(1) Can niacin slow the development of atherosclerosis in coronary artery disease patients already taking statins? Brown, B. Greg. Medicine and Cardiology, University of Washington School of Medicine, Seattle, WA, USA. Nature Clinical Practice Cardiovascular Medicine (2005), 2(5), 234-235.

Abstract

A review. Background: Low HDL-cholesterol concns. can be successfully raised by niacin. A low HDL-cholesterol level is recognized as a coronary risk factor and increases the risk of unfavorable events related to coronary atherosclerosis. Unlike for LDL cholesterol, the National Cholesterol Education Program guidelines do not provide- target levels for HDL-cholesterol concn. Few studies have investigated the effect of niacin on coronary events, alone or in combination with statin therapy. Objectives: To explore the effect of niacin on carotid intima-media thickness (CIMT), and to find out whether extended-release niacin therapy provides added cardiovascular protection to patients receiving statin monotherapy for coronary artery disease. Design: The Arterial Biol. for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 trial was a US-based, randomized, placebo-controlled; double-blind study carried out from Dec. 2001 to May 2003. Patients aged over 30 years old were eligible for the study if they had coronary vascular disease, were receiving statin therapy and had HDL-cholesterol levels below 1.7 mM/l (45 mg/dL) and LDL-cholesterol levels under 3.4 mM/l (130 mg/dL). Men and women were excluded if their liver-assocd. enzyme levels were 3 times the upper normal limit, if they had previous liver disease or were intolerant to niacin. Intervention: Eligible patients were randomly assigned 500 mg extended-release niacin (Niaspan, Kos Pharmaceuticals) daily or placebo, both to be taken at night. After 30 days, niacin dose was raised to 1000 mg daily and maintained at this dose for 1 yr. Each patient’s CIMT was assessed by linear-array 8 MHz probe ultrasonog. at baseline and at 1 yr. Anal. of CIMT images was masked. Outcome measures: The main endpoint was change in CIMT over 1 yr. An increase in liver-assocd.
enzymes, changes in serum lipid levels and admission to hospital for stroke, arterial revascularization, acute coronary syndrome or sudden cardiac death, among others, were some of the secondary endpoints. Results: Of the 167 patients on baseline statin treatment, 87 patients were assigned addnl. niacin therapy and 80 were assigned placebo. In total, 149 patients (89.2%) were reassessed at 1 yr (study end). Treatment with statin and niacin significantly increased HDL-cholesterol levels by 21%, from 1.00.2 mM/l (397 mg/dL) to 1.20.4 mM/l (47 16 mg/dL), when compared with statin and placebo (P=0.002). Although not significant, patients treated with statin and placebo had a higher av. increase in CIMT than the statin and niacin-treated patients (0.0440.100 mm vs 0.0140.104 mm, P=0.08). Importantly, the rise in av. CIMT was significant for statin and placebo-treated patients but not for patients receiving niacin (0.0440.100 mm, P<0.001 and 0.0140.104 mm, P = 0.23, resp.). Conclusion: Extended-release niacin slowed the development of atherosclerosis in adults with coronary artery disease, independently from statin therapy. (2) Maximizing coronary disease risk reduction using nicotinic acid combined with LDL-lowering therapy. Brown, B. Greg. Division of Cardiology, University of Washington, Seattle, WA, USA. European Heart Journal Supplements (2005), 7(Suppl. F), F34-F40. Abstract A review. Treatment with statins markedly reduces levels of LDL-cholesterol, and large, well-designed evaluations of these agents have demonstrated redns. in cardiovascular event rates of .apprx.20-40%. Addnl. therapeutic strategies will be required to make further inroads into the substantial residual burden of cardiovascular disease in statin-treated patients. Epidemiol. studies over several decades and outcome studies with agents that raise levels of this lipoprotein (nicotinic acid or fibrates) have established low HDL-cholesterol as an important therapeutic target. Combining agents which decrease LDL-cholesterol and increase HDL-cholesterol within a single regimen might provide a means of improving cardiovascular prognosis beyond that possible with statins alone. Six randomized clin. trials involving treatment with nicotinic acid in combination with a statins or bile acid sequestrant have demonstrated regression, or markedly slowed progression, of atherosclerosis in patients at high risk of a cardiovascular event. Three of these trials, the HDL-Atherosclerosis Treatment Study, the Familial Atherosclerosis Treatment Study, and the Armed Forces Regression Study, have assocd. these benefits with significant improvements in clin. outcomes. Correcting low HDL-cholesterol in statin-treated patients may provide a means to achieve the next leap forward in the management of cardiovascular disease. (3) Beyond LDL-cholesterol reduction: The way ahead in managing dyslipidaemia. Chapman, John. National Institute for Health and Medical Research, Paris, Fr. European Heart Journal Supplements (2005), 7(Suppl. F), F56-F62. Abstract A review. Observational cohort studies and anal. of the populations of intervention trials at baseline reveal a strong inverse assocn. between circulating levels of high-d. lipoprotein (HDL)-cholesterol at baseline and the risk of a fatal or non-fatal cardiovascular event. Intervention with a statin is as effective, in abs. terms, in reducing the risk of coronary events in patients across a wide range of dyslipidemic phenotypes, including those with low HDL-cholesterol. However, statins exert little effect on the levels of HDL-cholesterol, and treatment with a statin does not eliminate the excess risk assocd. with low HDL-cholesterol. Addnl. therapy is clearly required to address this residual risk. The success of clin. evaluations of agents that increase HDL-cholesterol, such as nicotinic acid or fibrate drugs, in reducing the incidence of cardiovascular events points to a way forward. Evidence from outcome studies already points to superior cardiovascular risk redns. in patients receiving a statin plus nicotinic acid, and intensive multi-drug regimens based on such combinations probably represent the way to achieve cardiovascular risk redns. greater than those possible with a statin alone. Accurate and well-validated assays for measuring HDL-cholesterol and more precise definition of optimal levels of HDL-cholesterol in patients with different levels of cardiovascular risk are required. These advances will facilitate the future drafting of guidelines that include correction of low HDL-cholesterol alongside redn. of low-d. lipoprotein cholesterol within clin. algorithms for reducing cardiovascular risk. (4) Modern intervention strategies for managing dyslipidaemia: the case for combination therapy. Drexel, Heinz. Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Academic Hospital, Feldkirch, Austria. British Journal of Diabetes & Vascular Disease (2005), 5(Suppl. 1), S17-S23. Abstract A review. A steady decline in cardiovascular mortality has occurred in recent decades, but a substantial burden of cardiovascular mortality remains. Intervention with statins, for example, has resulted in significant redns. in cardiovascular event rates in a broad range of patient populations, but these agents reduce cardiovascular event rates by only about 20-40%, despite profound redns. in low-d. lipoprotein cholesterol (LDL-C) in some trials. Low high-d. lipoprotein cholesterol (HDL-C) is a risk factor for adverse cardiovascular outcomes independent of levels of LDL-C. Well designed intervention trials have demonstrated marked improvements in cardiovascular outcomes with agents that raise levels of HDL-C. Combinations of statins with nicotinic acid, the most potent agent for increasing levels of HDL-C currently available, appear to be the most effective strategy for managing cardiovascular risk. Indeed, redns. in the risk of cardiovascular events of up to 90% relative to placebo with a nicotinic acid-statin combination were obsd. in the double-blind, randomized HDL Atherosclerosis Treatment Study (HATS). A once-daily, prolonged-release formulation of nicotinic acid, Niaspan is as effective as immediate-release nicotinic acid with superior tolerability and safety. A randomized, double-blind placebo-controlled evaluation of Niaspan added to a statin, the Arterial Biol. for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER 2) study, demonstrated significant inhibition of atherosclerosis in men with low HDL-C over only one year of treatment. Patients with low HDL-C are at elevated cardiovascular risk and combination treatment with nicotinic acid and a statin represents a rational and evidence-based treatment for this population. (5) Natural neuroprotectants after stroke. Maynard, Kenneth I. Aventis Pharmaceuticals, Inc., Bridgewater, NJ, USA. Science & Medicine (Narberth, PA, United States) (2002), 8(5), 258-267. Abstract A review. Brain ischemia triggers a cascade of cytotoxic events in cells deprived of blood flow, and this cascade rapidly spreads to neighboring tissues, expanding the zone of ischemic injury. Stroke research has attempted to find agents that can protect brain tissue after stroke by limiting the extent of injury and preserving “at-risk” cells, but to date no drugs have proved successful in clin. trials. With their varied mechanisms of action and lack of serious side effects, various natural and endogenous substances are being examd. for their neuroprotective effects, with encouraging results. Nicotinamide, a crucial nutrient and deriv. of niacin (vitamin B3), is one promising agent approaching clin. testing. (6) Extended release nicotinic acid – a novel oral agent for phosphate control. Sampathkumar, Krishnaswamy; Selvam, Manickam; Sooraj, Yesudas Santhakumari; Gowthaman, Sankaran; Ajeshkumar, Rajappan Nair Prabha. Department of Nephrology, Meenakshi Mission Hospital and Research Centre, Madurai, India. International Urology and Nephrology (2006), 38(1), 171-174. Abstract Hyperphosphatemia is common in hemodialysis patients. Recent animal studies show that nicotinamide inhibits the sodium dependent phosphate co-transport in the small intestine and thereby reduces serum phosphorus levels. Nicotinic acid which is the prodrug of nicotinamide is widely used as antihyperlipidemic agent. We examd. in a prospective study whether it reduces serum phosphorus levels in hemodialysis patients. Patients who were on maintenance hemodialysis were enrolled in to the study if their predialysis serum phosphorus was more than 6 mg/dL. During the pre-trial run in period of 1 wk all phosphate binders were stopped. A single dose of extended release nicotinic acid (375 mg) tablet was given with meal. Repeat measurements of serum calcium, phosphorus and alk. phosphatase were carried out after 8 wk. Then the drug was stopped in a subgroup of patients and serum phosphorus remeasured after 2 wk. There were 34 patients with varied etiol. spectrum of end stage renal disease. They were on hemodialysis for a mean period of 8.7 mo. Serum phosphorus levels changed significantly from a pre treatment level of 7.7  1.5 mg/dL to post treatment level of 5.6  1 mg/dL (p < 0.001). There was no significant variance across age groups, sex, disease categories and dialysis duration. The calcium level increased from 8.11.0 to 8.5  1.0 mg/dL (p < 0.015). The serum alk. phosphatase level decreased significantly from 107  66 IU/l to 82  46 IU/l (p < 0.001 ). There was a significant redn. of calcium phosphate product from 63.1 + 15.1 mg2 to 48.7  10.9 mg2/dL2 (p < 0.001). Oral nicotinic acid was well tolerated. Mild pruritus was encountered in 2 patients. Oral nicotinic acid may emerge as a safe, low cost yet powerful agent for phosphorus control in dialysis patients. (7) Anti-inflammatory effect is an important property of niacin on atherosclerosis beyond its lipid-altering effects. Yu, Bi-lian; Zhao, Shui-ping. Department of Cardiology, Middle Ren-Min Road, The Second Xiangya Hospital of Central South University, No. 139, Changsha, Hunan, Medical Hypotheses (2007), 69(1), 90-94. Abstract Summary: Niacin has been used for decades to lower the plasma concns. of cholesterol, free fatty acids, and triglycerides in humans, and in addn. it raises more than any other drug the levels of the protective high d. lipoprotein. These effects have been used to treat dyslipidemic states. Trials have shown that treatment with niacin reduces progression of atherosclerosis, and clin. events and mortality from coronary heart disease. The beneficial clin. efficacy of niacin appropriately emphasizes the prominent role of its lipid-altering effects; however, high expression of niacin receptor in a variety of immune cell types, lowering of inflammatory markers, and beneficial impact on adipokines expression could provide rational to the hypothesis that anti-inflammatory effect is also an important property of niacin on atherosclerosis beyond its lipid-altering effects.
(8) Raising HDL-cholesterol and lowering CHD risk: Does intervention work? Shepherd, James. Department of Vascular Biochemistry, Division of Cardiovascular and Medical Sciences, North Glasgow University Hospital Division, Glasgow, UK. European Heart Journal Supplements (2005), 7(Suppl. F), F15-F22.

Abstract

A review. Epidemiol. studies have assocd. low HDL-cholesterol with an increased risk of morbid coronary events. Accordingly, intervention to correct low HDL-cholesterol may be cardioprotective. A no. of randomized intervention studies have addressed this hypothesis using fibrates (the Veterans Affairs HDL Intervention trial, the Helsinki Heart Study, and the Bezafibrate Infarction Prevention trial), or nicotinic acid, alone [Coronary Drug Project (CDP)] or in combination [the HDL Atherosclerosis Treatment Study (HATS) and the Stockholm Ischemic Heart Disease study (IHD)]. These trials demonstrate conclusively that treatments to increase HDL-cholesterol deliver clin. significant improvements in prognosis. Of these trials, the largest improvement in outcomes occurred in the HATS trial, where the incidence of a combined coronary endpoint (coronary death, non-fatal myocardial infarction, confirmed stroke, or revascularization for worsening ischemia) was reduced by 60-90% in patients receiving treatment based on nicotinic acid combined with a statin. The benefits of nicotinic acid-based treatment appear to be durable, as significant outcome benefits were visible in the group of patients initially randomized to nicotinic acid in the CDP 15 years after randomization, i.e. 9 years after the end of double-blind treatment. The combination of nicotinic acid with a statin appears to be a rational, effective, and safe strategy for minimizing cardiovascular risk in patients with dyslipidemia.