Dr. Ron’s Research Review – January 22, 2020

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This week’s research review focuses on niacin products for hypercholesterolemia.

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. (Boden et al., 2014)
Niacin also exhibits antioxidant, anti-inflammatory and other beneficial effects on atherosclerosis. (Sanyal et al., 2007)

Flushing

Virtually all niacin users initially experience flushing, typically commencing 15 to 30 minutes after ingesting immediate-release niacin, 30 to 120 minutes after ingesting extended-release niacin, or at more variable times after sustained-release niacin ingestion. Niacin users often experience “prickly heat” or a sense of warmth in the face, neck, ears, trunk, and, less frequently, the upper or lower extremities. Other common features include erythema, itching, and tingling. Symptoms typically last for less than 1 hour to 2.5 hours. (Jacobson, 2010)

Aspirin

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. (Jacobson, 2010)

No-Flush Niacin

No-flush niacin is the most expensive of the niacin preparations, yet contains no free nicotinic acid and should not be used to treat dyslipidemia. Sustained- release brands are inexpensive and contain a full amount of free nicotinic acid, but several preparations have been as- sociated with increased hepatotoxicity. Immediate-release niacin brands are the least expensive preparations, with some brands costing less than $5 per month. Furthermore, immediate-release niacin contains a full amount of nicotinic acid and is the only form of niacin shown to prevent cardiovascular disease and death. We recommend immediate-release niacin (Rugby), which comes in scored 500-mg tablets. The patient begins therapy with 250 mg after dinner for the first week. Additional 250-mg doses after breakfast and lunch are added each week, and the dose is titrated up to 500 mg 3 times a day over the course of 6 weeks. The patient must be told that they will flush with the first dose of niacin. The flushing can be markedly lessened with a few simple steps: 1) Take niacin at the end of a meal; 2) take aspirin (81 mg) before the meal; and 3) avoid hot drinks and alcohol around the time of niacin ingestion. (Meyers et al., 2003)

Inositol Hexaniacinate

Although treatment with inositol hexaniacinate showed promising lipid-lowering effects in a rabbit model of hyperlipidemia, this agent has little if any effect on lipid levels in humans. To our knowledge, no randomized, placebo-controlled trials have shown the efficacy of inositol hexaniacinate in lowering lipid levels, and several studies suggest the treatment has no effect on lipoprotein levels. Although vendors of inositol hexaniacinate may not explicitly claim beneficial lipid-lowering effects, uninformed patients may purchase and use these preparations to treat dyslipidemia. (Meyers et al., 2003)

Rugby Immediate-Release Niacin

There are several reasons to consider the use of Rugby immediate-release niacin. In addition to the efficacy and safety shown in the clinical trial, Rugby is the least expensive brand of immediate-release niacin we studied. It effectively treats dyslipidemia for less than $3 per month. The tablets are scored, making dosing titration easier. With any form of immediate-release niacin, patients must be willing to tolerate more flushing and 3-times-daily dosing. (Meyers et al., 2003) (McKenney et al., 1994)

 

Dr. Ron

 


Articles

 

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.

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.

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.

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.

 

References

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
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
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
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