THE BENEFITS OF NIACIN: A LITERATURE REVIEW 1. Kaitlin Deason. FCS 606- Vitamin and Mineral Metabolism

Transcription

1 THE BENEFITS OF NIACIN: A LITERATURE REVIEW 1 The benefits of niacin: A literature review Kaitlin Deason FCS 606- Vitamin and Mineral Metabolism

2 THE BENEFITS OF NIACIN: A LITERATURE REVIEW 2 Introduction Niacin or vitamin B3 has been demonstrated as an effective therapeutic agent in a number of health conditions. The active forms of niacin are nicotinic acid and nicotinamide and both are used to achieve beneficial effects (Gropper, Smith & Groff, 2005). Nicotinamide is the precursor to NAD + and NADP +, which play a role in countless oxidation- reduction reactions in the body. Nicotinic acid, on the other hand, does not have as large a role in body reactions, but it is the type of niacin that has the greatest effect on improving lipid profile in the body. Nicotinamide in large doses has not caused noticeable side effects, but nicotinic acid can cause niacin flushing (vasodilatory effects). Both forms of Niacin have been established as safe, and valuable therapeutic agents in several clinical studies both human and animal models. This paper will review a variety of studies conducted within the last five years in order to determine niacin s role in preventing or improving lipid profiles in an assortment of diseased and normal populations, Parkinson s disease (PD), Alzheimer s disease (AD), and hyperphosphatemia. Niacin and the Lipid Profile Many clinical studies have focused on niacin, specifically nicotinic acid, alone and in combination with statins for lowering LDL cholesterol, total cholesterol, triglycerides (TG), and raising HDL cholesterol. High levels of LDL, total cholesterol and TG in combination with low levels of HDL greatly increase the risk for developing coronary heart disease (CHD), cardiovascular disease (CVD), coronary artery disease (CAD), and can lead to adverse effects on health (Fazio et al., 2010; Guyton et al., 2008; Linke et al., 2009). It is hypothesized that decreasing LDL by 40% and increasing HDL by 30% may reduce the risk

3 THE BENEFITS OF NIACIN: A LITERATURE REVIEW 3 of CAD by 70% (Guyton et al. 2008). This shows how important it is to manage lipid levels especially in high risk disease populations. A study conducted by Guyton et al. (2008) which lasted for 24 weeks and then was extended by Fazio et al. (2010) for an additional 40 weeks compared the lipid altering effects of Ezetimibe/Simvastatin (E/S), niacin, and combination E/S plus niacin in patients with hyperlipidemia. Both studies were conducted at 106 different sites in the U.S. and were randomized, and double- blind. 1,220 participants started in the 24- week study and 770 completed this leg of the research. Of these, 574 completed the full 64- week trial and were further subcategorized with 84 having diabetes mellitus (DM), 235 having metabolic syndrome, and 255 with no additional disease. For the first 24 weeks subjects were randomly selected to receive 10/20 mg/day of E/S only, 10/20 mg/day of E/S plus 2 g/day of niacin, or 2 g/day of niacin only. Dosage of niacin increased from 500mg to 2g during the first 12 weeks in order to improve tolerance to the treatment. Results from the first 24 weeks showed that combination E/S plus niacin had the greatest LDL lowering effect at 58.3%, the greatest HDL raising effects at 30.2%, and lowered TG more compared to either treatment alone. Groups being treated with niacin had the highest drop out rate due to niacin flushing. However, the researchers believed this could be prevented in future studies with proper participant education and concurrent dosage with aspirin or ibuprofen. This study has strength in generalizability due to the large study population, but the internal validity may be affected due to the multi- clinic design. Also, there was a very large drop out rate (about 63%), which needs to be addressed in future studies. The dosage of niacin might be too high for the general population. Overall the results show strong indications of niacin being a beneficial treatment for improving lipid levels.

4 THE BENEFITS OF NIACIN: A LITERATURE REVIEW 4 At the conclusion of the 24 weeks, Fazio et al (2010) made some minor changes to the treatment group design and continued the study for an additional 40 weeks to show the long term effects of niacin. The 770 remaining participants were, as stated previously, classified as having DM, metabolic syndrome, or no additional disease. Also, those in the niacin only treatment group from the first 24 weeks were randomly assigned to either the E/S only group or the E/S plus niacin group. Again, 574 individuals completed the full 64- week trial. Combination treatment continued to be most effective for increasing HDL in all groups and had the greatest LDL lowering effect except in the group with DM where the results were similar to E/S alone. Uric acid level increase in the combination treatment group and was associated with niacin. Therefore, caution should be observed in individuals who are prone to developing gout. Also, plasma glucose levels increased with combination treatment. It is important to monitor these levels to avoid new cases of diabetes. However, this was not a significant issue in this study. The results indicate that long- term combination treatment is more effective than E/S alone and continues to improve and maintain lipid levels. Once more, adverse events should be watched to avoid study subject drop out, and insure safety of treatment. Overall, niacin has few serious adverse effects and improves outcomes for individuals with hyperlipidemia in the short and long- term. A study conducted by Alrasadi et al. (2008), compared the effects of Atorvastatin, Fenofibrate, and Extended Release (ER) niacin (Niaspan) in the treatment of severe HDL deficiency in men with a genetic disposition to this problem. 19 men completed this 40- week crossover trial in which they were assigned to 8 weeks of each 20 mg/day Atorvastatin, 200 mg/day Fenofibrate, or 2 g/day Niaspan in that order. Between each treatment there was a four- week washout period. Niaspan was the only treatment to

5 THE BENEFITS OF NIACIN: A LITERATURE REVIEW 5 significantly raise HDL and it did this by 22%. Fenofibrate actually increased LDL and did not effect HDL in this study. The reason for this was unknown, but it should not be advised within this population without further research due to its adverse results. Women were not included because researchers felt the impact of estrogen could have an effect on the results. However, this is a weakness of the study because these drugs still could have improved the lipid outcome in this population as well. Also, the sample size is small which decreases the generalizability and validity of these results. Overall, this study does still show that niacin, in the form of Niaspan, does significantly increase HDL levels, even in those individuals who have a genetic condition resulting in low HDL. Research by Linke et al. (2009), looked at the effects of ER niacin on adipocyte biology and lipid levels in individuals with impaired glucose tolerance. There were 60 participants who were randomly selected into a treatment group (1000 mg/day ER niacin) or a control group (no treatment) for the 6- month trial. There was a 4- week run- in period to progress the niacin dosage in order to increase tolerance to the treatment. Results illustrated a 24% increase in HDL, 38% decrease in lipoprotein (a), and a 12% decrease in fasting TG in the treatment group. In addition, adipocyte volume and diameter were significantly decreased in the treatment group. These results indicate significant benefits from ER niacin in individuals with impaired glucose intolerance. Limitations of this study are that the sample size was relatively small, and only adipocytes from subcutaneous fat were used. Therefore, additional studies are needed to confirm the effects of niacin on visceral fat cells and to improve the generalizability of these results. Finally, a study by Taylor et al. (2009) compared the effects of ER niacin or Ezetimibe on carotid intima- media thickness, HDL levels, and LDL levels in individuals with

6 THE BENEFITS OF NIACIN: A LITERATURE REVIEW 6 atherosclerotic coronary or vascular disease, or with a CHD risk equivalent. Participants were already receiving statin treatment, which they continued throughout the trial. 208 subjects completed this 14- month open- label study, and were randomized to receive either 2000 mg/day ER niacin or 10 mg/day Ezetimibe. Similar to pervious studies, niacin was increased from a staring dose of 500 mg/day to improve treatment tolerance. To determine carotid artery thickness, an ultrasound was used. The results demonstrate that ER niacin was more effective than Ezetimibe in raising HDL, lowering TG and decreasing carotid artery thickness. In fact, Ezetimibe had no effect on carotid artery thickness or HDL levels. Ezetimibe was however, a better LDL and total cholesterol- lowering agent, but ER niacin did still have a significant impact on these levels compared to the baseline. A limitation to this study is that is was not blinded and because no placebo was included, this may affect the validity of results. Overall, this study establishes ER niacin as the most efficient treatment in improving CHD risk. All of these studies illuminate the beneficial effects of niacin in regard to improving the lipid- profile and decreasing the risk of developing CAD, CVD, and CHD. More research should be conducted to work on improving the adverse effect of the niacin flush since this did impact study participation. Niacin, Renal Disease, and Phosphate Levels In addition to niacin s lipid- altering abilities, it may also be useful for improving symptoms of kidney disease. People with chronic kidney disease (CKD), especially those on dialysis, experience difficulty with controlling phosphorus levels (Cheng, Young, Huang, Delmez & Coyne, 2008). High levels of phosphorus can lead to hypertension, increased risk for CVD and arterial stiffening in individuals with CKD (Maccubbin, Tipping, Kuznetsova,

7 THE BENEFITS OF NIACIN: A LITERATURE REVIEW 7 Hanlon & Bostom, 2010). Finally progression of CDK may be exacerbated by inflammatory disorders, hypertension, and lipid disorders (Cho, Kim, Kamanna, & Vaziri, 2010). If niacin can improve phosphorus levels and decrease concurrent disorders associated with CKD, it may improve quality of life within this population group. A study conducted by Maccubbin et al. (2010) looked at the effects of ER niacin, and combination ER niacin plus laropiprant on phosphorus levels, calcium levels, and calcium- phosphorus products in individuals without renal failure. The clinical lab values used in this study were extracted form a parent study. 1,547 participants completed the 24- week placebo controlled, double- blind trial in which they received either 1 g/day ER niacin, 1 g/day ER niacin plus 20 gm/day laropiprant, or a placebo. Treatment increased to 2 g/day ER niacin and 2 g/day plus 40 mg/day ER niacin plus laropiprant after the first 4 weeks. Laropiprant was used because it has been shown to reduce the effects of niacin flushing. The results represent a significant reduction in phosphorus levels for both ER niacin and combination laropiprant/er niacin compared to the placebo. The maximum effect was achieved in the eighth week of the trial and then continued to lower phosphorus throughout the remaining weeks. An overall 11% reduction in phosphorus and a 12% reduction in calcium- phosphorus product were observed with no increase in calcium level for the treatment groups. A limitation to this study is that the researchers did not collect the samples themselves. However, many of the same authors were involved in the parent study. The large sample size improves strength and generalizability of these results. Niacin is an effective phosphorus lowering agent and shown by this study population. Research preformed by Cheng et al. (2008), examines the effects of niacin, in the form of nicotinamide, in combination with phosphorus binding drug treatment on

8 THE BENEFITS OF NIACIN: A LITERATURE REVIEW 8 phosphorus levels in patients on dialysis. 33 people participated in this 16- week, randomized, double blind, crossover study. Of these participants only 25 were greater than 80% compliant with the treatment. Each subject was randomly assigned to 8 weeks of niacin treatment and then 8 weeks of placebo. During niacin treatment, the dosage first 2 week was 250 mg twice daily, weeks 3 and 4 increased to 500 mg twice daily, and week 5-8 maxed out at 750 mg twice daily. Since phosphorus level could significantly affect health outcome in this population, niacin dosage was appropriately adjusted when problems arose or improvements were made. Results showed a significant reduction in phosphorus when participants were receiving nicotinamide. The most significant change occured during the first 2 weeks but continued through the remainder of treatment as dosage was increased. There were no reports of flushing and the researchers concluded that nicotinamide does no cause flushing compared to nicotinic acid. Finally, a study carried out by Cho et al. (2010) used rats to determine the efficacy of niacin in reducing dyslipidemia and inflammation in order to slow the progression of renal disease. 18 male rats were randomly assigned to one of three groups: chronic renal failure induced by 5/6 nephrectomy untreated, chronic renal failure induced by 5/6 nephrectomy treated with niacin, or a control. The rate that were treated with niacin had decreased blood pressure, lower left ventricle hypertrophy, and decreased urine output compared to the untreated rats with renal failure. In addition, kidney TG and total cholesterol was lower in the niacin treated rats compared to the untreated rats with kidney failure. These results display niacin as a good therapeutic agent for slowing the progression in rats with renal failure. Studies need to be conducted within a human population in order to determine safety with kidney failure patients.

9 THE BENEFITS OF NIACIN: A LITERATURE REVIEW 9 Based on the findings represented in these reviews studies, niacin, specifically nicotinamide, has a lot of potential in helping improve the quality of life in those with kidney disease. Since nicotinamide did not display any adverse side effects in these studies, it should be considered a safe way to treat hyperkalemia and lipid dysfunction for individuals experiencing kidney disease. Niacin and Neurodegenerative Disorders The last topic reviewed is the effect of niacin on neurodegenerative disorders. While niacin could potentially help improve outcomes for many neurodegenerative disorders, only Parkinson s disease (PD) and Alzheimer s disease are represented in this paper. Niacin as a potential treatment for PD and AD is a new topic of interest and to date there is only published research in non- human models. Parkinson s Disease Currently, there is no treatment for PD and for this reason preventing its occurrence is very important (Jia et al., 2009). Research preformed by Jia et al. (2008) explored the effects of nicotinamide on mitochondrial dysfunction and oxidative stress in extracted human neuroblastoma cells induced with PD, and also explored the effect of nicotinamide on motor function in Drosophila flies induced with PD. Results indicated that neuroblastoma cells pre- treated with nicotinamide exhibited antioxidant effects preventing DNA damage, enzyme damage and mitochondrial damage. The flies that were induced with PD, experienced improved motor function, as seen in the fly s climbing ability, when treated with nicotinamide. These results indicate a definite possibility for preventing and/or improving outcomes of PD in human populations. However, clinical trails need to be executed to replicate these results in humans.

10 THE BENEFITS OF NIACIN: A LITERATURE REVIEW 10 Alzheimer s Disease Alzheimer s disease is defined by extensive memory loss and cognitive decline most commonly affecting the brain regions of the hippocampus, amygdala, and the cortex (Green et al., 2008). A clinical study conducted by Green et al. (2008) used mice to determine the effects of nicotinamide on AD implications. Mice were given 200 mg/kg/day of nicotinamide for four months and then given multiple tests to determine niacin s effect on the three areas of the brain most impacted by AD. Results showed that nicotinamide improved the degenerative effects of AD through numerous mechanisms. Treatment enhanced short and long- term memory, learning, and cognition in mice with AD. In addition, mice that were free from disease also exhibited an improvement in short- term memory. These improvements related to the hippocampus and amygdala, but no improvement was seen in the cortex region of the brain in this study. Finally, treatment with nicotinamide improved microtubule stability, thereby preventing neurodegeneration. This all provides important evidence that niacin may be a useful therapeutic agent in humans with AD. While more research, especially using human models, is needed to determine the effects of niacin on the neurodegenerative disorders reviewed in this paper and others not represented, niacin has many clinical benefits. Niacin, especially nicotinic acid, certainly warrants human studies, and could be the next big break through in the treatment and prevention of neurodegenerative disorders. Human trails are currently being done and those results should be available in the recent future. Conclusion

11 THE BENEFITS OF NIACIN: A LITERATURE REVIEW 11 As a whole, all of these research studies show that niacin is a safe treatment method and should be used to improve health outcomes in an assortment of diseases if tolerated. With limited adverse effects, especially with nicotinamide, niacin can be very useful in prevent CHD, CVD, CAD, and possibly an array of neurodegenerative disorders. Health professionals should consider the information presented in this paper when treating patients at risk for these diseases because of the significant positive response that niacin induced in each study that was reviewed.

12 THE BENEFITS OF NIACIN: A LITERATURE REVIEW 12 References Alrasadi, K., Awan, Z., Alwaili, K., Ruel, I., Hafiane, A., Krimbou, L. & Genest, J. (2008). Comparison of treatment of severe high-density lipoprotein cholesterol deficiency in men with daily atorvastatin (20 mg) versus fenofibrate (200 mg) versus extended-release niacin (2 g). American Journal of Cardiology, 102, Cheng, S. C., Young, D. O., Huang, Y., Delmez, J. A., & Coyne D. W. (2008). A randomized, double-blind, placebo-controlled trial of niacinamide for reduction of phosphorus in hemodialysis patients. Clinical Journal of the American Society of Nephrology, 3, Cho, K., Kim, H., Kamanna, V. S., & Vaziri, N. D. (2010). Niacin improves renal lipid metabolism and slows progression in chronic kidney disease. Biochimica et Biophysica Acta, 1800, Fazio, S., Guyton, J. R., Lin, J., Tomassini, J. E., Shah, A. & Tershakovec, A. M. (2010). Longterm efficacy and safety of ezetimibe/simvastatin coadministered with extended-release niacin in hyperlipidaemic patients with diabetes or metabolic syndrome. Diabetes, Obesity and Metabolism, 12, Green, K. N., Steffan, J. S., Martinez-Coria, H., Sun, X., Schreiber, S. S., Thompson, L. M., & LaFerla, F. M. (2008). Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231- phosphotau. The Journal of Neuroscience, 28(45), Gropper, S. S., Smith, J. L., & Groff, J. L. (2005) Water-soluble vitamins: Niacin (vitamin B 3 ). In E. Howe (Ed.), Advanced nutrition and human metabolism (pp ). Belmont, CA: Thompson Wadsworth

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