Niacin and Heart Health: 3 Things to Know

Recent studies published in The New England Journal of Medicine are adding to concerns about the safety and effectiveness of niacin, a popular drug for the prevention of cardiovascular disease. 

The studies reveal that although this B vitamin can reduce triglyceride levels, raise “good” cholesterol levels (HDL) and reduce “bad” cholesterol levels (LDL), it does not produce the benefits that patients and their doctors might expect. And the studies are revealing serious harms. Here are three things you need to know about niacin.

First, these new studies failed to show that niacin reduced the risk of heart disease and stroke.

The studies found that patients taking niacin had about the same rates of heart disease, stroke and death as those who took a placebo pill with no active ingredients.

Niacin has been known to affect lipid levels since the 1950s. Scientists have examined it in countless studies, almost all of which were not designed to determine if it led to fewer heart attacks, strokes and deaths. The largest previous study to assess whether niacin reduced the risk of heart disease compared with a placebo started in the 1960s, an era that is hardly relevant to medicine today, when so many patients are taking cholesterol-lowering statins.

Therefore, scientists designed these two new studies to determine whether niacin helped patients avoid heart disease and stroke in the statin era. The National Institutes of Health sponsored an American study, and the drug company Merck funded a large international study. One tested extended-release niacin, and the other evaluated a combination of extended-release niacin and laropiprant, an agent designed to make the niacin more tolerable.

Both studies failed to show that niacin reduced the risks of heart disease, stroke and death. Researchers even stopped the American study prematurely because the possibility of finding any benefit became so remote that its continuation seemed futile. Additional follow-up analyses conducted in both studies did not show that niacin provided a convincing benefit to any group of patients.

Second, niacin causes multiple side effects, many of which are serious.

Niacin can be hard to tolerate. It frequently causes uncomfortable flushing and itching, the reason the Merck trial tested niacin with another agent designed to block these nuisance effects.

A disturbing aspect of these recent studies is that in addition to the discomfort that many patients have, they show that niacin can cause more serious side effects. In the international study, niacin:

• increased the risk of gastrointestinal events such as diarrhea and ulcers by 28 percent
• musculoskeletal problems such as muscle damage and gout by 26 percent
• rashes, skin ulcerations and other serious skin-related problems by 67 percent
• infections by 22 percent
• gastrointestinal bleeding or other bleeding by 38 percent

In addition, patients on niacin were 32 percent more likely to receive a diagnosis of diabetes than those not on the drug, and in those with diabetes, niacin increased the risk of serious problems with disease management by 55 percent. 

Safety problems were also apparent in the American study, in which those taking niacin had a higher risk of gastrointestinal problems and infections than those taking a placebo. It is the concordance of these studies in showing harms that is so convincing.

But perhaps the most striking finding of the international study occurred before the trial started. Like many large trials, the study was designed to determine if patients would tolerate the drug before they were randomly assigned to receive niacin with laropiprant or a placebo. 

In this so-called run-in phase of the study, a third of those who were deemed ideal candidates and received the niacin combination withdrew from the study, mainly because of skin, gastrointestinal, musculoskeletal and diabetes side effects. 

So, under careful study conditions, a third of the patients could not even tolerate the drug. The risks that were discovered seem all the more important, because they occurred among individuals who initially tolerated the medication.

Third, there are still experts who say that the recent studies do not provide adequate evidence to stop recommending niacin.

No study is perfect, and for niacin advocates, many of whom have spent their careers promoting and prescribing the drug, the results of the new trials evoked disbelief. 

I was on a panel with a prevention specialist who told an audience of doctors that it made no sense to believe the published trials when personal experience told them otherwise. He then launched into a defense of treatments like niacin.

More reasoned critiques have rightly indicated that the trials focused on high-risk patients, almost all of whom were taking statins and had low levels of LDL cholesterol, the bad stuff. They ask whether niacin might be useful in patients with different lipid profiles, or in those who cannot tolerate statins or who had not already had a diagnosis of heart disease, or in patients with an even higher risk of heart disease and stroke. 

They mostly question whether these trials studied populations that were already receiving intensive treatment and were unlikely to benefit from more drugs. Even the authors of the Merck-sponsored study acknowledge, in the last sentence of their article, that they cannot say whether niacin might be beneficial for patients at even higher risk of having a heart attack or stroke or those with higher LDL levels.

The predicament is that the pursuit of more trials of niacin, particularly given the harms that were recently shown, is unlikely. 

Uncertainty about niacin may linger, accompanied by uncertainty about which patients it may benefit. Harder to dispute will be the drug’s serious side effects. Safety issues alone, even if niacin were beneficial, should give many people reason to avoid it.

Bottom line: If you are taking niacin, talk with your doctor about whether you should continue. 

Many patients will probably choose to bypass a medication without clear benefit and with documented harms. 

For those who decide to continue taking the medication, the hope would be for an experience different from those of the tens of thousands of participants in the recent trials. 

If you are not taking niacin, then realize that there is little reason to start.

An Investigation Into Niacin Pharmacokinetics

Introduction 

The reduction of the plasma levels of cholesterol associated with proatherogenic ‘low-density lipoprotein’ (LDL) particles is one of the most important therapeutic measures to reduce cardiovascular morbidity and mortality. 

LDL cholesterol plasma levels can be pushed far below 100 mg per 100 ml by the inhibition of cholesterol synthesis, using HMG-CoAreductase inhibitors (statins) alone or in combination with cholesterol-resorption inhibitors. 

Despite this very efficacious treatment, clinical studies have shown that even an aggressive reduction in LDL cholesterol reduces the occurrence of cardiovascular events by only 25–40% (Mahley and Bersot, 2006). 

This result is due to the fact that high LDL cholesterol levels are not the only risk factor for cardiovascular diseases. In addition to genetic factors, hypertension, age and cigarette smoking, low ‘high-density lipoprotein’ (HDL) cholesterol levels are also an independent risk factor (Gordon et al., 1977; Castelli et al., 1986). 

Currently, HDL cholesterol levels of p40–45 mg per 100 ml are regarded as a risk factor for coronary heart disease, whereas levels 460 mg per 100 ml are considered protective (Grundy et al., 2004). 

The development of new strategies to elevate HDL cholesterol plasma levels has therefore been intensified in recent years (Chapman, 2006; Rader, 2006). One of the most promising new approaches to raise HDL cholesterol levels, inhibition of the cholesterol ester transfer protein (CETP) (Le Goff et al., 2004), has recently suffered a setback when the CETP inhibitor torcetrapib failed in the phase III trials (Nissen et al., 2007). 

Currently, the oldest lipid-modifying drug, nicotinic acid (niacin), is attracting renewed attention as it has the strongest HDL cholesterol-elevating effect among the drugs currently approved for the treatment of lipid disorders (Table 1). In this review, we will summarize the pharmacology of nicotinic acid with particular focus on recent findings that have elucidated the mechanisms underlying some of the effects of nicotinic acid.

Clinical use of nicotinic acid 

Nicotinic acid has profound and unique effects on lipid metabolism and is thus referred to as a ‘broad-spectrum lipid drug’ (Carlson, 2005). 

In addition to elevating HDL cholesterol (Parsons and Flinn, 1959; Shepherd et al., 1979) as well as decreasing both LDL and total cholesterol (Altschul et al., 1955; Carlson et al., 1977), nicotinic acid also induces a decrease in the concentrations of both ‘very-low-density lipoproteins’ (VLDL) and plasma triglyceride (TG) (Table 1; Carlson et al., 1989). 

The plasma concentration of lipoprotein Lp(a), which has been suggested to play a role as an independent risk factor for coronary heart disease, is also decreased by nicotinic acid (Carlson et al., 1989; Berglund and Ramakrishnan, 2004). 

Soon after the initial discovery of the lipid-modifying effect of high doses of nicotinic acid (Altschul et al., 1955), the water-soluble vitamin nicotinic acid was introduced into clinical therapy as the first lipidmodifying drug. In the Coronary drug project, conducted from 1966 to 1975, nicotinic acid administered as monotherapy at 3 g day 1 was shown to lead to an efficient secondary prevention of myocardial infarction (Table 2) (Coronary Drug Project Research Group, 1975). 

A follow-up study of the Coronary Drug project revealed that nicotinic acid also reduced the mortality of patients who had been treated with nicotinic acid (Canner et al., 1986). 

The Stockholm ischaemic heart disease secondary prevention study came to similar findings (Carlson and Rosenhamer, 1988). 

With the introduction of cholesterol synthesis inhibitors (statins) in the therapy of hypercholesterolaemia during the late 1980s, interest in the therapeutic potential of nicotinic acid decreased. However, in recent years, several clinical studies have been conducted to test whether nicotinic acid provides a benefit to patients who are receiving treatment with statins but still display low HDL cholesterol levels. 

Both the HDL Atherosclerosis Treatment Study and the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol study indicate that patients with low HDL cholesterol levels benefit from a treatment with nicotinic acid in addition to statins (Brown et al., 2001; Taylor et al., 2004). However, both studies are relatively small and have some limitations, including the lack of an ideally designed control group in HDL Atherosclerosis Treatment Study or the evaluation of the intima-media thickness of the carotid artery as a surrogate parameter for the development of clinically relevant atherosclerosis in the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol study. 

In any case, there is good evidence supporting a therapeutic benefit of nicotinic acid (Brown, 2005), and randomized long-term studies to evaluate the effect of nicotinic acid in addition to statins in patients with low HDL cholesterol levels and increased cardiovascular risk have recently been initiated (Brown, 2006).

Nicotinic acid effects on lipid metabolism 

The most rapid effect of nicotinic acid on lipid metabolism is a decrease in plasma levels of free fatty acid, which can be observed within minutes upon administration of the drug. After a few hours, the plasma VLDL and TG levels are reduced, whereas the LDL and HDL cholesterol levels are changed only after several days of treatment (Carlson et al., 1968a). 

Soon after the discovery of the cholesterol-lowering effect of nicotinic acid, the still-prevailing hypothesis was formulated that the effects of nicotinic acid on LDL and HDL cholesterol levels are the result of a very rapid antilipolytic effect on adipocytes (Figure 1). This was based on studies in vivo as well as in vitro using isolated adipocytes (Carlson and Oro¨, 1962; Carlson, 1963; Butcher et al., 1968). 

The rapid decrease in plasma free fatty acid levels due to the antilipolytic effect of nicotinic acid is believed to result in reduced supply of substrate for the hepatic synthesis of TGs and VLDL particles (Lewis, 1997), which in turn leads to reduced formation of LDL particles (Figure 1). 

Recent studies in a hepatoblastoma cell line have suggested that nicotinic acid may have direct effects on hepatocytes, and may decrease hepatic VLDL and TG synthesis by the inhibition of diacylglycerol acyl transferase 2 and accelerating the intracellular degradation of apoprotein B (Jin et al., 1999; Ganji et al., 2004). However, these in vitro effects were observed only at nicotinic acid concentrations considerably higher than the plasma concentrations required for the in vivo effects on the plasma levels of TG and VLDL. 

It is also not clear how nicotinic acid induces an increase in HDL cholesterol levels. The most plausible hypothesis is based on the well-established inverse correlation between TG levels and plasma HDL cholesterol concentrations (Szapary and Rader, 2001), which is primarily due to the exchange of TGs and cholesterol esters between apoprotein B-containing lipoproteins (especially VLDL and LDL) and HDL, which is mediated by CETP. 

According to this concept, the decrease in TG concentration in VLDL and LDL particles in response to nicotinic acid results in a reduced exchange of cholesterol esters and TGs and a subsequent increase in the plasma concentration of HDL cholesterol (Figure 1). This hypothesis is supported by the fact that inhibition of CETP has very similar effects to nicotinic acid treatment on the plasma concentration of HDL, in that both cause an elevation of the HDL2 fraction (Le Goff et al., 2004). 

Interestingly, in mice, which do not express CETP, the relatively high basal HDL cholesterol levels are rather decreased by nicotinic acid. Yet transgenic mice expressing the human CETP gene show lowered levels of basal HDL cholesterol and respond with an increase in HDL cholesterol levels to nicotinic acid treatment (Hernandez et al., 2007). 

However, it has also been proposed that nicotinic acid increases plasma HDL levels by decreasing the catabolism of HDL (Blum et al., 1977; Shepherd et al., 1979). 

In addition, millimolar concentrations of nicotinic acid have been shown to decrease the uptake of HDL-apoprotein A-I by a hepatoma cell line in vitro (Jin et al., 1997). Recent studies have also suggested that some of the beneficial long-term effects of nicotinic acid may, at least in part, involve macrophages. 

Nicotinic acid has been shown to increase the expression of peroxisome proliferator activated receptor-g and to enhance peroxisome proliferator-activated receptor-g transcriptional activity in macrophages (Rubic et al., 2004; Knowles et al., 2006). However, the mechanism underlying this effect and its pharmacological relevance are still unclear. 

The nicotinic acid receptor 

Over 25 years ago, a nicotinic acid receptor on adipocytes was postulated based on the observation that the strong and rapid antilipolytic effects of nicotinic acid are mediated by a Gi-dependent inhibition of adenylyl cyclase (Aktories et al., 1980). 

Following the demonstration of specific binding sites for nicotinic acid on plasma membranes of adipocytes and spleen cells (Lorenzen et al., 2001), the receptor for nicotinic acid was identified (Soga et al., 2003; Tunaru et al., 2003; Wise et al., 2003) as the orphan receptor GPR109A, also referred to as HM74A in humans and protein up-regulated in macrophages by interferone-g (PUMA-G) in mice. 

In addition to brown and white adipose tissue, GPR109A is also expressed in various immune cells, including monocytes, macrophages, dendritic cells and neutrophils (Yousefi et al., 2000; Schaub et al., 2001; Soga et al., 2003; Tunaru et al., 2003; Wise et al., 2003; Maciejewski-Lenoir et al., 2006). GPR109A is coupled to Gi type G proteins, and its activation by nicotinic acid results in a Gi-mediated inhibition of adenylyl cyclase, resulting in a decrease in intracellular cyclic AMP levels. 

This cyclic nucleotide is the principal mediator of adipocyte lipolysis (Figure 1). Lipolysis is increased when cAMP levels are elevated due to increased adenylyl cyclase activity, for example, by b-adrenergic receptor activation or by decreased phosphodiesterase-mediated cAMP degradation (Duncan et al., 2007). 

Thus, the nicotinic acid-induced, GPR109A-mediated adenylyl cyclase inhibition counteracts the prolipolytic effects of elevated intracellular cAMP levels. The relevance of the nicotinic acid receptor GPR109A as a mediator of the pharmacological effects of nicotinic acid could be demonstrated in mice lacking GPR109A. In these animals, the nicotinic acid-induced antilipolytic effects on fat cells as well as the decrease in the plasma levels of free fatty acid and TG in response to nicotinic acid are abrogated (Tunaru et al., 2003). 

Thus, strong evidence exists that at least the initial steps of the nicotinic acid-induced changes in lipid metabolism are mediated by GPR109A. The closest homologue of the human GPR109A is GPR109B, which is not found in rodents and clearly represents the result of a relatively recent gene duplication (Zellner et al., 2005). 

Interestingly, nicotinic acid and related drugs with comparable pharmacological effects, such as acipimox (Fuccella et al., 1980; Tornvall and Walldius 1991), bind to GPR109A but not to GPR109B (Soga et al., 2003; Tunaru et al., 2003; Wise et al., 2003). However, the furan carboxylic acid acifran is able to activate both receptors (Wise et al., 2003; Figure 2). 

Several heterocyclic small molecules have been shown to act as selective agonists of GPR109A, however, none of them appear to surpass nicotinic acid with regard to potency (Wang and Fotsch, 2006; Gharbaoui et al., 2007; Jung et al., 2007; Soudijn et al., 2007). 

Recently, a variety of 1- and 2-substituted benzotriazole-5-carboxylic acids, such as 1-isopropyl-benzotriazole-5- carboxylic acid, have been reported to be selective and relatively potent agonists at GPR109B (Semple et al., 2006). Nicotinamide, which shares with nicotinic acid its function as a vitamin but has no pharmacological effects comparable to nicotinic acid, does not activate any of the receptors (Soga et al., 2003; Tunaru et al., 2003; Wise et al., 2003). 

Under physiological conditions, nicotinic acid concentrations in the plasma are relatively low, thus nicotinic acid is unlikely to be the endogenous ligand for GPR109A. Recently, the endogenous ketone body b-hydroxybutyrate was shown to selectively activate GPR109A (Taggart et al., 2005). 

The potency of b-hydroxybutyrate is relatively low (EC50 ¼ 750 mM) yet does fall within its physiological concentrations in the plasma, which range from 50 to 400 mM under normal conditions to as high as 6–8 mM under starvation conditions. Thus, GPR109A appears to mediate the known antilipolytic effect of high concentrations of b-hydroxybutyrate, a negative feedback mechanism that may contribute to metabolic homoeostasis during starvation (Senior and Loridan, 1968). 

All known agonists of the nicotinic acid receptor GPR109A have in common that they are relatively small molecules, which contain a carboxylic acid moiety. Intensive mutagenesis studies of the nicotinic acid receptor suggest that the binding pocket is formed by transmembrane helices 2, 3 and 7 (Figure 3), and that an arginine residue (Arg111) in the transmembrane helix 3 represents the anchor point for the carboxylic acid group of nicotinic acid and other receptor agonists (Tunaru et al., 2005). 

Other important contacts of the pyridine ring of nicotinic acid with the receptor have been suggested to be localized at the extracellular junction of transmembrane helix 2, the extracellular loop 1 and the transmembrane helix 7. A serine residue (Ser178) in the extracellular loop 2 is essential for binding nicotinic acid to the receptor and may mediate the interaction with the nitrogen of the pyridine ring (Tunaru et al., 2005). 

Pharmacokinetics 

After oral administration, nicotinic acid is absorbed rapidly and maximal plasma concentrations are reached after 30–60 min. The plasma half-life after administration of 1 g nicotinic acid is around 1 h (Carlson et al., 1968b; Svedmyr and Harthon, 1970). 

Nicotinic acid is in part metabolized by the liver and in part excreted unchanged by the kidney. At low doses, a considerable fraction of nicotinic acid is metabolized via nicotinamide to N-methyl-nicotinamide, which is then further metabolized to N-methyl-2-pyridon-5- carboxamide and N-methyl-4-pyridon-5-carboxamide and are then renally excreted (Stern et al., 1992). 

At intermediate and high pharmacological doses (1–3 g), an increasing fraction of nicotinic acid is conjugated with glycin and then excreted as nicotinuric acid by the kidney. With increasing doses, the direct renal excretion of nicotinic acid predominates (Petrack et al., 1966). 

The nicotinic acid-induced flushing response Nicotinic acid, when given at pharmacological doses, has several unwanted yet harmless effects. The most common and most prominent unwanted effect of nicotinic acid is a cutaneous vasodilation, most prominently in the upper half of the body and in the face, which lasts for 1–2 h after an oral dose of nicotinic acid (Goldsmith and Cordill, 1943). 

This cutaneous reaction, called flushing, is relatively unpleasant and therefore negatively influences patients’ compliance. This dilatory effect on dermal blood vessels is also the basis of the local effects of some dermatic formulations of nicotinic acid esters, including propyl-, benzyl- or methylnicotinate. 

In contrast to the nicotinic acid effects on lipid metabolism that are stable over long periods of treatment with nicotinic acid, the nicotinic acid-induced flushing response is subject to some tolerance, resulting in a reduced flushing response in the course of weeks (Stern et al., 1991). 

Recent studies in GPR109A-deficient mice have shown that the nicotinic acid-induced flushing response is mediated by the nicotinic acid receptor (Benyo´ et al., 2005). The failure of GPR109A-deficient mice to respond to nicotinic acid with cutaneous vasodilation can be rescued by transplanting wild-type bone marrow to irradiated GPR109A-deficient animals (Benyo´ et al., 2005), strongly suggesting that the receptor on bone marrow-derived cells and not on adipocytes mediates the flushing response. 

This finding, along with the fact that topical application of skin-permeable nicotinic acid esters results in a cutaneous reaction indistinguishable from the response induced by systemic application of nicotinic acid, suggests that the nicotinic acid-induced flushing response is a local phenomenon induced by activation of the receptor on dermal or epidermal immune cells. 

Strong evidence has been provided that epidermal Langerhans cells are critically involved in the nicotinic acid-induced flushing response (Benyo´ et al., 2006; Maciejewski-Lenoir et al., 2006). This is based on the observation that Langerhans cells express GPR109A and respond to nicotinic acid with an increase in intracellular Ca2 þ as well as the formation of prostanoids (MaciejewskiLenoir et al., 2006). 

In addition, nicotinic acid does not induce a flushing response in mice, which are depleted of Langerhans cells (Benyo´ et al., 2006). It has long been known that treatment with COX inhibitors can reduce the nicotinic acid-induced flushing response while having no effect on the beneficial effects of nicotinic acid (Andersson et al., 1977; Eklund et al., 1979; Kaijser et al., 1979). Indeed, prostanoids, especially prostaglandin D2 (PGD2) or their metabolites, have been shown to be produced after administration of nicotinic acid (Morrow et al., 1989; Stern et al., 1991). 

Pharmacological and genetic evidence from studies in mice clearly indicates that the nicotinic acid-induced flushing response is mediated by PGD2 and prostaglandin E2, which dilate dermal blood vessels via the activation of DP1 and EP2/EP4 receptors (Benyo´ et al., 2005; Cheng et al., 2006). 

From these and other data, a model of the nicotinic acid-induced flushing response has emerged. 

Nicotinic acid induces an increase in intracellular Ca2 þ via activation of GPR109A on epidermal Langerhans cells. This results in the activation of a Ca2 þ - sensitive phospholipase A2 and the formation of arachidonic acid, which is further metabolized to PGD2 and prostaglandin E2. 

Both prostanoids are then able to induce the dilation of blood vessels in the upper layer of the dermis by activation of their Gs-coupled receptors (Figure 4). Several strategies have been proposed to reduce nicotinic acid-induced flushing. 

It is, for example, generally recommended to gradually increase the daily dose over a period of 1–4 months. As the onset of flushing rapidly follows the increase in nicotinic acid plasma levels after oral ingestion, slow-release formulations of nicotinic acid have been generated, which result in a delay and decrease of the peak plasma concentration of nicotinic acid and hence lead to fewer flushing events (Knopp et al., 1998). 

The fact that the antilipolytic effects of nicotinic acid as well as the flushing response are mediated by GPR109A makes it difficult to dissociate these two effects by generating new synthetic agonists of GPR109A. However, recent data indicate that partial agonists of GPR109A may have a reduced efficacy with regard to the induction of flushing while retaining mainly their antilipolytic activity (Richman et al., 2007). 

An alternative approach to reduce the unwanted flushing response could be the co-application of drugs that interfere with the downstream mechanisms of the nicotinic acidinduced flushing response. COX inhibitors including aspirin have been shown to reduce the flush response to nicotinic acid (Oberwittler and Baccara-Dinet, 2006), however, their side effects preclude long-term administration. 

Based on the recent elucidation of the mechanisms underlying nicotinic acid-induced flushing (see above), the specific inhibition of PGD2 and prostaglandin E2 formation or action appears to be a very promising strategy. In fact, it has recently been shown that the DP1 receptor antagonist laropiprant (MK-0524) inhibits the nicotinic acid-induced flushing response in humans (Cheng et al., 2006; Lai et al., 2007). 

Other unwanted effects 

In some cases, the application of nicotinic acid has been reported to result in gastrointestinal effects, such as dyspepsia, diarrhoea or nausea. The mechanisms of these unwanted effects are unclear. 

Increases in plasma transaminase activity indicating a hepatotoxic effect have been reported in patients treated with nicotinic acid. This effect appears to be more frequently observed when sustained-release formulations of nicotinic acid are given, suggesting that an increased hepatic metabolism underlies this hepatotoxic effect (Etchason et al., 1991; Dalton and Berry, 1992). 

Patients predisposed to hyperuricaemia and gout have been reported to display a tendency towards elevated plasma levels of uric acid in response to nicotinic acid, which is likely due to a competition of nicotinic acid and uric acid for the same renal excretion mechanism (Anzai et al., 2007). 

Patients suffering from type II diabetes mellitus often have dyslipidaemic changes characterized by an increase in TG levels as well as a decrease in HDL cholesterol levels. 

Given the characteristic profile of the pharmacological effects of nicotinic acid on lipid metabolism, nicotinic acid should counteract the dyslipidaemic changes in diabetic patients. However, several reports have been published indicating that nicotinic acid increases insulin resistance (Garg and Grundy, 1990; McCulloch et al., 1991). 

The mechanisms of this unwanted effect remain unclear. Recent analyses have, however, indicated that the risk–benefit ratio of nicotinic acid therapy in diabetic patients was similar to that of patient with normal glucose tolerance (Grundy et al., 2002; Canner et al., 2005). 

A final assessment of the effects of long-term nicotinic acid treatment in patients with diabetes mellitus is currently not possible, and rigid glycemic control should be ensured in diabetic or prediabetic patients treated with nicotinic acid. 

Conclusions 

Nearly 50 years ago, nicotinic acid was introduced into clinical practice as the first lipid-modifying drug. Its status among the growing number of antidyslipidaemic drugs has changed over the years. 

With the increased awareness of the role low HDL cholesterol levels play as a risk factor for cardiovascular diseases, the strong HDL cholesterol-elevating effect of nicotinic acid has resulted in an increased interest in the pharmacological properties of this drug. The clinical use of nicotinic acid, however, has been hampered by harmless but unpleasant side effects, primarily the flushing phenomenon. 

With the recent discovery of a specific receptor for nicotinic acid, the molecular mechanisms underlying the pharmacological effects of nicotinic acid have become clearer. In the upcoming years, it will be important to fully understand which of the effects are mediated by the receptor and which are not. 

Research on the mechanisms of nicotinic acid has already strongly influenced the development of new drugs for the treatment of dyslipidaemic states. New agents acting via the nicotinic acid receptor are currently being developed in various pharmaceutical companies. In addition, new co-medications, which aim to suppress the nicotinic acid-induced flushing response without affecting the wanted effects of nicotinic acid, are being tested.

Niacin Risk of Death

After 50 years of being a mainstay cholesterol therapy, niacin should no longer be prescribed for most patients due to potential increased risk of death, dangerous side effects and no benefit in reducing heart attacks and strokes, writes Northwestern Medicine® preventive cardiologist Donald Lloyd-Jones, M.D., in a New England Journal of Medicine editorial published July 16.

Lloyd-Jones’s editorial is based on a large new study published in the journal that looked at adults, ages 50 to 80, with cardiovascular disease who took extended-release niacin (vitamin B3) and laropiprant (a drug that reduces face flushing caused by high doses of niacin) to see if it reduced heart attack and stroke compared to a placebo over four years. All patients in the trial were already being treated with a statin medication.

Niacin did not reduce heart attacks and stroke rates compared with a placebo. More concerning, niacin was associated with an increased trend toward death from all causes as well as significant increases in serious side effects: liver problems, excess infections, excess bleeding, gout, loss of control of blood sugar for diabetics and the development of diabetes in people who didn’t have it when the study began.

“There might be one excess death for every 200 people we put on niacin,” said Lloyd-Jones,

chair of preventive medicine at Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital. “With that kind of signal, this is an unacceptable therapy for the vast majority of patients.”

“For the reduction of heart disease and stroke risk, statins remain the most important drug-based strategy by far because of their demonstrated benefit and their good safety profile,” said Lloyd-Jones, who was a member of the task force that rewrote cholesterol treatment guidelines in 2013 for the American College of Cardiology and the American Heart Association.

Niacin should be reserved only for patients at very high risk for a heart attack and stroke who can’t take statins and for whom there are no other evidence-based options, Lloyd-Jones said.

Niacin raises “good” HDL (high density lipoprotein) cholesterol levels, and having high HDL levels means a lowered risk for cardiovascular events. But clinical trials have not shown that niacin reduced the risk of coronary heart disease or the broader cardiovascular disease specifically by raising HDL. Niacin also produces a modest reduction in low-density lipoprotein (LDL cholesterol) and a more substantial reduction in triglyceride levels, which might be expected to lower the risk of coronary heart disease, Lloyd-Jones notes in the article.

But the new study suggests that higher HDL levels only are a sign of lowered risk for heart attacks and stroke. Raising HDL levels with niacin does not appear to impact cardiovascular outcomes nor does lowering triglyceride levels, Lloyd-Jones points out.

“The recent niacin clinical trials offer important new evidence that raising ‘good’ cholesterol (HDL) levels on top of statin therapy does not have the positive outcome that had been hoped for," said Neil Stone, M.D., the Robert Bonow MD Professor in Cardiology at Feinberg and a cardiologist at Northwestern Memorial Hospital. "Lowering ‘bad’ cholesterol (LDL) with an optimal intensity of tolerated statins and adherence to healthy lifestyle changes remains the most effective approach to prevent strokes and heart attacks for patients at risk of cardiovascular disease.”

Stone was chair of the expert panel that wrote rewrote cholesterol treatment guidelines in 2013 for the American College of Cardiology and the American Heart Association.

Summary of Niacin Effects

• Niacin and its derivative nicotinamide are dietary precursors of nicotinamide adenine dinucleotide (NAD), which can be phosphorylated (NADP) and reduced (NADH and NADPH). NAD functions in oxidation-reduction (redox) reactions and non-redox reactions. 
• Pellagra is the disease of severe niacin deficiency. It is characterized by symptoms affecting the skin, the digestive system, and the nervous system and can lead to death if left untreated.
• Dietary tryptophan can be converted to niacin, although the efficiency of conversion is low in humans and affected by deficiencies in other nutrients. 
• Causes of niacin deficiency include inadequate oral intake, poor bioavailability from unlimed grains, defective tryptophan absorption, metabolic disorders, and the long-term use of chemotherapeutic treatments. 
• The requirements for niacin are based on the urinary excretion of niacin metabolites. 
• NAD is the sole substrate for PARP enzymes involved in DNA repair activity in response to DNA strand breaks; thus, NAD is critical for genome stability. Several studies, mostly using in vitro and animal models, suggest a possible role for niacin in cancer prevention. Nevertheless, large studies are needed to investigate the association between niacin deficiency and cancer risk in human populations. 
• Despite promising initial results, nicotinamide administration has failed to prevent or delay the onset of type 1 diabetes in high-risk relatives of type 1 diabetics. Future research might explore the use of nicotinamide in combined therapy and evaluate activators of NAD-dependent enzymes. 
• At pharmacologic doses, niacin, but not nicotinamide, improves the lipid profile and reduces coronary events and total mortality in patients at high risk for coronary heart disease. Several clinical trials have explored the cardiovascular benefit of niacin in combination with other lipid-lowering medications. 
• Elevated tryptophan breakdown and niacin deficiency have been reported in HIV-positive people. This population is also at high risk for cardiovascular disease, and current data show that they could benefit from niacin supplementation. 
• The tolerable upper intake level (UL) for niacin is based on skin flushing, niacin's most prominent side effect. A new drug, laropiprant, has been developed to reduce skin flushing. Adverse effects have also been reported with pharmacologic doses of niacin administrated alone or in combination with other lipid-lowering medications. 

Niacin is a water-soluble vitamin, which is also known as nicotinic acid or vitamin B3. Nicotinamide is the derivative of niacin and used by the body to form the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP).

Niacin Overview - Usage and Effects

Overview

Vitamin B3 is one of 8 B vitamins. It is also known as niacin (nicotinic acid) and has 2 other forms, niacinamide (nicotinamide) and inositol hexanicotinate, which have different effects from niacin.

All B vitamins help the body convert food (carbohydrates) into fuel (glucose), which the body uses to produce energy. These B vitamins, often referred to as B-complex vitamins, also help the body use fats and protein. B-complex vitamins are needed for a healthy liver, healthy skin, hair, and eyes, and to help the nervous system function properly.

Niacin also helps the body make various sex and stress-related hormones in the adrenal glands and other parts of the body. Niacin helps improve circulation, and it has been shown to suppress inflammation.

All the B vitamins are water-soluble, meaning that the body does not store them.

You can meet all of your body's needs for B3 through diet. It is rare for anyone in the developed world to have a B3 deficiency. In the U.S., alcoholism is the main cause of vitamin B3 deficiency.

Symptoms of mild B3 deficiency include:
Indigestion
Fatigue
Canker sores
Vomiting
Poor circulation
Depression

Severe deficiency can cause a condition known as pellagra. Pellagra is characterized by cracked, scaly skin, dementia, and diarrhea. It is generally treated with a nutritionally balanced diet and niacin supplements. Niacin deficiency also causes burning in the mouth and a swollen, bright red tongue.

Very high doses of B3, available by prescription, have been studied to prevent or improve symptoms of the following conditions. However, at high doses niacin can be toxic. You should not take doses higher than the Recommended Daily Allowance (RDA) except under your doctor's supervision. Researchers are trying to determine if inositol hexanicotinate has similar benefits without serious side effects. But results are inconclusive.

High cholesterol

Niacin, but not niacinamide, has been used since the 1950s to lower elevated LDL (bad) cholesterol and triglyceride (fat) levels in the blood. However, side effects can be unpleasant and even dangerous. High doses of niacin cause:

Flushing of the skin
Stomach upset (which usually subsides within a few weeks)
Headache
Dizziness
Blurred vision
An increased risk of liver damage

A time-release form of niacin reduces flushing. But long-term use is associated with liver damage. In addition, niacin can interact with other cholesterol-lowering medicines. You should not take niacin at high doses without your doctor's supervision.
Atherosclerosis and heart disease

In one study, men with existing heart disease slowed down the progression of atherosclerosis by taking niacin along with colestipol. They experienced fewer heart attacks and deaths, as well.

In another study, people with heart disease and high cholesterol who took niacin along with simvastatin (Zocor) had a lower risk of having a first heart attack or stroke. Their risk of death was also lower. In another study, men who took niacin alone seemed to reduce the risk of having a second heart attack, although it did not reduce the risk of death.
Diabetes

In type 1 diabetes, the body's immune system mistakenly attacks the cells in the pancreas that make insulin, eventually destroying them. Niacinamide may help protect those cells for a time. More research is needed.

Researchers have also looked at whether high-dose niacinamide might reduce the risk of type 1 diabetes in children at risk for the disease. One study found that it did. But another, larger study found it did not protect against developing type 1 diabetes. More research is needed.

The effect of niacin on type 2 diabetes is more complicated. People with type 2 diabetes often have high levels of fats and cholesterol in the blood. Niacin, often along with other medications, can lower those levels. However, niacin may also raise blood sugar levels, which is particularly dangerous for someone with diabetes. For that reason, if you have diabetes, you should take niacin only under the direction of your doctor, and you should be carefully monitored for high blood sugar.

Osteoarthritis

One preliminary study suggested that niacinamide may improve arthritis symptoms, including increasing joint mobility and reducing the amount of non-steroidal anti-inflammatory drugs (NSAIDs) needed. More research is needed.

Other

Alzheimer disease: Population studies show that people who get higher levels of niacin in their diet have a lower risk of Alzheimer disease. No studies have evaluated niacin supplements, however.

Cataracts: One large population study found that people who got a lot of niacin in their diets had a lower risk of developing cataracts.

Skin conditions: Researchers are studying topical forms of niacin as treatments for rosacea, aging, and prevention of skin cancer, although it is too early to know whether it is effective.

Although there is no evidence that it helps treat any of these conditions, researchers are also studying the use of vitamin B3 in treating:

ADHD
Migraines
Dizziness
Depression
Motion sickness
Alcohol dependence

Dietary Sources

The best food sources of vitamin B3 are:

Beets
Brewer's yeast
Beef liver
Beef kidney
Fish
Salmon
Swordfish
Tuna
Sunflower seeds
Peanuts

Bread and cereals are usually fortified with niacin. In addition, foods that contain tryptophan, an amino acid the body coverts into niacin, include poultry, red meat, eggs, and dairy products.

Available Forms

Vitamin B3 is available in several different supplement forms:

Niacinamide
Niacin
Inositol hexaniacinate.

Niacin is available as a tablet or capsule in both regular and timed-release forms. The timed-release tablets and capsules may have fewer side effects than regular niacin. However, the timed-release versions are more likely to cause liver damage. Regardless of which form of niacin you are using, doctors recommend periodic liver function tests when using high doses (above 100 mg per day) of niacin.

How to Take It
Generally, high doses of niacin are used to control specific diseases. Such high doses must be prescribed by a doctor who will increase the amount of niacin slowly, over the course of 4 to 6 weeks. 

Take niacin with meals to avoid stomach irritation.

Daily recommendations for niacin in the diet of healthy individuals are:

Pediatric
Infants, birth to 6 months: 2 mg (adequate intake)
Infants, 7 months to 1 year: 4 mg (adequate intake)
Children, 1 to 3 years: 6 mg (RDA)
Children, 4 to 8 years: 8 mg (RDA)
Children, 9 to 13 years: 12 mg (RDA)
Boys, 14 to 18 years: 16 mg (RDA)
Girls, 14 to 18 years: 14 mg (RDA)

Adult
Men, 19 years and older: 16 mg (RDA)
Women, 19 years and older: 14 mg (RDA)
Pregnant women: 18 mg (RDA)
Breastfeeding women: 17 mg (RDA)

Precautions

Because of the potential for side effects and interactions with medications, you should take dietary supplements only under the supervision of a knowledgeable health care provider. Side effects may include diarrhea, headache, stomach discomfort, and bloating.

High doses (50 mg or more) of niacin can cause side effects. The most common side effect is called "niacin flush," which is a burning, tingling sensation in the face and chest, and red or flushed skin. Taking an aspirin 30 minutes prior to the niacin may help reduce this symptom.

At very high doses, used to lower cholesterol and treat other conditions, liver damage and stomach ulcers can occur. Your doctor will regularly check your liver function through a blood test.

People with a history of liver disease, kidney disease, or stomach ulcers should not take niacin supplements. Those with diabetes or gallbladder disease should do so only under the close supervision of their doctors.

Stop taking niacin or niacinamide at least 2 weeks before a scheduled surgery.

Niacin and niacinamide may make allergies worse by increasing histamine.

People with low blood pressure should not take niacin or niacinamide because they may cause a dangerous drop in blood pressure. DO NOT take niacin if you have a history of gout.

People with coronary artery disease or unstable angina should not take niacin without their doctor's supervision, as large doses can raise the risk of heart rhythm problems.

Taking any one of the B vitamins for a long period of time can result in an imbalance of other important B vitamins. For this reason, you may want to take a B-complex vitamin, which includes all the B vitamins.

Possible Interactions

Because of its impact on the liver, vitamin B3 can interact with several medications. If you are currently taking medications, or regularly drink alcohol, you should not use niacin without talking to your health care provider first. Below is a partial list of medications that may interact with vitamin B3.

Antibiotics, tetracycline: Niacin should not be taken at the same time as the antibiotic tetracycline because it interferes with the absorption and effectiveness of this medication. All vitamin B complex supplements act in this way and should be taken at different times from tetracycline.

Aspirin: Taking aspirin before taking niacin may reduce flushing from niacin. But take it only under your doctor's supervision.

Anti-seizure medications: Phenytoin (Dilantin) and valproic acid (Depakote) may cause niacin deficiency in some people. Taking niacin with carbamazepine (Tegretol) or mysoline (Primidone) may increase levels of these medications in the body.

Anticoagulants (blood thinners): Niacin may make the effects of these medications stronger, increasing the risk of bleeding.

Blood pressure medications, alpha-blockers: Niacin can make the effects of medications taken to lower blood pressure stronger, leading to the risk of low blood pressure.

Cholesterol-lowering medications: Niacin binds the cholesterol-lowering medications known as bile-acid sequestrants and may make them less effective. For this reason, niacin and these medications should be taken at different times of the day. Bile-acid sequestrants include colestipol (Colestid), colesevelam (Welchol), and cholestyramine (Questran).

Statins: Some scientific evidence suggests that taking niacin with simvastatin (Zocor) appears to slow the progression of heart disease. However, the combination may also increase the likelihood for serious side effects, such as muscle inflammation or liver damage.

Diabetes medications: Niacin may increase blood sugar levels. People taking insulin, metformin (Glucophage), glyburide (Dibeta, Micronase), glipizide (Glucotrol), or other medications used to treat high blood glucose levels should monitor their blood sugar levels closely when taking niacin supplements.

Isoniazid (INH): INH, a medication used to treat tuberculosis, may cause a niacin deficiency.

Nicotine patches: Using nicotine patches with niacin may worsen or increase the risk of flushing associated with niacin.

These medications may lower levels of niacin in the body:

Azathioprine (Imuran)
Chloramphenicol (Chloromycetin)
Cycloserine (Seromycin)
Fluorouracil
Levodopa and carbidopa
Mercaptopurine (Purinethol)

Vitamin B3 - Niacin

Vitamin B3, also known as niacin/nicotinic acid, is one of 8 B vitamins. It comes in two other forms:

• niacinamide (nicotinamide) 
• inositol hexanicotinate 

These additional forms have different effects from niacin.

All of the B vitamins, commonly referred to as B-complex vitamins, help convert carbohydrates into glucose, which the body uses for energy. B vitamins also help the body use fats and protein and are essential for a liver,  skin, hair, and eye health, as well as helping the nervous system function.

Niacin also helps the body make various sex and stress-related hormones in the adrenal glands and other parts of the body. It can improve circulation and suppress inflammation. All B vitamins are water-soluble, meaning the body doesn't store them.

It's rare for anyone in the developed world to have a vitamin B3 deficiency. In most developed countries, alcoholism is the main cause of vitamin B3 deficiency.

High cholesterol

Niacin has been used since the 1950s to lower elevated LDL bad cholesterol and triglyceride levels in the blood. However, side effects can be unpleasant and even dangerous. High doses of niacin cause:

• Flushing of the skin
• Stomach upset (which usually subsides within a few weeks)
• Headache
• Dizziness
• Blurred vision
• An increased risk of liver damage

A time-release form of niacin can reduce flushing, but long-term use of the time release form has been associated with liver damage. 

Niacin can interact with other cholesterol-lowering medicines and you shouldn't take niacin at high doses without your doctor's supervision.

In one study, men with heart disease slowed down the progression of atherosclerosis by taking niacin along with colestipol. They experienced fewer heart attacks and deaths.

In another study, people with heart disease and high cholesterol who took niacin along with simvastatin (Zocor) had a lower risk of having a first heart attack or stroke, along with an overall lower risk of death. 

A study also showed that men who took niacin alone seemed to reduce the risk of having a second heart attack, although it did not reduce the risk of death.

The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 study investigated the incremental effect of adding niacin (1 gram daily) to statin therapy in 167 patients with known CHD and low HDL levels on carotid intima-media thickness (CIMT), a surrogate endpoint for the development of atherosclerosis. 

The addition of extended-release niacin prevented the increase in CIMT compared to simvastatin monotherapy. A comparative efficacy trial (ARBITER6) also showed a significant reduction of baseline CIMT with extended-release niacin (2 grams daily for 14 months), as opposed to ezetimibe (a cholesterol-lowering drug), in patients on statins.

The effects of niacin are dose-dependent. Doses of niacin higher than 1 gram/day are typically used to treat hyperlipidemia. 

A placebo-controlled study in 39 patients taking statins (cerivastatin, atorvastatin, or simvastatin) found that a very low dose of niacin, 100 mg daily, increased HDL cholesterol by only 2.1 mg/dL, and the combination had no effect on LDL cholesterol, total cholesterol, or triglyceride levels. 

At the pharmacologic dose required for cholesterol-lowering effects, the use of niacin should be approached as if it were a drug. Individuals should only undertake cholesterol-lowering therapy with niacin under the supervision of a qualified health care provider in order to minimize potentially adverse effects and maximize therapeutic benefits.

Niacin Stimulates Growth Hormone

While extolling the benefits of niacin, one frequently overlooked side effect is that niacin is a powerful releaser of growth hormone.

Quabbe and colleagues administered 500 mg niacin intravenously to humans and noted a dramatic rise in growth hormone. In a second phase of their study, they simultaneously administered an infusion of fatty acids. Note that the fat completely blunted any rise in growth hormone.

The practical take-home lesson of this study is that anyone using niacin as a growth hormone stimulant should take it on an empty stomach (glucose and insulin also inhibit growth hormone, as well as fatty acids).

The results is the MENS. (Melatonin, Exercise, Niacin, Sleep) routine. This routine has shown good success with young people whose growth plates are still open.

In order for the Niacin to properly work, it is recommended to take on an empty stomach, 3+ hours after eating or in the morning upon waking up. After taking the niacin, you cannot eat for another 3 hours so it is best to take it at night before bed or morning right after waking up. Take every odd day, take melatonin every odd day before sleep, Melatonin helps decrease excess estrogen and promotes good sleep. Sprint for 5 minutes every other day, sprinting increases GH. Sleep 8-10 hours a day.