Vitamin B3 Abstracts 5

© 2013

Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy

         (Boden, Probstfield 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.).

Safety considerations with niacin therapy

         (Guyton and Bays 2007) Download

Niacin has beneficial effects on plasma lipoproteins and has demonstrated clinical benefits in reducing cardiovascular events and atherosclerosis progression. The side effects of niacin, however, have limited its use in general clinical practice. An understanding of cutaneous flushing based on the best available evidence should enhance patient education efforts and improve adherence. Although serious hepatic toxicity from niacin administration has been reported, it is largely confined to the use of slow-release formulations given as unregulated nutritional supplements. Niacin has been shown to induce insulin resistance in short-term trials, but the glycemic response in subjects with and without diabetes is usually minor. Niacin can be used safely in patients with diabetes. Despite a few case reports of myopathy associated with niacin-statin (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) combination therapy, 2 decades of clinical evidence since the introduction of statins do not support a general myopathic effect of niacin either alone or in combination with statins. Rare, less well-defined side effects of niacin include blurred vision due to cystoid macular edema, nausea and vomiting, and the exacerbation of peptic ulcers. Laboratory abnormalities that are usually small (< or =10%) and clinically unimportant include increased prothrombin time, increased uric acid, and decreases in platelet count and serum phosphorus. Overall, the perception of niacin side effects is often greater than the reality. As a result, a valuable medication for cardiovascular risk is underused.


Stages in the recognition of epidemic pellagra in the United States: 1865-1960

         (Lanska 1996) Download

Recognition of the U.S. pellagra "epidemic" in the early part of this century occurred in stages. The recognition process distorted impressions of magnitude, rate of spread, and virulence. Unrecognized cases: Endemic pellagra developed from dietary deficiencies after the Civil War. Initially, cases were misdiagnosed as other more traditional disorders. Tradition and authority inhibited recognition. Recognition of severe cases: Beginning in 1907, outbreaks were reported in asylums. Existing severe cases came rapidly to medical attention, inflating the apparent rate of spread. Recognized cases had a fulminant course and a high case fatality. Expanded spectrum: Milder cases were increasingly recognized, leading to an exaggerated rate of increase in number of cases and a decrease in case fatality and apparent virulence. Greater sensitivity resulted largely from a shift in diagnostic thresholds, with loss of specificity and increase in false positive diagnoses. Standardization of diagnosis: Although no suitable diagnostic marker test was developed, diagnosis was ultimately standardized by development of a workable case definition and by assessment of response to an effective therapy (nicotinic acid) applied to presumptive cases.

Chapter 30: historical aspects of the major neurological vitamin deficiency disorders: the water-soluble B vitamins

         (Lanska 2010) Download

This historical review addresses major neurological disorders associated with deficiencies of water-soluble B vitamins: beriberi, Wernicke-Korsakoff syndrome, pellagra, neural tube defects, and subacute combined degeneration of the spinal cord.


Is niacin ineffective? Or did AIM-HIGH miss its target?

         (Nicholls 2012) Download

The AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) found, in an interim analysis, no cardiovascular benefit from taking extended-release niacin (Niaspan). In fact, there was a trend toward a greater risk of ischemic stroke, which did not reach statistical significance. But questions remain about this complex trial, which included intensive statin therapy in the active-treatment group and the control group.

The power to reduce: pyridine nucleotides--small molecules with a multitude of functions

         (Pollak, Dolle et al. 2007) Download

The pyridine nucleotides NAD and NADP play vital roles in metabolic conversions as signal transducers and in cellular defence systems. Both coenzymes participate as electron carriers in energy transduction and biosynthetic processes. Their oxidized forms, NAD+ and NADP+, have been identified as important elements of regulatory pathways. In particular, NAD+ serves as a substrate for ADP-ribosylation reactions and for the Sir2 family of NAD+-dependent protein deacetylases as well as a precursor of the calcium mobilizing molecule cADPr (cyclic ADP-ribose). The conversions of NADP+ into the 2'-phosphorylated form of cADPr or to its nicotinic acid derivative, NAADP, also result in the formation of potent intracellular calcium-signalling agents. Perhaps, the most critical function of NADP is in the maintenance of a pool of reducing equivalents which is essential to counteract oxidative damage and for other detoxifying reactions. It is well known that the NADPH/NADP+ ratio is usually kept high, in favour of the reduced form. Research within the past few years has revealed important insights into how the NADPH pool is generated and maintained in different subcellular compartments. Moreover, tremendous progress in the molecular characterization of NAD kinases has established these enzymes as vital factors for cell survival. In the present review, we summarize recent advances in the understanding of the biosynthesis and signalling functions of NAD(P) and highlight the new insights into the molecular mechanisms of NADPH generation and their roles in cell physiology.


Testing the functional capacity of the tryptophan-niacin pathway in man by analysis of urinary metabolites

         (Price, Brown et al. 1965) Download Download2 Download3

Clinical inquiries. Should liver enzymes be checked in a patient taking niacin?

         (Rizakallah, Mertens et al. 2005) Download


References

Boden, W. E., J. L. Probstfield, et al. (2011). "Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy." N Engl J Med 365(24): 2255-67 PMID: 22085343

Guyton, J. R. and H. E. Bays (2007). "Safety considerations with niacin therapy." Am J Cardiol 99(6A): 22C-31C PMID: 17368274

Lanska, D. J. (1996). "Stages in the recognition of epidemic pellagra in the United States: 1865-1960." Neurology 47(3): 829-34 PMID: 8797491

Lanska, D. J. (2010). "Chapter 30: historical aspects of the major neurological vitamin deficiency disorders: the water-soluble B vitamins." Handb Clin Neurol 95: 445-76 PMID: 19892133

Nicholls, S. J. (2012). "Is niacin ineffective? Or did AIM-HIGH miss its target?" Cleve Clin J Med 79(1): 38-43 PMID: 22219232

Pollak, N., C. Dolle, et al. (2007). "The power to reduce: pyridine nucleotides--small molecules with a multitude of functions." Biochem J 402(2): 205-18 PMID: 17295611

Price, J. M., R. R. Brown, et al. (1965). "Testing the functional capacity of the tryptophan-niacin pathway in man by analysis of urinary metabolites." Adv Metab Disord 2: 159-225 PMID: 4250300

Rizakallah, G. S., M. K. Mertens, et al. (2005). "Clinical inquiries. Should liver enzymes be checked in a patient taking niacin?" J Fam Pract 54(3): 265-8 PMID: 15755381