Targeting mulitple dyslipidemias with fixed combinations – focus on extended release niacin and simvastatin

Dyslipidemia is a major risk factor in the initiation and progression of cardiovascular diseases such as atherosclerosis. Several pharmacological agents have been developed over the past 50 years which target various lipid components such as low density lipoprotein (LDL) cholesterol, triglyceride, and high density lipoprotein (HDL) cholesterol. Similar to other risk factors such as hypertension and diabetes mellitus, the management of dyslipidemia can be complicated and may require combination therapy for effective treatment. This review discusses the biochemical mechanisms of action and clinical uses for simvastatin (the most widely available and commercially prescribed statin) and niacin, and the combination of these agents in the management and treatment of dyslipidemia.     

Niacin for Stroke Prevention: Evidence and Rationale

Low levels of high‐density lipoprotein (HDL) cholesterol are associated with increased atherothrombotic events, including stroke. Niacin is a safe and effective means of raising HDL, yet its role in stroke prevention is not well characterized. The purpose of the study is to determine the role of niacin in stroke prevention. A search of the PUBMED database using the keywords niacin, stroke, atherosclerosis, and/or carotid artery was undertaken to identify studies for review. National guidelines from the American Heart Asssociation and National Cholesterol Education Program were reviewed. Treatment of low serum HDL (<40 mg/dL) is an identified goal of dyslipidemic therapy. Niacin is effective in raising HDL levels and reducing cardiovascular events in individuals with high vascular risk and can be used for treatment of stroke patients with low serum HDL. Niacin can be used safely in combination with statins, the first‐line dyslipidemic treatment for secondary stroke risk reduction, with increased efficacy. Studies are needed to better define the role for niacin in secondary stroke prevention. Treatment of stroke patients with extended‐release (ER) of niacin, alone or in combination with statins, should be considered in stroke patients with atherosclerotic mechanisms with low serum HDL‐C levels.     

An open-label comparison of the effects of simvastatin and niacin alone and combined on the lipid profile and lipoprotein (a) level in an Indian population with dyslipidemia

Abstract

Background:

Patients with dyslipidemia often require the use of >1 lipid-altering agent to achieve the target levels recommended by the National Cholesterol Education Program Adult Treatment Panel III.

Objective:

The aim of this study was to compare the effects of simvastatin and niacin alone and combined on the lipid profile and lipoprotein (a) (Lp[a]) level in an Indian population with dyslipidemia.

Methods:

This 12-week, open-label, nonrandomized study was conducted at the Departments of Pharmacology and Medicine, Government Medical College, Amritsar (Punjab), India. Patients aged 30 to 70 years with dyslipidemia were eligible. Patients were assigned to 1 of 3 treatment groups. Group 1 received simvastatin 20 mg/d for 12 weeks. Group 2 received niacin at doses of 375 mg/d for 1 week, 500 mg/d for 1 week, and 500 mg BID for 10 weeks. Group 3 received simvastatin 10 mg/d plus niacin (375 mg for 1 week and 500 mg for 11 weeks). The lipid profile (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], total cholesterol [TC], and triglycerides [TG]) and Lp(a) were measured before the start of therapy and at 6 and 12 weeks of treatment. Percentage changes from baseline were calculated. Adverse effects (AEs) were recorded at weeks 6 and 12 and through spontaneous reporting.

Results:

Ninety patients were enrolled (50 men, 40 women; 30 patients per treatment group). In group 1, the mean (SD) percentage decrease in LDL-C level at 12 weeks was 42.79% (16.29%) (P < 0.05), but no significant change was seen in group 2 or 3. The mean (SD) percentage increases in HDL-C level were 18.43% (13.28%) and 20.82% (17.57%) in groups 2 and 3, respectively (both, P < 0.05), but no significant change was seen in group 1. TC levels decreased by a mean (SD) of 32.97% (13.66%) in group 1 (P < 0.05), but no significant change was seen in group 2 or 3. TG and Lp(a) levels did not change significantly in any of the 3 treatment groups. Flushing, myalgia, and dyspepsia were the most common AEs in patients receiving niacin.

Conclusions:

In this study in Indian patients with dyslipidemia, simvastatin-niacin combination therapy was associated with greater changes in lipid profile compared with either agent used alone. Niacin was also associated with greater changes in Lp(a) levels. AEs were less prevalent with combination therapy than with niacin alone.Key words: dyslipidemia, simvastatin, niacin, combination therapy     

Pellagra: a rare complication of anorexia nervosa

Pellagra is a potentially fatal, nutritional disease with cutaneous, gastrointestinal, and neuropsychiatric manifestations. Because of the diversity of pellagra's signs and symptoms, diagnosis is difficult without an appropriate index of suspicion. A case of pellagra in a 14-year-old girl with anorexia nervosa is presented. Signs and symptoms of pellagra were resolved after niacin therapy and dietary treatment.     

Combination niacin and statin therapy in primary and secondary prevention of cardiovascular disease

Statin monotherapy may not be sufficient to reach serum lipid goals in many patients, especially in those with combined lipid abnormalities. Statins cause only a modest increase in high-density lipoprotein cholesterol (HDL)--an established independent protective factor for coronary heart disease (CHD)--and a modest decrease in triglycerides (TG). Niacin is an effective pharmacologic agent for increasing HDL, as well as lowering TG. Used in combination with a statin, niacin provides an option to help patients attain their low-density lipoprotein cholesterol (LDL-C) goals, non-HDL goals, and HDL goals. Based on the National Health and Nutrition Examination Survey, 1999 to 2000, only 12% of the surveyed adult population were under treatment for diagnosed hypercholesterolemia. Furthermore, only 5.4% of the surveyed population had attained goal total cholesterol levels of < 5.2 mmol/I (< 200 mg/dl). Combination therapy offers a means to get more people to goal. This paper reviews the impact of lipid-modifying combination therapy with niacin plus a statin on lipid profile outcomes.     

Role of prostaglandin D2 and the autonomic nervous system in niacin‐induced flushing (前列腺素D2与自主神经系统在烟酸引起的脸红中的作用)

Background: Although niacin often has beneficial effects on the lipoprotein profile, flushing is an untoward effect associated with its use. Aspirin can only reduce the flushing response by 30–40%. Thus, the aim of the present study was to investigate the mechanisms of niacin‐induced flushing, with and without aspirin, in normal, healthy individuals. Methods: Niacin‐induced flushing was evaluated in 30 healthy individuals after oral administration of 1000 mg niacin alone or with 325 mg aspirin. Neurological, autonomic nervous system, and skin blood flow measurements (using laser Doppler on the glabrous and hairy skin of each participant) were made at various times after drug administration. In addition, the systemic release of 9α,11β‐prostaglandin (PG) F₂ was determined. Flushing symptoms of redness, warmth, tingling, itching, and intensity were recorded using the modified Flushing ASsessment Tool (FAST). Results: After aspirin, the mean flushing scores for all symptoms decreased significantly; however, 36–53% of participants still had some degree of symptoms, even though aspirin completely blocked 11β‐PGF₂ synthesis. Maximum skin blood flow (MaxSkBF) in both the glabrous and hairy forearm increased significantly after niacin, but decreased significantly after aspirin only in hairy skin. Regression analysis showed that, in glabrous skin, both PGF₂ and parasympathetic activity were significant predictors of MaxSkBF after niacin, contributing 26% and 14%, respectively (total R² = 40%). Conclusions: The present study indicates, for the first time, that the parasympathetic nervous system, in addition to PGD₂, may play an important role in niacin‐induced flushing. Changing the sympathetic/parasympathetic balance in favor of parasympathetic activation may be a good therapeutic target to reduce niacin‐induced flushing.     

Extended-release niacin/lovastatin: the first combination product for dyslipidemia

Many clinical studies have demonstrated that lipid-altering drug treatments, including the use of statin and niacin monotherapy, can be effective in the primary and secondary prevention of coronary heart disease, but only in a minority of patients relative to placebo. Since statins and niacin have entirely different mechanisms of action and predominantly different effects on blood lipid levels, the combined use of both a statin and niacin may confer complementary benefits on multiple lipid parameters, produce a more global improvement in lipid blood levels and result in greater reductions in coronary heart disease risk factors than the administration of either agent alone. This may be of particular importance in patients with complex dyslipidemias, such as those with Type 2 diabetes mellitus and metabolic syndrome. This review summarizes the efficacy and safety of extended-release niacin/lovastatin (Advicor^®, Kos Pharmaceuticals Inc.), the first combination product approved for the management of dyslipidemia.