Vitamin B3 Abstracts 6

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Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy
            (AIM-HIGH et al., 2011) Download
BACKGROUND: In patients with established cardiovascular disease, residual cardiovascular risk persists despite the achievement of target low-density lipoprotein (LDL) cholesterol levels with statin therapy. It is unclear whether extended-release niacin added to simvastatin to raise low levels of high-density lipoprotein (HDL) cholesterol is superior to simvastatin alone in reducing such residual risk. METHODS: We randomly assigned eligible patients to receive extended-release niacin, 1500 to 2000 mg per day, or matching placebo. All patients received simvastatin, 40 to 80 mg per day, plus ezetimibe, 10 mg per day, if needed, to maintain an LDL cholesterol level of 40 to 80 mg per deciliter (1.03 to 2.07 mmol per liter). The primary end point was the first event of the composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization. RESULTS: A total of 3414 patients were randomly assigned to receive niacin (1718) or placebo (1696). The trial was stopped after a mean follow-up period of 3 years owing to a lack of efficacy. At 2 years, niacin therapy had significantly increased the median HDL cholesterol level from 35 mg per deciliter (0.91 mmol per liter) to 42 mg per deciliter (1.08 mmol per liter), lowered the triglyceride level from 164 mg per deciliter (1.85 mmol per liter) to 122 mg per deciliter (1.38 mmol per liter), and lowered the LDL cholesterol level from 74 mg per deciliter (1.91 mmol per liter) to 62 mg per deciliter (1.60 mmol per liter). The primary end point occurred in 282 patients in the niacin group (16.4%) and in 274 patients in the placebo group (16.2%) (hazard ratio, 1.02; 95% confidence interval, 0.87 to 1.21; P=0.79 by the log-rank test). CONCLUSIONS: Among patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of less than 70 mg per deciliter (1.81 mmol per liter), there was no incremental clinical benefit from the addition of niacin to statin therapy during a 36-month follow-up period, despite significant improvements in HDL cholesterol and triglyceride levels. (Funded by the National Heart, Lung, and Blood Institute and Abbott Laboratories; AIM-HIGH ClinicalTrials.gov number, NCT00120289.).


 

Influence of nicotinic acid on serum cholesterol in man.
            (Altschul et al., 1955) Download
In summary, nicotinic acid decreases serum cholesterol. Hypercholesterolemic levels are more affected than normal levels. Parallel tests with nicotinic acid amide showed no definite influence on serum cholesterol levels in 20 health medical students. All the students who took nicotinic acid reacted with “flushes,” i.e., hyperemic skin reactions, and with “burning” sensations in the skin.

The therapeutic role of niacin in dyslipidemia management.
            (Boden et al., 2014) Download
There is abundant epidemiologic evidence to support the independent, inverse relationship between low levels of high-density lipoprotein cholesterol (HDL-C) and incident cardiovascular (CV) risk, the clinical importance of which is underscored by the high prevalence of low HDL-C in populations with coronary heart disease (CHD), with or without elevated levels of low-density lipoprotein cholesterol (LDL-C). The National Cholesterol Education Program recommended that optimal treatment for high-risk patients includes both lowering LDL-C and non-HDL-C to risk stratified levels and raising HDL-C when it is <40 mg/dL, although no target level for the latter lipoprotein was suggested. Niacin is the most powerful agent currently available for raising low levels of HDL-C. It also induces significant reductions in triglycerides, lipoprotein(a), and LDL-C levels while also favorably altering LDL particle size and number. In the Coronary Drug Project, niacin treatment was associated with significant reductions in CV events and long-term mortality, similar to the reductions seen in the statin monotherapy trials. In combination trials, niacin plus a statin or bile acid sequestrant produces additive reductions in CHD morbidity and mortality and promotes regression of coronary atherosclerosis. Recently, 2 clinical outcome trials (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes [AIM-HIGH] and Second Heart Protection Study [HPS-2 THRIVE]) failed to show a reduction in CV events in patients treated to optimally low levels of LDL-C. Despite favorable effects on HDL-C and triglycerides, these studies did not demonstrate incremental clinical benefit with niacin when added to simvastatin, although notable limitations were identified in each of these trials. Thus, there is insufficient evidence from clinical trials to recommend HDL-targeted therapy for additional event reduction at the present time. However, niacin should continue to be used as an adjuvant therapy for reducing atherogenic lipoprotein burden in patients who have not reached their risk stratified LDL-C and non-HDL-C targets.


 

Politics and pellagra: the epidemic of pellagra in the U.S. in the early twentieth century.
            (Bollet, 1992) Download
The epidemic of pellagra in the first half of this century at its peak produced at least 250,000 cases and caused 7,000 deaths a year for several decades in 15 southern states. It also filled hospital wards in other states, which had a similar incidence but refused to report their cases. Political influences interfered, not only with surveillance of the disease, but also in its study, recognition of its cause, and the institution of preventive measures when they became known. Politicians and the general public felt that it was more acceptable for pellagra to be infectious than for it to be a form of malnutrition, a result of poverty and thus an embarrassing social problem. Retrospectively, a change in the method of milling cornmeal, degermination, which began shortly after 1900, probably accounted for the appearance of the epidemic; such a process was suggested at the time, but the suggestion was ignored.

Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia.
            (Goldberg et al., 2000) Download
This multicenter trial evaluated the safety and efficacy of escalating doses of Niaspan (niacin extended-release tablets) and placebo (administered once-a-day at bedtime) in patients with primary hyperlipidemia on the percent change from baseline in levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein B. Extended-release niacin was initiated at a dose of 375 mg/day, raised to 500 mg/day, and further increased in 500-mg increments at 4-week intervals to a maximum of 3,000 mg/day. A total of 131 patients (n = 87, extended-release niacin; n = 44, placebo) were treated for 25 weeks with study medication after a 6-week diet lead-in/drug washout phase and 2-week baseline LDL cholesterol stability phase. Significant decreases from baseline in levels of LDL cholesterol and apolipoprotein B became apparent with the 500-mg/day dose and were consistent at all subsequent doses (p < or =0. 05), reaching 21% and 20%, respectively, at the 3,000-mg/day dose. Significant increases from baseline in levels of high-density lipoprotein cholesterol became apparent with the 500-mg/day dose and were consistent at all subsequent doses (p < or = 0.05), reaching 30% at the 3,000-mg dose. Significant decreases from baseline in triglycerides and lipoprotein(a) occurred at the 1,000-mg dose and were apparent at all subsequent doses (p < or =0.05), reaching 44% and 26%, respectively, at the 3,000-mg dose. The most common adverse events were flushing and gastrointestinal disturbance. Transaminase increases were relatively small, and the proportion of patients who developed liver function abnormalities on extended-release niacin was not significantly different from placebo. Thus, extended-release niacin was generally well tolerated and demonstrated a dose-related ability to alter favorably most elements of the lipid profile.


A "hot" topic in dyslipidemia management--"how to beat a flush": optimizing niacin tolerability to promote long-term treatment adherence and coronary disease prevention.
            (Jacobson, 2010) Download
Niacin is the most effective lipid-modifying agent for raising high-density lipoprotein cholesterol levels, but it also causes cutaneous vasodilation with flushing. To determine the frequency of flushing in clinical trials, as well as to delineate counseling and treatment approaches to prevent or manage flushing, a MEDLINE search was conducted of English-language literature from January 1, 1985, through April 7, 2009. This search used the title keywords niacin or nicotinic acid crossed with the Medical Subject Headings adverse effects and human. Niacin flushing is a receptor-mediated, mainly prostaglandin D(2)-driven phenomenon, the frequency, onset, and duration of which are largely determined by the distinct pharmacological and metabolic profiles of different niacin formulations. Subjective assessments include ratings of redness, warmth, itching, and tingling. In clinical trials, most (>60%) niacin users experienced mild or moderate flushing, which tended to decrease in frequency and severity with continued niacin treatment, even with advancing doses. Approximately 5% to 20% of patients discontinued treatment because of flushing. Flushing may be minimized by taking niacin with meals (or at bedtime with a low-fat snack), avoiding exacerbating factors (alcohol or hot beverages), and taking 325 mg of aspirin 30 minutes before niacin dosing. The current review advocates an initially slow niacin dose escalation from 0.5 to 1.0 g/d during 8 weeks and then from 1.0 to 2.0 g in a single titration step (if tolerated). Through effective counseling, treatment prophylaxis with aspirin, and careful dose escalation, adherence to niacin treatment can be improved significantly. Wider implementation of these measures should enable higher proportions of patients to reach sufficient niacin doses over time to prevent cardiovascular events.

Niacin: chemical forms, bioavailability, and health effects.
            (MacKay et al., 2012) Download
Elevated low-density lipoprotein cholesterol (LDL-C) has been the main target of lipid-altering therapy to reduce cardiovascular risk associated with dyslipidemia. Residual cardiovascular risk remains, however, after achievement of goal LDL-C levels and is associated in part with other risk markers of cardiovascular disease, including low high-density lipoprotein cholesterol (HDL-C), high lipoprotein a, and hypertriglyceridemia. Niacin is considered a valuable agent for therapy to modify high LDL-C as well as low HDL-C, high lipoprotein a, and hypertriglyceridemia. The forms of niacin available in the marketplace include unbound niacin, or free nicotinic acid (NA); extended-release NA, a form of NA that is released gradually over a period of time; inositol hexanicotinate, six molecules of NA covalently bonded to one molecule of inositol; and nicotinamide, or niacinamide, the amide form of NA, which is readily bioavailable. This review is designed to assist healthcare professionals in evaluating the form(s) of niacin best suited for a particular therapeutic goal. Further, it provides a literature-based evaluation of risk for NA, extended-release NA, inositol hexanicotinate, and nicotinamide.

A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients.
            (McKenney et al., 1994) Download
OBJECTIVE:  To compare escalating doses of immediate-release (IR) and sustained-release (SR) niacin for effectiveness in reducing levels of low-density lipoprotein cholesterol and triglycerides and increasing levels of high-density lipoprotein cholesterol, and for the occurrence of adverse reactions, especially hepatotoxicity. DESIGN:  Randomized, double-blind, parallel comparison of IR and SR niacin administered sequentially at 500, 1000, 1500, 2000, and 3000 mg/d, each for 6 weeks. SETTING:  Cholesterol research center. PATIENTS:  Forty-six adults, 23 in each group, with low-density lipoprotein cholesterol levels greater than 4.14 mmol/L (160 mg/dL) after 1 month of a step 1 National Cholesterol Education Program diet. OUTCOME MEASURES:  Fourteen-hour fasting lipid and lipoprotein cholesterol levels, results of clinical laboratory tests, a symptom questionnaire, and withdrawal rates. RESULTS:  The SR niacin lowered low-density lipoprotein cholesterol levels significantly more than IR niacin did at the dosage of 1500 mg/d and above, while IR niacin increased high-density lipoprotein cholesterol levels significantly more than SR niacin did at all dosage levels. The reduction in triglyceride levels was similar with IR and SR niacin. Nine (39%) of the 23 patients assigned to the IR dosage form withdrew before completing the 3000-mg daily dose; the most common reasons for withdrawal were vasodilatory symptoms, fatigue, and acanthosis nigricans. Eighteen (78%) of the 23 patients assigned to the SR dosage form withdrew before completing the 3000-mg daily dose; the most common reasons for withdrawal were gastrointestinal tract symptoms, fatigue, and increases in levels of liver aminotransferases, often with symptoms of hepatic dysfunction. None of the patients taking IR niacin developed hepatotoxic effects, while 12 (52%) of the 23 patients taking SR niacin did. CONCLUSION:  The SR form of niacin is hepatotoxic and should be restricted from use. The IR niacin is preferred for the management of hypercholesterolemia but can also cause significant adverse effects and should be given only to patients who can be carefully monitored by experienced health professionals.

Varying cost and free nicotinic acid content in over-the-counter niacin preparations for dyslipidemia.
            (Meyers et al., 2003) Download
BACKGROUND:  Nicotinic acid is an effective treatment for dyslipidemia, but the content of over-the-counter niacin is not federally regulated. As a result, patients may use preparations of over-the-counter niacin that do not contain free nicotinic acid. OBJECTIVE:  To characterize the types, costs, and free nicotinic acid content of over-the-counter niacin preparations and to review literature on the use of over-the-counter niacin for dyslipidemia. DATA SOURCES:  Commonly used over-the-counter niacin preparations (500-mg tablets or capsules) from the 3 categories of immediate-release, sustained-release, and no-flush were purchased at health food stores and pharmacies and from Internet-based vitamin companies. Pertinent literature on the use of over-the-counter niacin was obtained by searching PubMed. MEASUREMENTS:  For each preparation studied, the monthly cost of therapy (at 2000 mg/d) and the free nicotinic acid content (quantified by high-performance liquid chromatography) were reported. DATA SYNTHESIS:  On average, immediate-release niacin preparations cost 7.10 dollars per month, sustained-release preparations cost 9.75 dollars per month, and no-flush preparations cost 21.70 dollars per month. The average content of free nicotinic acid was 520.4 mg for immediate-release niacin, 502.6 mg for sustained-release niacin, and 0 for no-flush niacin. CONCLUSIONS:  No-flush preparations of over-the-counter niacin contain no free nicotinic acid and should not be used to treat dyslipidemia. Over-the-counter sustained-release niacin contains free nicotinic acid, but some brands are hepatotoxic. Immediate-release niacin contains free nicotinic acid and is the least expensive form of over-the-counter niacin.

Nicotinic acid in treatment of angina pectoris.
            (Neuwahl, 1942) Download
Six cases of angina pectoris were treated by intravenous drip infusion of a 0. 05 per cent, solutionof nicotinic acid. Six infusions of about 100 to 300 mg. over a period of 3 weeks are reported tohave caused a complete regression of symptoms for a period of 3 to 7 months.

Effect of niacin on erectile function in men suffering erectile dysfunction and dyslipidemia.
            (Ng et al., 2011) Download
INTRODUCTION:  Dyslipidemia is closely related to erectile dysfunction (ED). Evidence has shown that the lipid-lowering agent, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statins), can improve erectile function. However, information about the potential role of another class of lipid-lowering agent, niacin, is unknown. AIM:  To assess the effect of niacin alone on erectile function in patients suffering from both ED and dyslipidemia. METHODS:  A single center prospective randomized placebo-controlled parallel-group trial was conducted. One hundred sixty male patients with ED and dyslipidemia were randomized in a one-to-one ratio to receive up to 1,500 mg oral niacin daily or placebo for 12 weeks. MAIN OUTCOME MEASURES:  The primary outcome measure was the improvement in erectile function as assessed by question 3 and question 4 of the International Index of Erectile Function (IIEF Q3 and Q4). Secondary outcome measurements included the total IIEF score, IIEF-erectile function domain, and Sexual Health Inventory for Men (SHIM) score. RESULTS:  From the overall analysis, the niacin group showed a significant increase in both IIEF-Q3 scores (0.53 ± 1.18, P < 0.001) and IIEF-Q4 scores (0.35 ± 1.17, P = 0.013) compared with baseline values. The placebo group also showed a significant increase in IIEF-Q3 scores (0.30 ± 1.16, P = 0.040) but not IIEF-Q4 scores (0.24 ± 1.13, P = 0.084). However, when patients were stratified according to the baseline severity of ED, the patients with moderate and severe ED who received niacin showed a significant improvement in IIEF-Q3 scores (0.56 ± 0.96 [P = 0.037] and 1.03 ± 1.20 [P < 0.001], respectively) and IIEF-Q4 scores (0.56 ± 1.03 [P = 0.048] and 0.84 ± 1.05 [P < 0.001], respectively] compared with baseline values, but not for the placebo group. The improvement in IIEF-EF domain score for severe and moderate ED patients in the niacin group were 5.28 ± 5.94 (P < 0.001) and 3.31 ± 4.54 (P = 0.014) and in the placebo group were 2.65 ± 5.63 (P < 0.041) and 2.74 ± 5.59 (P = 0.027), respectively. There was no significant improvement in erectile function for patients with mild and mild-to-moderate ED for both groups. For patients not receiving statins treatment, there was a significant improvement in IIEF-Q3 scores (0.47 ± 1.16 [P = 0.004]) for the niacin group, but not for the placebo group. CONCLUSIONS:  Niacin alone can improve the erectile function in patients suffering from moderate to severe ED and dyslipidemia.

Present-day uses of niacin: effects on lipid and non-lipid parameters.
            (Sanyal et al., 2007) Download
Existing guidelines for the prevention and treatment of coronary artery disease focus on lowering low-density lipoprotein cholesterol (LDL-C) as the primary lipid target. However, there has been increasing interest in raising high-density lipoprotein cholesterol (HDL-C) due to strong evidence linking low HDL-C levels with an increased risk of atherosclerosis. Raising HDL-C levels with lifestyle changes and pharmacologic interventions appear to reduce the risk of coronary artery disease beyond that of lowering LDL-C alone. Niacin has a substantial HDL-C raising effect, and also may beneficially alter total cholesterol, LDL-C and triglyceride levels. Niacin also exhibits antioxidant, anti-inflammatory and other beneficial effects on atherosclerosis. Niacin is safe and effective to use in women, in patients with diabetes mellitus and/or metabolic syndrome, and when used in combination with statins. Niacin has the promise of being a powerful pharmacologic agent in the fight against atherosclerotic disease, although additional clinical studies are required to examine this further.

Nicotinic Acid In The Treatment Of Angina Pectoris.
            (Stokes, 1944) Download
Changes in the electrocardiogram of cardiac ischemia in man, following the administration of nicotinic acid, suggest that the drug can improve coronary blood flow; but this only results from a dosage large enough to produce peripheral flushing, which in itself is an uncertain and unpleasant effect. In a controlled clinical trial no improvement resulted from the oral administration of nicotinic acid in moderate dosage, either in the prevention or relief of angina, and nicotinamide in larger doses failed to give better results. Once again glyceryl trinitrate has shown that it has no equal in the treatment of angina pectoris, and nicotinic acid has no claim to routine use in this complaint.

 


References

AIM-HIGH, Investigators, et al. (2011), ‘Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy’, N Engl J Med, 365 (24), 2255-67. PubMed: 22085343
Altschul, R, A Hoffer, and JD Stephen (1955), ‘Influence of nicotinic acid on serum cholesterol in man.’, Arch Biochem Biophys, 54 (2), 558-59. PubMed: 14350806
Boden, WE, MS Sidhu, and PP Toth (2014), ‘The therapeutic role of niacin in dyslipidemia management.’, J Cardiovasc Pharmacol Ther, 19 (2), 141-58. PubMed: 24363242
Bollet, AJ (1992), ‘Politics and pellagra: the epidemic of pellagra in the U.S. in the early twentieth century.’, Yale J Biol Med, 65 (3), 211-21. PubMed: 1285449
Goldberg, A, et al. (2000), ‘Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia.’, Am J Cardiol, 85 (9), 1100-5. PubMed: 10781759
Jacobson, TA (2010), ‘A “hot” topic in dyslipidemia management--”how to beat a flush”: optimizing niacin tolerability to promote long-term treatment adherence and coronary disease prevention.’, Mayo Clin Proc, 85 (4), 365-79. PubMed: 20360295
MacKay, D, J Hathcock, and E Guarneri (2012), ‘Niacin: chemical forms, bioavailability, and health effects.’, Nutr Rev, 70 (6), 357-66. PubMed: 22646128
McKenney, JM, et al. (1994), ‘A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients.’, JAMA, 271 (9), 672-77. PubMed: 8309029
Meyers, CD, et al. (2003), ‘Varying cost and free nicotinic acid content in over-the-counter niacin preparations for dyslipidemia.’, Ann Intern Med, 139 (12), 996-1002. PubMed: 14678919
Neuwahl, FJ (1942), ‘Nicotinic acid in treatment of angina pectoris.’, Lancet, PubMed:
Ng, CF, et al. (2011), ‘Effect of niacin on erectile function in men suffering erectile dysfunction and dyslipidemia.’, J Sex Med, 8 (10), 2883-93. PubMed: 21810191
Sanyal, S, RH Karas, and JT Kuvin (2007), ‘Present-day uses of niacin: effects on lipid and non-lipid parameters.’, Expert Opin Pharmacother, 8 (11), 1711-17. PubMed: 17685887
Stokes, W (1944), ‘Nicotinic Acid In The Treatment Of Angina Pectoris.’, Br Heart J, 6 (3), 157-60. PubMed: 18609972