, particularly in diabetic patients, have undoubtedly limited the therapeutic use of NA.²⁴ The clinical evidence base indicates conclusively that such considerations should not present a barrier to the routine therapeutic use of Niaspan.

Two randomized, double-blind studies have evaluated the effects of Niaspan on lipids and glycaemia in patients with type 2 diabetes. The Assessment of Diabetes Control and EValuation of the Efficacy of Niaspan Trial (ADVENT) evaluated Niaspan 1000–1500 mg in comparison with placebo in 148 patients, half of whom received a statin.²⁵ A further trial, Advicor In The Treatment Of Diabetic Patients With Dyslipidemia Using Thiazolidinedione and/or Metformin (ANTHEM) evaluated Niaspan 1000–1500 mg administered in combination with lovastatin 40 mg in comparison with fenofibrate in 197 patients also receiving an insulin sensitizer.²⁶ Mean HDL-cholesterol increased by up to 24 and 26% from baseline, respectively. Mean triglycerides decreased by up to 36% in ADVENT, and non-HDL-cholesterol decreased also by up to 36% in ANTHEM (triglycerides per se were not measured in this study). Changes in glycaemia were minor. Mean changes in HbA_1C were +0.29% units in the Niaspan 1500 mg group in ADVENT and +0.2% units in the Niaspan 1500 mg/lovastatin 40 mg group in ANTHEM. Thus, changes in glycaemia in these studies were small and easily accommodated by routine adjustment of oral antidiabetic medications.

A recent evaluation of Niaspan at a dose of 2000 mg in 17 patients with the metabolic syndrome, of whom nine had type 2 diabetes, has confirmed and extended these findings.²⁷ NA suppresses lipolysis, and previous studies had linked observations of hyperglycaemia in patients receiving IR NA with a subsequent rebound in free fatty acid (FFA) levels as plasma levels of NA declined during the later part of the dosing interval.²⁸ This study showed that, after 4 months of treatment, the rebound effect with Niaspan on FFA levels was far less than that expected with IR NA. Consistent with this observation, plasma glucose and insulin profiles during an oral glucose tolerance test were essentially indistinguishable before and after treatment with Niaspan (Figure 2).

View larger version (10K): [in this window] [in a new window]   Figure 2 Effects of 4 months of treatment with Niaspan 2000 mg on plasma glucose and insulin during an oral glucose tolerance test in patients with the metabolic syndrome with or without type 2 diabetes (n=9 and n=8, respectively) (from Vega et al.,27 with permission from Excerpta Medica Inc. ©2005).

 
NA, glycaemia, and outcomes
The Coronary Drug Project (CDP) was a double-blind, randomized trial that evaluated IR NA among other interventions with a duration of double-blind treatment of 6 years.²⁹ Significant (P<0.05) risk reductions in the NA group compared with placebo were observed for the secondary composite endpoint of non-fatal MI or death from CHD (–14%), individual endpoints of non-fatal MI (–27%), stroke or transient ischaemic attack (–26%), or cardiovascular surgery (–41%). The primary endpoint of all-cause mortality was not affected significantly at the end of double-blind treatment. However, 9 years later (i.e. 15 years after randomization), a retrospective analysis of a subset of the CDP population found significantly lower all-cause mortality (risk reduction –11%, P=0.0004) and coronary mortality (–12%, P<0.01) in patients originally randomized to NA compared with placebo.³⁰ These benefits were observed despite there having been no attempt to maintain study conditions or treatment at the close of the 6-year double-blind phase.

These benefits from treatment with NA did not depend on glycaemic status at baseline, as shown by a retrospective analysis of the CDP population stratified for various levels of blood glucose (Figure 3).³¹ Although the test for interaction did not indicate significant differences within this data set (P=0.66), there was a qualitative trend towards greater benefit as the level of glycaemia increased, with an apparent risk reduction of 57% in patients with a blood glucose level consistent with a diagnosis of diabetes.

View larger version (11K): [in this window] [in a new window]   Figure 3 Incidence of MI during 6 years of double-blind treatment in the CDP study according to glycaemic status at baseline (from Canner et al.,31 with permission from Exerpta Medica Inc. ©2005).

 

	Myth 3: flushing renders treatment with NA impractical

Top Abstract Introduction Myth 1: 'statins are... Myth 2: 'diabetic patients... Myth 3: flushing renders... Myth 4: the clinical... Conclusions References

 
Flushing is the principal side effect associated with Niaspan, and the majority of patients receiving treatment with Niaspan will experience flushing.¹² Although the efficacy of Niaspan is equivalent with that of IR NA,³² the frequency of flushing with Niaspan is markedly lower than that observed with IR NA (Figure 4A).^32–34 Moreover, the frequency of flushing tended to decrease with time during long-term studies (Figure 4B).^33,34

View larger version (16K): [in this window] [in a new window]   Figure 4 Incidence of flushing with IR NA and Niaspan® in clinical trials32–34 adapted 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.

 
Most flushing episodes are mild or moderate in severity and infrequently led to discontinuation of study treatment in clinical trials. For example, 4% of patients receiving Niaspan at doses up to 3000 mg/day withdrew for treatment-related flushing in a randomized 4-month trial³² (the recommended maximal dose for therapeutic use is 2000 mg/day).³⁵ The randomized, double-blind Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 trial evaluated Niaspan vs. placebo, each in addition to pre-existing therapy with a statin, for a treatment period of 1 year.³⁶ The protocol for ARBITER 2 included follow-up of adherence to therapy by tablet, counting at 90-day intervals by a clinical pharmacist blinded to study treatment. This analysis demonstrated an adherence to therapy between 90.3 and 94.5%, with no significant difference between patients randomized to Niaspan and placebo.

Maintaining adherence to therapy is crucial for maximizing the therapeutic benefit from any treatment, and physicians have an important role to play in optimizing the therapeutic response to a NA-based therapy, such as Niaspan. The following are proved and effective ways to minimize the incidence and impact of flushing with Niaspan:

1. Niaspan should be taken at bedtime, with a low-fat snack.
   
2. Titrate the dosage slowly and limit the dose to 1000 mg if necessary, as the maximum lipid benefit with Niaspan therapy may take 12–18 months to become apparent.
   
3. Encourage patients to avoid spicy foods or hot or alcoholic beverages near the time of Niaspan administration.
   
4. Analgesic doses of aspirin (not enteric-coated tablets) taken before taking Niaspan can minimize flushing.
   

	Myth 4: the clinical evidence base for combination therapy including NA or Niaspan is insufficient

Top Abstract Introduction Myth 1: 'statins are... Myth 2: 'diabetic patients... Myth 3: flushing renders... Myth 4: the clinical... Conclusions References

 
Well-designed intervention trials have evaluated combination regimens involving a cholesterol-lowering agent and IR NA or Niaspan. These are reviewed in detail elsewhere³⁷ and are summarized in Table 1. The HDL-Atherosclerosis Treatment Study (HATS)³⁸ and the Familial Atherosclerosis Treatment Study (FATS)³⁹ were randomized, controlled evaluations of IR NA plus a lipid-lowering agent (a statin and a bile acid sequestrant, respectively). ARBITER 2 and ARBITER 3 evaluated Niaspan. The design of ARBITER 2 is described earlier; ARBITER 3 was an open-label extension to ARBITER 2 in which patients originally randomized to Niaspan continued this therapy, and patients originally randomized to placebo switched to Niaspan.⁴⁰

View this table: [in this window] [in a new window]   Table 1 Outcome studies evaluating progression of atherosclerosis or clinical outcomes in patients receiving IR NA or Niaspan

 
NA or Niaspan markedly increased levels of HDL-cholesterol in every trial (Table 1). Levels of LDL-cholesterol were also markedly reduced in HATS and FATS because of the new application of lipid-lowering therapy. In ARBITER 2 and ARBITER 3, however, LDL-cholesterol was already well controlled to <2.6 mmol/L (100 mg/dL) at baseline by pre-existing statin therapy, and this parameter was little affected by the addition of Niaspan.

HATS and FATS each demonstrated regression of atherosclerosis in the coronary arteries of patients randomized to a combination of a lipid-lowering agent and IR NA. HATS also measured clinical outcomes and demonstrated a 90% reduction (P=0.03) in the risk of major coronary events (death, MI, stroke, or revascularization). This effect was attenuated by the addition of antioxidant vitamins to some extent (risk reduction 60%, P=0.02), which attenuated the beneficial effect of NA on the atheroprotective HDL2 subfraction of HDL-cholesterol. ARBITER 2, and its open-label follow-up study, ARBITER 3, demonstrated conclusively that Niaspan shares the anti-atherogenic benefits of IR NA. Niaspan is currently being evaluated in a randomized trial measuring clinical outcomes (the AIM-HIGH study).

	Conclusions

Top Abstract Introduction Myth 1: 'statins are... Myth 2: 'diabetic patients... Myth 3: flushing renders... Myth 4: the clinical... Conclusions References

 
The success of the statins has proved that we can reduce significantly the incidence of morbid cardiovascular events. The potential for further improvements in outcomes by further reduction of LDL-cholesterol with these agents appears questionable, however. As we move beyond the statin era, the importance of other cardiovascular risk factors, including low HDL-cholesterol, is increasingly realized. NA is the most effective means of correcting low HDL-cholesterol available, and the introduction of a prolonged release formulation of this agent, Niaspan, facilitates the delivery of this treatment in a formulation that is as effective as the IR formulation, but is associated with fewer episodes of flushing and very low potential for exacerbation of dysglycaemia. Moreover, a randomized trial has shown that Niaspan shares the antiatherogenic benefits of IR NA that have been shown to underlie significant improvements in clinical outcomes when combined with a statin. Niaspan–statin combination therapy is a rational and effective strategy that addresses the atherogenic dyslipidaemia phenotype commonly found in the large population of patients with insulin resistance syndromes, such as the metabolic syndrome or type 2 diabetes.

Conflict of interest: C.A.R. is a member of the speaker's bureau of KOS and Merck (Germany) Pharmaceutical Companies.

	References

Top Abstract Introduction Myth 1: 'statins are... Myth 2: 'diabetic patients... Myth 3: flushing renders... Myth 4: the clinical... Conclusions References

 

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