Niaspan®: a powerful treatment option for ‘diabetic dyslipidaemia’
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
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Abstract |
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 Top Abstract IntroductionRising tide of insulin...Low HDL-cholesterol and clinical...Clinical benefits of HDL...Optimizing the use of...ConclusionsReferences |
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Low HDL-cholesterol is a common feature of the dyslipidaemia commonly encountered in patients with type 2 diabetes or the metabolic syndrome. Nicotinic acid, the most effective agent available for increasing levels of HDL-cholesterol, has been shown to improve cardiovascular outcomes in major outcome trials. These benefits are observed in patients with or without diabetes, and the magnitude of the outcome benefit was unaffected by changes in glycaemia during treatment. Niaspan® is a new prolonged-release formulation of nicotinic acid with equivalent efficacy and superior tolerability compared with the older, immediate-release formulation. Well-designed trials and retrospective analyses have shown that Niaspan, given alone or with a statin, improves HDL-cholesterol and other lipid components in patients with diabetes or the metabolic syndrome, resulting in a less atherogenic lipid profile. The changes in glycaemia during treatment with Niaspan are minimal and can be easily corrected by adjustments to antidiabetic medications. Niaspan provides a potent and practical means of correcting low HDL-cholesterol in patients with dysglycaemia.
Key Words: Type 2 diabetes • Dyslipidaemia • HDL-cholesterol • Nicotinic acid • Niacin • Metabolic syndrome
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Introduction |
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TopAbstractIntroductionRising tide of insulin...Low HDL-cholesterol and clinical...Clinical benefits of HDL...Optimizing the use of...ConclusionsReferences |
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Cardiovascular events are the most common cause of death in patients with type 2 diabetes, and controlling cardiovascular risk in this population is therefore an urgent clinical priority. Correcting dyslipidaemia is an important part of intervention programmes targeting cardiovascular risk factors in the type 2 diabetic population, as in non-diabetic subjects. However, the pattern of lipoprotein abnormalities commonly found in insulin-resistant or type 2 diabetic patients often differs in important respects from the typical lipid profile of non-diabetic, dyslipidaemic patients. Low HDL-cholesterol, in particular, is an important determinant of cardiovascular outcomes in patients with type 2 diabetes or the metabolic (insulin resistance) syndrome.
Nicotinic acid (niacin) is the most effective treatment available for correcting low HDL-cholesterol, although tolerability issues and concerns over exacerbation of hyperglycaemia have limited its use to date in diabetic patients. Niaspan, a novel, prolonged-release formulation of nicotinic acid, delivers equivalent efficacy to standard, immediate-release nicotinic acid preparations, with a superior tolerability profile and has been studied extensively in patients with type 2 diabetes.1,2 This review summarizes the aetiology of dyslipidaemia in the setting of insulin resistance or type 2 diabetes, and evaluates the evidence base for the use of nicotinic acid in type 2 diabetic patients at risk of cardiovascular disease.
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Rising tide of insulin resistance and dyslipidaemia |
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TopAbstractIntroductionRising tide of insulin...Low HDL-cholesterol and clinical...Clinical benefits of HDL...Optimizing the use of...ConclusionsReferences |
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Characteristics of dyslipidaemia in insulin resistance
Dyslipidaemia in patients with type 2 diabetes is characterized by the appearance low HDL-cholesterol and elevated triglycerides (Figure 1).3 In contrast to the dyslipidaemia commonly encountered in non-diabetic subjects, total cholesterol and LDL-cholesterol are often not markedly elevated, although a shift towards small, dense, LDL-cholesterol particles is often observed.4 This lipid profile is believed to be highly atherogenic and probably accounts for a substantial proportion of the excess cardiovascular risk evident in the type 2 diabetic population.
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The term ‘diabetic dyslipidaemia’, often used to describe these lipid abnormalities, is to some extent a misnomer. The appearance of low HDL-cholesterol and elevated triglycerides is driven by insulin resistance,5 and all are key elements of the cluster of cardiovascular risk factors known as the metabolic syndrome, as defined both in the USA and in Europe.6 The presence of the metabolic syndrome itself confers a roughly two to four-fold increase in risk of coronary heart disease in diabetic or non-diabetic subjects.7,8 Therapeutic interventions for diabetic or non-diabetic patients must therefore address specifically the spectrum of changes to the lipid profile in insulin-resistant individuals, if effective reductions in cardiovascular risk are to be achieved in these patients.
Rising tide of obesity, insulin resistance, dyslipidaemia, and type 2 diabetes
An increasing tendency to sedentary lifestyles and energy-rich diets is leading to an epidemic of obesity, insulin resistance, and type 2 diabetes. For example, type 2 diabetes, once a disease of middle age, and its precursor, the metabolic syndrome, are appearing in ever-younger patients. A recent study surveyed the incidence of cardiovascular risk factors in 390 children or adolescents, who were non-obese, overweight, moderately obese, or severely obese, on the basis of a Z-score derived from their body mass index.9 Figure 2 shows the levels of insulin resistance, HDL-cholesterol, triglycerides, LDL-cholesterol, and systolic blood pressure in each group. Insulin resistance, triglycerides, and blood pressure increased, and HDL-cholesterol decreased, in parallel with the severity of obesity. Interestingly, LDL-cholesterol did not change with obesity, consistent with a metabolic phenotype dominated by insulin resistance, as described previously.
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It is not surprising that the prevalence of the metabolic syndrome is increasing in western populations. The current age-adjusted prevalence figure for the USA, based on data from the third National Health and Nutrition examination survey (NHANES III), is 23% for women and 24% for men.10 However, this conceals important differences in prevalence in subgroups of the population (for example, 32% of Mexican-Americans have the metabolic syndrome), and prevalence increases steeply with age to >40% of subjects aged >60. In addition, the metabolic syndrome is commonly found in patients with coronary heart disease, with a prevalence inversely correlated with age.11 Abdominal adiposity may provide the causal link between obesity and the metabolic syndrome. Abdominal fat is a highly active endocrine organ and secretes a number of metabolically active molecules, including free fatty acids, tumour necrosis factor-alpha (TNF
), C-reactive protein, leptin, resistin, plasminogen activator inhibitor-1 (PAI-1), and angiotensinogen, whereas subcutaneous fat is relatively inert.12,13 Consistent with these observations, a recent study has shown that surgical removal of subcutaneous fat by liposuction does not reduce cardiovascular risk.14 |
Low HDL-cholesterol and clinical outcomes in insulin-resistant populations |
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TopAbstractIntroductionRising tide of insulin...Low HDL-cholesterol and clinical...Clinical benefits of HDL...Optimizing the use of...ConclusionsReferences |
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The Framingham study15 and other large epidemiological analyses16–19 have consistently demonstrated significant associations between low HDL-cholesterol and adverse cardiovascular prognosis in general populations. According to Framingham, reducing HDL-cholesterol from 1.3 mmol/L (50 mg/dL) to 0.8 mmol/L (30 mg/dL) in men or from 1.4 mmol/L (55 mg/dL) to 1.0 mmol/L (40 mg/dL) in women would increase the risk of a cardiovascular event by 80–100%.20 An increasing body of epidemiological evidence links HDL-cholesterol to adverse clinical outcomes, specifically in individuals who are likely to be insulin resistant, through the presence of type 2 diabetes or the metabolic syndrome. For example, significant associations were found between low HDL-cholesterol or elevated triglyceride content of LDL in the setting of hypertriglyceridaemia and the subsequent development of cardiovascular disease (P=0.005 and P=0.004, respectively) in a cohort of 133 newly diagnosed diabetic patients followed for 15 years.3 In contrast, levels of neither total cholesterol nor LDL-cholesterol significantly predicted the onset of cardiovascular disease in this cohort.
A similar relationship between low HDL-cholesterol and adverse outcomes exists for the metabolic syndrome. NHANES III explored retrospectively the association between individual cardiovascular risk factors and clinical outcomes in 15 922 subjects with the metabolic syndrome.21 When compared with patients without a history of cardiovascular events, patients with prior myocardial infarction or stroke were more likely to have low HDL-C (50 vs. 36%, P<0.001) or elevated triglycerides (54 vs. 29%, P<0.0001). These data clearly identify low HDL-cholesterol as an important target for therapy in these populations.
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Clinical benefits of HDL-cholesterol raising in insulin-resistant populations |
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TopAbstractIntroductionRising tide of insulin...Low HDL-cholesterol and clinical...Clinical benefits of HDL...Optimizing the use of...ConclusionsReferences |
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Pharmacological treatments for raising HDL-cholesterol
Intervention trials in substantial populations of patients with type 2 diabetes or the metabolic syndrome have evaluated the potential of raising HDL-cholesterol for improving cardiovascular outcomes. Two classes of drugs are noted for their ability to increase HDL-cholesterol: fibrates (gemfibrozil and fenofibrate) and nicotinic acid. In general, nicotinic acid increased HDL-cholesterol by
10–30%,22 whereas fibrates increase this parameter by roughly 10–15%.23 The principal intervention trials evaluating these treatments are described subsequently.
Fibrates
The Veterans Affairs HDL Intervention Trial (VA-HIT) was a randomized, double-blind, placebo-controlled, parallel-group comparison of the fibrate, gemfibrozil (1200 mg/day), or placebo in men with isolated low HDL-cholesterol [<1.0 mmol/L (<40 mg/dL)] and a history of coronary heart disease (myocardial infarction, angina with evidence of myocardial ischaemia, coronary revascularization, or angiographic evidence of >50% stenosis of at least one major epicardial coronary artery).24 The mean duration of follow-up was 5.1 years, and the primary endpoint was the combined incidence of non-fatal myocardial infarction and death from coronary heart disease.
A total of 2531 patients were randomized, of whom 25% already had a diagnosis of diabetes at baseline, though a further 6% were found to have undiagnosed diabetes based on their fasting plasma glucose at entry to the study.25 Mean HDL-cholesterol at baseline was 31 mg/dL in the diabetic subgroup and increased by 5% during treatment, whereas triglycerides decreased by 20% from a baseline value of 1.9 mmol/L (164 mg/dL), and LDL-cholesterol was unaffected.25 These changes in lipids were accompanied by marked improvements in clinical outcomes (Figure 3A). Reductions in the risk of a combined endpoint of non-fatal myocardial infarction plus death from coronary heart disease (by 32%), and death from coronary heart disease (by 41%), achieved statistical significance relative to placebo, whereas the corresponding reductions in the non-diabetic group did not. The magnitude of the benefit with gemfibrozil was greater in patients with more severe insulin resistance, as indicated by the severity of fasting hyperinsulinaemia (Figure 3B). The relative risk vs. placebo of the combined endpoint of major cardiovascular events for patients in the highest quartile of fasting plasma insulin indicated a statistically significant protective effect in favour of gemfibrozil [hazard ratio 0.65 (95% CI 0.43–0.97), P=0.04].
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Nicotinic acid
Three intervention trials, the Coronary Drug Project (CDP),26 the HDL-Atherosclerosis Treatment Study,27 and the Stockholm Ischaemic Heart Disease Study,28 have evaluated the efficacy of nicotinic acid, alone and in combination, in patients with a history of myocardial infarction. The CDP was the largest of these trials and provided the most substantial data from dysglycaemic patients, and only this trial will be discussed here.
The CDP was a double-blind, placebo-controlled evaluation of five regimens (nicotinic acid, clofibrate, d-thyroxine, and oestrogens given at two dosage levels) in a total of 8341 men. The oestrogen and thyroxine arms were terminated early, due to adverse events, and no evidence of efficacy was found for the prototype fibrate, clofibrate, and this description will focus on the effects of nicotinic acid. The primary endpoint was total mortality, with secondary endpoints of the incidence of coronary events or stroke/transient ischaemic attacks. The duration of double-blind follow-up was 6.2 years, though a retrospective analysis of these data has been conducted after a total of 15 years post-baseline.29
Treatment with nicotinic acid was associated with significant (P<0.05) risk reductions in the incidence of the combined endpoint of non-fatal myocardial infarction or death from coronary heart disease (risk reduction –14%) and the single endpoints of non-fatal myocardial infarction (–27%), stroke or transient ischaemic attack (–26%), or cardiovascular surgery (–41%) at the end of double-blind treatment.26 Total mortality was little affected (24.4% on nicotinic acid vs. 25.4% on placebo) after the initial 6.2 years of follow-up. However, after a further 9 years of follow-up after the close of the trial (15 years in all), significant reductions in the risk of adverse outcomes in the group originally randomized to nicotinic acid were observed for total mortality (risk reduction –11%, P=0.0004) and coronary mortality (–12%, P<0.01).29
Importantly, the magnitude of the benefit was similar for patients with fasting blood glucose above and below the current American Diabetes Association (ADA) cut-off point for the diagnosis of impaired fasting glucose, 5.6 mmol/L (100 mg/dL),30 with risk reductions of –9% (P<0.05) and –12% (P<0.005), respectively. Moreover, clinical benefits were observed irrespective of changes in fasting blood glucose during the study. A recent re-analysis of these data has shown that risk reductions for non-fatal myocardial infarction or total mortality were similar after 15 years of follow-up across a broader range of blood glucose values that also encompassed the ADA diagnostic cut-off value for type 2 diabetes of 7.0 mmol/L (126 mg/dL) (Figure 4).31,33 Although the differences between groups no longer achieved statistical significance after subdividing the patient population in these analyses, these data clearly indicate that the benefits of HDL-cholesterol raising were preserved irrespective of glycaemia at baseline.
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Finally, the CDP database has been explored retrospectively to determine the influence of the metabolic syndrome on the efficacy of nicotinic acid.32,33 There were no significant differences between patients with and without the metabolic syndrome (n=563 and n=3343, respectively) in the incidence of non-fatal myocardial infarction at 6 years (relative hazards 0.75 and 0.70, respectively, Z-test for homogeneity is 0.07) or total mortality at 15 years (relative hazards 0.91 and 0.83, respectively, Z-test for homogeneity is 0.64).
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Optimizing the use of nicotinic acid with Niaspan in patients with dysglycaemia |
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TopAbstractIntroductionRising tide of insulin...Low HDL-cholesterol and clinical...Clinical benefits of HDL...Optimizing the use of...ConclusionsReferences |
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Effects on the lipid profile in patients with type 2 diabetes
Well-designed clinical trials have evaluated the effects of Niaspan on the lipid profile in patients with type 2 diabetes. The randomized, double-blind Assessment of Diabetes Control and EValuation of the Efficacy of Niaspan Trial (ADVENT) compared the effects of 16 weeks of treatment with Niaspan at doses of 1000 or 1500 mg, with placebo in 148 patients with stable type 2 diabetes [fasting blood glucose
11.1 mmol/L (200 mg/dL) and HbA1C 9%].34 The inclusion criteria relating to lipid profiles were as follows. Patients receiving a statin were required to have LDL-C 
3.4 mmol/L (130 mg/dL), HDL-C 1.0 mmol/L (40 mg/dL), or triglycerides 2.2 mmol/L (200 mg/dL). Patients not receiving a statin were required to have LDL-C 3.4 mmol/L (130 mg/dL), as they may have received placebo, together with HDL-C 1.0 mmol/L (40 mg/dL), or triglycerides 2.2 mmol/L (200 mg/dL). Lipid values at baseline for the overall patient population were HDL-C 1.1 mmol/L (41 mg/dL), LDL-C 2.7 mmol/L (103 mg/dL), and triglycerides 3.0 mmol/L (268 mg/dL). The effects of Niaspan on the lipid profile are shown in Figure 5. Treatment with Niaspan markedly, significantly, and dose-dependently increased HDL-cholesterol and reduced triglycerides and LDL-cholesterol, with changes from baseline for one or both doses achieving statistical significance vs. placebo by 16 weeks of treatment.
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About half of the patients in ADVENT (47%) were also treated with a statin, suggesting that Niaspan adds additional efficacy to statin treatment, as found previously in a mainly non-diabetic patient population.35 This has been confirmed in a double-blind, randomized evaluation of Niaspan combined with lovastatin.36 Patients had type 2 diabetes and diabetic dyslipidaemia characterized by HDL-C
1.0 mmol/L (40 mg/dL) (men) or 1.3 mmol/L (50 mg/dL) (women) and triglycerides 1.7 mmol/L (150 mg/dL). In addition, all patients were receiving a stable dose of metformin and/or a thiazolidinedione. Patients were randomized to Niaspan 1000 mg+lovastatin 40 mg, Niaspan 1500 mg+lovastatin 40 mg, or fenofibrate 200 mg, given once daily in the evening. The primary efficacy and safety endpoints were the per cent changes in HDL-cholesterol and HbA1C following 20 weeks of double-blind treatment. The patient population had a lipid profile consistent with diabetic dyslipidaemia, consistent with the inclusion criteria: at baseline, mean HDL-cholesterol was 0.9 mmol/L (34 mg/dL), mean LDL-cholesterol was 3.3 mmol/L (126 mg/dL), and mean triglyceride was 3.2 mmol/L (281 mg/dL). Niaspan 1500 mg combined with lovastatin 40 mg increased HDL-cholesterol significantly (P<0.05) vs. fenofibrate at week 20 (Figure 6). In addition, both dosage strengths of the Niaspan-based combination significantly (P<0.05) reduced LDL-cholesterol, non-HDL-cholesterol, and the atherogenic lipoprotein, Lp(a), compared with fenofibrate (Figure 6).
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Lipid subprofiles
The effects of Niaspan on lipid subprofiles were evaluated retrospectively in 53 patients from a diabetes research clinic in a major city in the USA, in whom Niaspan therapy was titrated over a period of 1–4 months.37 Patients received Niaspan alone or Niaspan combined with atorvastatin, and lipids were analysed following at least 6 weeks of stable dosing. HDL-cholesterol subprofiles were measured in patients in whom HDL2-cholesterol amounted to <40% of total HDL-cholesterol, and LDL-cholesterol subprofiles were measured in patients with peak LDL-cholesterol particle diameter
263 A°. Niaspan, both with and without atorvastatin, markedly increased total HDL-cholesterol in this analysis, from 1.0 mmol/L (38 mg/dL) to 1.4 mmol/L (54 mg/dL) in each case (P<0.0001 for each), whereas atorvastatin alone was without significant effect. The proportion of HDL-cholesterol accounted for by the atheroprotective HDL2-cholesterol increased significantly in all groups, from 29 to 43% for Niaspan alone (P<0.0001), from 32 to 47% for Niaspan combined with atorvastatin (P<0.001), and from 30 to 42% for atorvastatin alone (P<0.001). The effects of the Niaspan-based combination were significantly greater compared with atorvastatin alone both for total HDL-cholesterol (P<0.001) and for the proportion of HDL2-cholesterol (P<0.04). The mean peak particle diameter of LDL-cholesterol also increased significantly in all groups, from 253 to 263 A° for Niaspan alone (P<0.0001), from 250 to 263 A° for Niaspan combined with atorvastatin (P<0.0001), and from 251 to 256 A° for atorvastatin alone (P<0.007). Effects on LDL-cholesterol particle size were significantly greater in either Niaspan group when compared with atorvastatin alone (P<0.05).
Overall, Niaspan induced a shift away from small, dense lipoprotein particles towards larger, more buoyant particles. These changes are consistent with a reduction in the atherogenicity of the lipid profile overall.
Efficacy of Niaspan in the metabolic syndrome
A retrospective analysis of data from patients enrolled in a long-term evaluation of a combination tablet containing Niaspan and lovastatin has been used to evaluate the effects of Niaspan-based treatment on lipid profiles in patients with the metabolic syndrome.38 Patients initially received open-label Niaspan 500 mg combined with lovastatin 10 mg, and these dosages were titrated towards a target final dose of Niaspan 2000 mg plus lovastatin 40 mg. The metabolic syndrome was defined using National Cholesterol Education Program/Adult Treatment Panel III criteria,39 except that body mass index 30 was substituted for the original requirement in this definition based on waist circumference (>102 cm in men and >88 cm in women).
A total of 757 patients were included in the analysis, of whom all but one were stratified for the presence or absence of the metabolic syndrome (n=347 and n=409, respectively). On average, patients with the metabolic syndrome had lower mean HDL-C [1.1 mmol/L (44 mg/dL) vs. 1.3 mmol/L (52 mg/dL)] and higher triglycerides [2.3 mmol/L (210 mg/dL) vs. 1.6 mmol/L (140 mg/dL)], as would be expected. Marked changes from baseline were seen in patients with and without the metabolic syndrome for HDL-C (+36 vs. +32%, respectively) and triglycerides (–47 and –32%, respectively). Lp(a) was also improved in both groups (–22 and –26%, respectively).
Niaspan and glycaemia
Changes in HbA1C and fasting plasma glucose in the ADVENT study during treatment with Niaspan at doses of up to 1500 mg for 16 weeks were minor (Figure 7A).34 Similarly, changes in HbA1C during combined treatment with Niaspan plus lovastatin in the 20 week study described previously were minimal (Figure 7B).36
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Conclusions |
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TopAbstractIntroductionRising tide of insulin...Low HDL-cholesterol and clinical...Clinical benefits of HDL...Optimizing the use of...ConclusionsReferences |
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Low HDL-cholesterol is a common finding in patients with type 2 diabetes or the metabolic syndrome. The associations between low HDL-cholesterol and adverse cardiovascular outcomes and the potential of nicotinic acid to reduce the risk of cardiovascular events in high-risk patients are proved beyond doubt. Niaspan is as efficacious as standard, immediate-release nicotinic acid in improving HDL-cholesterol and other lipid components. The superior tolerability profile of Niaspan, together with minimal effects on glycaemia, identify this treatment as an effective and practical therapeutic option for the management of low HDL-cholesterol.
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References |
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TopAbstractIntroductionRising tide of insulin...Low HDL-cholesterol and clinical...Clinical benefits of HDL...Optimizing the use of...ConclusionsReferences |
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- Guyton JR. Extended-release niacin for modifying the lipoprotein profile. Expert Opin Pharmacother 2004;5:1385–1398.[CrossRef][ISI][Medline]
- McGovern ME. Use of nicotinic acid in patients with elevated fasting glucose, diabetes, or metabolic syndrome. Br J Diabetes Vasc Dis 2004;4:78–85.
- Niskanen L, Turpeinen A, Penttila I et al. Hyperglycemia and compositional lipoprotein abnormalities as predictors of cardiovascular mortality in type 2 diabetes: a 15-year follow-up from the time of diagnosis. Diabetes Care 1998;21:1861–1869.[Abstract]
- Krauss RM. Lipids and lipoproteins in patients with type 2 diabetes. Diabetes Care 2004;27:1496–1504.
[Abstract/Free Full Text] - Watson KE, Horowitz BN, Matson G. Lipid abnormalities in insulin resistant states. Rev Cardiovasc Med 2003;4:228–236.[Medline]
- Eschwege E. The dysmetabolic syndrome, insulin resistance and increased cardiovascular (CV) morbidity and mortality in type 2 diabetes: aetiological factors in the development of CV complications. Diabetes Metab 2003;29:6S19–6S27.[Medline]
- Isomaa B, Almgren P, Tuomi T et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24:683–689.
[Abstract/Free Full Text] - Lakka HM, Laaksonen DE, Lakka TA et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709–2716.
[Abstract/Free Full Text] - Weiss R, Dziura J, Burgert TS et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 2004;350:2362–2374.
[Abstract/Free Full Text] - Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287:356–359.
[Abstract/Free Full Text] - Milani RV, Lavie CJ. Prevalence and profile of metabolic syndrome in patients following acute coronary events and effects of therapeutic lifestyle change with cardiac rehabilitation. Am J Cardiol 2003;92:50–54.[ISI][Medline]
- Grundy SM. What is the contribution of obesity to the metabolic syndrome? Endocrinol Metab Clin North Am 2004;33:267–282.[CrossRef][ISI][Medline]
- Devaraj S, Rosenson RS, Jialal I. Metabolic syndrome: an appraisal of the pro-inflammatory and procoagulant status. Endocrinol Metab Clin North Am 2004;33:431–453.[CrossRef][ISI][Medline]
- Klein S, Fontana L, Young VL et al. Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. N Engl J Med 2004;350:2549–2557.
[Abstract/Free Full Text] - Gordon T, Castelli WP, Hjortland MC et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977;62:707–714.[CrossRef][ISI][Medline]
- Castelli WP, Doyle JT, Gordon T et al. HDL cholesterol and other lipids in coronary heart disease. The cooperative lipoprotein phenotyping study. Circulation 1977;55:767–772.
[Abstract/Free Full Text] - Assmann G, Cullen P, Schulte H. Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Munster (PROCAM) study. Circulation 2002;105:310–315.
[Abstract/Free Full Text] - Hanefeld M, Koehler C, Schaper F et al. Postprandial plasma glucose is an independent risk factor for increased carotid intima-media thickness in non-diabetic individuals. Atherosclerosis 1999;144:229–235.[CrossRef][ISI][Medline]
- Gordon DJ, Probstfield JL, Garrison RJ et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989;79:8–15.
[Abstract/Free Full Text] - Castelli WP. Cardiovascular disease and multifactorial risk: challenge of the 1980s. Am Heart J 1983;106:1191–1200.[CrossRef][ISI][Medline]
- Ninomiya JK, L'Italien G, Criqui MH et al. Association of the metabolic syndrome with history of myocardial infarction and stroke in the third national health and nutrition examination survey. Circulation 2004;109:42–46.
[Abstract/Free Full Text] - Meyers CD. Management of the metabolic syndrome—nicotinic acid. Endocrinol Metab Clin North Am 2004;33:557–575.[CrossRef][ISI][Medline]
- Steiner G. Fibrates in the metabolic syndrome and in diabetes. Endocrinol Metab Clin North Am 2004;33:545–555.[CrossRef][ISI][Medline]
- Rubins HB, Robins SJ, Collins D et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410–418.
[Abstract/Free Full Text] - Rubins HB, Robins SJ, Collins D et al. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT). Arch Intern Med 2002;162:2597–2604.
[Abstract/Free Full Text] - The Coronary Drug Project Research Group. Clofibrate and nicotinic acid in coronary heart disease. JAMA 1975;231:360–381.[CrossRef][ISI][Medline]
- 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;345:1583–1592.
[Abstract/Free Full Text] - Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand 1988;223:405–418.[ISI][Medline]
- Canner PL, Berge KG, Wenger NK et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245–1255.[Abstract]
- American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2004;27(Suppl. 1):S15–S35.
- Canner PL, Furberg CD, McGovern ME. Niacin decreases myocardial infarction and total mortality in patients with impaired fasting glucose or glucose intolerance: results from the Coronary Drug Project. Circulation 2002;106(Suppl. II):II–636.
- Canner PL, Furberg CD, Terrin ML et al. Niacin decreases total mortality and myocardial infarction in patients with metabolic syndrome: results from the Coronary Drug Project. (Abstract). J Am Coll Cardiol 2003;41(Suppl. A):291A.
- Canner PL, Furberg CD, Terrin ML et al. Benefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project). Am J Cardiol 2005;95:254–257.[CrossRef][ISI][Medline]
- Grundy SM, Vega GL, McGovern ME et al.; Diabetes Multicenter Research Group. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial. Arch Intern Med 2002;162:1568–1576.
[Abstract/Free Full Text] - Wolfe ML, Vartanian SF, Ross JL et al. Safety and effectiveness of Niaspan when added sequentially to a statin for treatment of dyslipidemia. Am J Cardiol 2001;87:476–479.[CrossRef][ISI][Medline]
- Grundy SM, Vega GL, McGovern ME. Comparative effects on lipids and glycemic control of niacin extended-release/lovastatin or fenofibrate in patients with diabetic dyslipidemia. (Abstract 29-LB). Presented at the 64th Scientific Sessions of the American diabetes Association, 4–8 June 2004, Orlando, Florida, USA.
- Van JT, Pan J, Wasty T et al. Comparison of extended-release niacin and atorvastatin monotherapies and combination treatment of the atherogenic lipid profile in diabetes mellitus. Am J Cardiol 2002;89:1306–1308.[CrossRef][ISI][Medline]
- McGovern ME, Malott CM, Simmons PD et al. Once-daily niacin-extended-release/lovastatin combination is effective and safe for treatment of dyslipidaemia associated with metabolic syndrome. (Abstract 820–5). Scientific session of the American College of Cardiology, 2004.
- Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486–2497.
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