Medication News & Update
What You Should Know About Niacin
What is Niacin?
Niacin, also known as nicotinic acid, is a form of vitamin B3 used to improve HDL ("good" cholesterol) and lower triglycerides and LDL ("bad" cholesterol). It is also used to treat niacin deficiency.
What types of niacin are available?
There are four different types of niacin used to improve cholesterol: immediate-release, extended-release, long-acting (also referred to as sustained-release, controlled-release, or timed-release), and no-flush niacin. Immediate-release products are available over-the-counter or also by prescription in the U.S. (e.g., Niacor). Niaspan is an extended-release prescription product. The long-acting products (e.g., Slo-Niacin in the U.S.) and no-flush niacin (inositol hexaniacinate or hexanicotinate) are available over-the-counter. Another form of vitamin B3 you might see is niacinamide. But niacinamide has no effect on cholesterol.
Do all niacin products work?
The immediate-release, extended-release, and long-acting niacin products are all effective. The no-flush niacin products probably don't work as well as regular niacin. When choosing a brand of niacin, you should be aware not all over-the-counter products contain the claimed amount of niacin. Products labeled with "USP," "NSF," or a DIN number (in Canada) have been tested for purity. Ask your pharmacist to help you select a good brand.
What are the side effects of niacin?
Niacin can cause flushing (redness) of the face and neck within the first two hours of taking a dose. Stomach upset, heartburn, nausea, vomiting, and diarrhea may also occur. At high doses, niacin can increase blood sugar, increase the risk for gout, and cause liver problems. Side effects can differ depending on the type of niacin you use.
The immediate-release niacins (e.g., Niacor) are more likely to cause flushing, especially when you first start taking them. Long-acting niacin (e.g., Slo-Niacin) is more likely to cause liver problems. The extended-release niacin (Niaspan) is less likely to cause the flushing that commonly occurs initially with immediate-release niacin. It is also less likely to cause liver problems than long-acting niacins, but it is much more expensive.
What can I do to decrease the side effects associated with taking niacin?
Flushing is a major complaint of patients taking niacin. Often this side effect will become less bothersome the longer you take niacin. Aspirin can help reduce flushing. If it's O.K. with your healthcare provider, take aspirin 325 mg 30 minutes before you take your niacin (45 to 60 minutes before, if using enteric-coated aspirin). Avoiding alcohol, spicy foods, hot drinks, and hot showers shortly after taking niacin can also help. Taking niacin with food not only helps reduce flushing, but stomach upset as well. It is important to let your healthcare provider know if the side effects become too bothersome or if you notice vision problems, yellowing eyes or skin, or muscle aches.
My doctor prescribed Niaspan, but it's too expensive. Can I use another niacin product?
Immediate-release niacin is a safe, effective, and much less expensive alternative to Niaspan. The downside is that immediate-release niacin causes more flushing initially and you'll need to take it two to three times a day. Niaspan is taken only once a day. If you decide to switch to immediate-release niacin, you will need to ask your healthcare provider for dosing instructions. When switching to a new type of niacin, you need to start with a low dose. Increasing slowly to your normal dose will help reduce side effects. Also, niacin doses differ depending on the type you choose. You should avoid the long-acting niacins, because they can cause liver problems. Also avoid no-flush niacins, since they probably aren't as effective.
Regardless of what type of niacin you use, it is important to see your healthcare provider on a regular basis so they can monitor your cholesterol, liver function, blood sugar, and uric acid.
High-density-lipoprotein (HDL), also referred to as "good cholesterol", is becoming a potential therapeutic target in the treatment of cardiovascular disease. This is because low levels of HDL contribute to cardiovascular risk and higher levels decrease this risk. One study showed that every 10% decrease in HDL corresponded with an increased cardiovascular risk of 13%.
In clinical trials, certain lifestyle interventions and drug therapies have been shown to increase HDL. These are summarized as follows:
Of the currently approved lipid-lowering therapies, niacin raises HDL more than any other agent.2-4 It also effectively lowers low-density-lipoprotein (LDL) by 5% to 25% and triglycerides by 20% to 50%.2 In addition, niacin has been shown in clinical trials to reduce the incidence of nonfatal myocardial infarctions and death.2 Niacin has been identified by the National Cholesterol Education Program Adult Treatment Panel (ATP) III as one of the major classes of drugs recommended for the treatment of hyperlipidemia. However, niacin remains underutilized because of confusion and concerns regarding formulations, side effects, and appropriate use.
Niacin Nomenclature, Formulations, and Prescription Status
Vitamin B3 includes niacin (nicotinic acid) and niacinamide (nicotinamide).5 Both niacin and niacinamide may be used as vitamin supplements and for the prevention and treatment of niacin deficiciency. However, only niacin is useful for the treatment of hyperlipidemia. Niacinamide does not effect lipoprotein levels and should not be used for lipid lowering.
Niacin is currently available in three main formulations. These include immediate-release (also referred to as crystalline), extended-release, and long-acting (also referred to as sustained-release, controlled-release, or timed-release). Immediate-release preparations are either available over-the-counter as miscellaneous generics or by prescription (e.g., Niacor). Niaspan is an extended-release preparation which requires a prescription. All long-acting products (e.g., Slo-Niacin) are available over-the-counter as dietary supplements, and none have been approved by the Food and Drug Administration (FDA) for the treatment of hyperlipidemia.
A forth type of niacin that may be seen over-the-counter is inositol hexaniacinate, also known as no-flush niacin.7 A recent survey evaluated the free nicotinic acid content of over-the-counter niacin preparations (immediate-release, long-acting, and no-flush). Both the immediate-release and long-acting formulations contained a full amount of free nicotinic acid. However, the no-flush preparations contained no free nicotinic acid. The authors of this survey concluded that the no-flush products are potentially ineffective lipid-lowering agents and should not be used to treat hyperlipidemia. Since there is no evidence it is better tolerated, and it is probably less effective than regular niacin, its use should be discouraged.
Side Effects, Contraindications, and Monitoring
The major side-effects associated with niacin are flushing, hyperglycemia, hyperuricemia or gout, upper gastrointestinal distress, and hepatotoxicity. The risk of hepatotoxicity, hyperglycemia, and hyperuricemia or gout increases with higher doses, especially at doses at or above 2,000 mg daily.
Niacin should be avoided in patients with chronic liver disease, severe gout, active peptic ulcer disease, and arterial bleeding. It should be used cautiously in patients with hyperuricemia and diabetes. Higher doses (> 3,000 mg daily) have been shown to worsen glycemic control in type 2 diabetes. However, lower doses have not been shown to cause significant deterioration of diabetes control. The American Diabetes Association (ADA) states that low doses of niacin (< 2,000 mg daily) may not have much of a negative effect on glycemic control and any deterioration can be corrected with adjustment of diabetic medications [Evidence level A, RCT].
The manufacturers of Niaspan and Niacor recommend liver function tests, including AST and ALT, be performed prior to the initiation of therapy, every six to 12 weeks for the first year, and periodically thereafter (e.g., at approximately six month intervals). It is recommended to obtain fasting glucose and uric acid levels12 at baseline, six to eight weeks after starting therapy, then annually, or more frequently if indicated, to monitor for hyperglycemia and hyperuricemia. If liver enzymes show evidence of progression, particularly if they rise to three times the upper limit of normal and are persistent, niacin should be discontinued. The drug should also be stopped if elevations are associated with symptoms of nausea, fever, and/or malaise.
Relationship between Pharmacokinetics and Side Effects
The prevalence of toxicities may also vary with the formulation of niacin utilized. For instance, the incidence of flushing is higher with immediate-release products and hepatotoxicity greater with long-acting preparations. Disparities in side effects between preparations are related to pharmacokinetic differences (dissolution rates and metabolism) between niacin formulations.
Immediate-release niacin is rapidly absorbed with peak serum levels obtained within 30 to 60 minutes. The dissolution rate of extended-release niacin varies between eight to 12 hours and that of long-acting niacin may exceed 12 hours. Niacin is metabolized by either conjugation or amidation pathways. Immediate-release niacin which is rapidly absorbed is primarily metabolized by conjugation. Long-acting niacin, which has a much slower dissolution rate, is primarily metabolized by amidation. Extended-release niacin with a more intermediate dissolution rate is metabolized by both pathways, approximately 60% by conjugation and 40% by amidation. The conjugative pathway results in the formation of glycine conjugates of niacin such as nicotinuric acid which has been associated with vasodilation and flushing. The amidation pathway results in the formation of nicotinamide and pyrimidine metabolites which have been associated with hepatotoxicity.
This theory is supported by the results of clinical trials that have shown that hepatotoxicity or increases in liver enzymes are more prevalent with long-acting than immediate-release niacin. Flushing was also found to be more frequent with the immediate-release than the long-acting formulation. In these studies long-acting niacin lowered LDL to a greater extent than immediate-release. However, the immediate-release product had a more beneficial effect on raising HDL than long-acting niacin.
In a 16 week study by Knopp et al (n=223) immediate-release niacin was compared to the extended-release formulation. At a total daily dose of 1500 mg the two preparations had similar effects on liver enzymes. During the first two weeks of therapy, patients receiving immediate-release niacin had a significantly greater incidence of flushing than those that received extended-release. However, during the remainder of the study the difference in flushing between groups did not reach statistical significance. The incidence of other side-effects such as gastrointestinal disturbances and rash did not differ significantly between groups. The changes in lipoproteins for a 1500 mg daily dose of niacin were also similar between formulations.
Extended-release niacin has not been directly compared to the long-acting preparation. Thus it is difficult to determine the differences between these two formulations with regards to lipoprotein effects and side effects. However, based on the theory that a more rapid niacin dissolution rate is associated with less hepatotoxicity, extended-release niacin appears to cause fewer elevations in liver enzymes than the long-acting preparation.
Immediate-release niacin should be initiated with small divided doses (e.g., 50 to 100 mg two or three times daily for the first week) and taken with meals. The dose should be increased slowly over several weeks to achieve treatment goals. The usual daily dose of immediate-release niacin is 1,500 mg to 3,000 mg. The maximum dose is 4,500 mg daily.
Extended-release niacin should be initiated at 500 mg at bedtime with a snack for one month and then increased to 1000 mg for one month. At this time the dose can be further titrated upward by 500 mg increments at a minimum of one-month intervals according to patient response. A maximum daily dose of 2,000 mg should not be exceeded.
Long-acting niacin preparations should also be started at a low dose (e.g., 250 mg to 500 mg daily) and slowly titrated upward. A dose of 2,000 mg daily should not be exceeded.
The major drawback to niacin therapy is its side effect profile. Many of the side effects of niacin can be lessened by utilizing smaller doses (< 2,000 mg daily) and starting with a low dose and slowly titrating the dose upward.6,12 Flushing occurs most frequently with the immediate-release preparations.2,4,6,13-15 However, it may still occur with the extended-release and long-acting formulations.4 Measures to reduce flushing include:
Most patients develop tolerance to the flushing with prolonged use of niacin, at which time aspirin use can be re-evaluated.
The choice between formulations can be tricky. An advantage of the immediate-release form is it is the least expensive option. However, immediate-release products require administration multiple times daily which may decrease adherence. Extended-release niacin (e.g., Niaspan) is a good option as it is dosed once daily, is associated with less initial flushing than immediate-release, and appears to have a reduced incidence of hepatotoxicity than long-acting niacin, but it is very expensive (up to $200/month). Long-acting preparations are the least desirable option because of a higher risk of hepatotoxicity. Equivalent doses of one niacin preparation should not be substituted for another.8,9 If switching between products, the proper starting dose and titration schedule for the new agent should be used. It is important to remember all niacin formulations, even those not requiring a prescription, require frequent health care provider follow-up and laboratory monitoring.
A currently available therapy which has also been shown to have clinical benefit in the management of patients with low HDL is gemfibrozil (Lopid). In the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) patients with a primary lipid abnormality of low HDL were treated with gemfibrozil (1200 mg/day) or placebo. In both diabetic and nondiabetic patients, gemfibrozil use was associated with a reduced risk of cardiovascular events. Based on these results, recent guidelines from the American College of Physicians recommend gemfibrozil (1200 mg/day) in patients with type 2 diabetes and low levels of both LDL and HDL.
In the future, more options may be available for raising HDL. In a recent trial, torcetrapib, a cholesteryl ester transfer protein inhibitor was found to increase HDL between 46% and 106% dependent on dose. However, torcetrapib is still a long way from becoming FDA approved. Of currently available agents, niacin remains the leader in ability to increase HDL.