Open access peer-reviewed chapter

# The Role of Niacin in the Management of Dyslipidemia

By Joseph M. Keenan

Submitted: April 23rd 2018Reviewed: September 28th 2018Published: November 5th 2018

DOI: 10.5772/intechopen.81725

## Abstract

Niacin or nicotinic acid has been used for the management of dyslipidemia for over 50 years, and it is the first medication that has been shown to reduce both coronary disease events and mortality. It is unique among the various lipid therapies in that it can not only reduce all of atherogenic lipid fractions (total cholesterol, low-density lipoprotein, very low-density lipoprotein, non-HDL lipoproteins, and triglycerides), but is also the most effective agent for raising high-density lipoprotein (specifically Apolipoprotein A-1). It is also the only lipid therapy that can lower lipoprotein (a). Niacin also has non-lipid benefits that improve vascular health and reduce atherogenesis. Niacin therapy was initially hampered by a high incidence of side effects, especially flushing, but this has largely been overcome by extended-release formulations and dosing and administering properly. Despite the failure of two recent clinical trials to show benefit of combining niacin with statins, there are many trials that support using niacin as monotherapy or in combination with other lipid agents including statins. Niacin is also the cheapest lipid agent available, and with the epidemic of cardiovascular disease in the world, it offers great value in the population-wide management of this health problem.

### Keywords

• niacin
• nicotinic acid
• HDL-C
• Lp(a)
• niacin formulations

## 1. Background: early niacin trials

Niacin or vitamin B3 comes in two forms, nicotinamide and nicotinic acid (NA), but only NA has lipid management benefits. The recommended daily allowance of vitamin B3 for nutritional benefit is only 20–30 mg/day, but the dose needed for lipid benefits is much higher and depends on whether one is using immediate-release (IRNA) 3000–6000 mg/day or extended-release (ERNA) 1000–2000 mg/day formulations [1, 2]. The lipid benefits of NA were discovered serendipitously in the 1940–1950s when mega-doses of vitamins were being used in the management of mental health disorders. It was noted that high doses of NA lowered total cholesterol significantly. It was at that same time that elevated cholesterol was found to be associated with increased risk of cardiovascular disease (CVD) that led to the early trials of NA for management of dyslipidemia. Investigators in those early studies did not know what the mechanism of action of NA was but they were impressed that not only did NA lower total cholesterol by 20+%, but also specifically lowered beta lipoprotein cholesterol (LDL-C), raised alpha lipoprotein cholesterol (HDL-C), and lowered triglycerides (TG) [3, 4].

It became evident at that time that high cholesterol was not only associated with increased risk of CVD, but also diet and lifestyle interventions were usually not adequate to reduce cholesterol levels. This led to a large clinical trial, The Coronary Drug Project, that was a head to head trial of the cholesterol lowering agents available then (Thyroxine, Estrogen-two forms, Clofibrate and IRNA). The study was conducted from 1969 to 1975 and had five treatment arms and a large placebo arm totaling 8341 subjects [5]. The thyroxine and both estrogen treatment arms were terminated early due to lack of benefit and the clofibrate arm had some lipid improvements that failed to show reduction in coronary events. The IRNA arm not only demonstrated significant improvements in clinically important lipid fractions (total cholesterol, LDL-C, HDL-C, and TG) but, more importantly, it had a significant decrease in coronary events compared to placebo group. In addition, long-term (15 years) follow-up showed 11% decrease in mortality in the IRNA group compared to the placebo [6]. The only negative aspect of the Coronary Drug Project was the high incidence of flushing (>60%) in the IRNA treatment group. The immediate-release formulation of NA was used in that study, and, even though the majority of subjects were able to develop some level of tolerance, 8% had to drop out due to flushing.

## 2. NA mechanism of action

Nicotinic acid offers multiple clinical benefits to the lipid profile but the most unique and important is its ability to raise HDL-C. The 2017 Guidelines on the Management of Dyslipidemia list low HDL-C and a major risk factor for coronary disease because of important role of HDL-C in reverse cholesterol transport [7]. No agent is more potent at raising HDL-C than NA. NA not only NA raises HDL-C but also selectively prevents liver catabolism of apolipoprotein A-1, which is the key HDL lipoprotein needed for reverse cholesterol transport [8]. Thus NA increases both the capacity and the efficiency of HDL-C cholesterol transport. The liver is the site of synthesis of TG, very low-density lipoprotein (VLDL), lipoprotein (a) (Lp(a)), and LDL-C, and NA attaches to and antagonizes the hydroxycarboxylic acid-2 receptor of hepatocytes. This inhibits a hepatic microsomal enzyme (diacylglycerol acyltransferase-2) that is necessary for the final step in the production of those lipids [8]. Not only does NA reduce the beta lipoproteins that make up LDL-C, but also more specifically NA reduces the small dense LDL-C particles that are most atherogenic. Furthermore, NA is one of the best agents to lower TG and is the only medication that significantly lowers Lp(a), which is also a significant independent risk factor for coronary disease [7].

In addition, in vitro research using human aortic endothelial cells has demonstrated impressive non-lipid benefits of NA in reducing risk of coronary disease. Researchers found that: (1) NA inhibits vascular inflammation by reducing reactive oxygen species, (2) NA reduces LDL-C oxidation making it less atherogenic, and (3) NA reduces vascular adhesion molecules and monocyte chemo-attractant protein-1, which decreases the attachment of monocytes and macrophages to the vascular wall, a key element in early atherogenesis [8]. An animal study demonstrated an additional non-lipid effect of NA, which is a neuroprotective benefit following stroke. The study involved inducing a stroke by middle cerebral artery occlusion in rats. Rats induced with NA within 2 hours of occlusion had a reduced volume of brain tissue damage and improved the functional recovery compared with controls [9] (Table 1).

 Lipid benefits -Lowers total cholesterol-Lowers LDL-C cholesterol (specifically low-density LDL-C)-Lowers triglycerides-Lowers Lp(a)-Raises HDL-C (specifically apolipoprotein A-1) Non-lipid benefits -Inhibits vascular inflammation/reduces reactive oxygen species-Reduces oxygenation of LDL-C-Reduces intravascular adhesion molecules and monocyte chemo-attractant protein-1 (atherogenesis initiators)-May reduce the size and functional recovery time of acute stroke

### Table 1.

Summary of niacin lipid and non-lipid cardiovascular benefits.

Ref. [7, 8, 9].

## 3. Side effects of NA

Despite its many benefits, NA utilization can be hampered by a number of adverse side effects. The good news is virtually all NA side effects are reversible, and most can be minimized or eliminated by appropriate dosing and administration. The most common side effect is flushing and that is more common with IRNA and the initial doses of ERNA. Flushing is caused by release of prostaglandin D2 and prostaglandin E2 from Langerhans cells in the skin and macrophages [8]. In most persons, this flushing response can be minimized by proper dosing and administration (discussed later). William Parsons Jr., a co-investigator in the Coronary Drug Project and an early proponent of NA, was quite disappointed that many clinicians never learned “how to do” niacin resulting in higher dropout rates in NA therapy than that was warranted. This led him to writing a book, “Cholesterol Control Without a Diet! The Niacin Solution” for both lay and professional persons in an effort to educate all on proper NA administration [10].

Another side effect that is sometimes seen with ERNA therapy (but almost never with IRNA) is impaired liver function. This is due to methyl group depletion in the hepatocytes, secondary to the metabolic amidization in the liver of NA to nicotinamide [8]. This problem was shown to be preventable or reversible in most cases without loss of lipid benefit in studies using wax-matrix ERNA (WM-ERNA; Endur-Acin by Endurance Products Inc.) by either dose reduction or methyl group supplementation with methionine [11, 12]. Hepatic transaminase levels should be monitored during NA therapy. Modest transaminase level increases are acceptable, but NA dose reduction should be implemented if levels approach 2–3 times normal limits.

Increased blood glucose levels with NA therapy had raised concerns about its use in persons with diabetes or impaired glucose tolerance (metabolic syndrome). Blood glucose should be monitored in patients on NA treatment but that concern has been largely dismissed by the results from clinical trials. A controlled trial using WM-ERNA in non-diabetics showed only a 1% rise in baseline glucose levels at 6 weeks that returned to baseline by 6 months [13]. The AIM-HIGH trial that used polygel ERNA (PG-ERNA; Niaspan, AbbVie Inc.) specifically recruited persons with low HDL-C and high TG (metabolic syndrome or MS) found a 5% rise initially from baseline glucose levels that returned to baseline over 2 years, and there was no difference in the development of diabetes in the two treatment groups [14]. A post-hoc analysis of the Coronary Drug Project (that used IRNA) found that the subgroup of subjects with MS had comparable reduction in coronary events and long-term mortality to the other subjects in the IRNA treatment group [15]. The consensus is that the benefits of treating lipid risk factors in persons with MS or diabetes outweighs any modest increase that NA treatment may cause to insulin resistance.

There are a number of less common side effects with NA treatment most of which are manageable without discontinuing therapy. Gastrointestinal upset can occur in some individuals and may be due to increased acid production on NA treatment. This is usually managed by splitting the daily dose and taking it with meals. Acid blocking agents may also help. Hyperuricemia may also occur with NA treatment and uric acid levels should be monitored routinely along with blood glucose levels and liver function tests. Nicotinuric acid is a by-product of liver metabolism of NA and can complete with renal excretion of uric acid causing levels to rise. The clinician must decide whether the continued use of NA would require additional management of uric acid levels is worth the lipid benefits. Increased homocysteine levels can occur with NA treatment and these should also be monitored routinely during NA therapy. Hyper-homocysteinemia is also a risk factor for cardiovascular disease that can be managed by folic acid supplementation. Some persons may experience a rash with flushing that usually clears with the development of tolerance, and in a rare instance, a darkened patch of skin may occur (acanthosis nigricans). All of these side effects are completely resolvable/reversible by discontinuing NA if other management of the side effect is unsuccessful.

## 4. Selecting appropriate patients for NA therapy

As described above, the pleiotropic benefits of NA treatment make it an excellent choice for mixed dyslipidemias. One of the most prevalent forms of mixed dyslipidemia that is uniquely suited to NA treatment is MS (low HDL-C, high TG). A study of prevalence of MS in the United States showed 34% of all adults and 55% of persons over the age of 60 has MS [16]. An 8 year prospective study of cardiovascular risk (Framingham) in 3323 middle-aged adults in the United States found the risk of developing CVD over that 8 year period for persons with MS was 34% for men and 16% for women [17]. An epidemiology study of the prevalence of MS in European countries found it as high as 71.7% of adults in some countries and MS-associated CVD prevalence as high as 52% [18]. Thus, the prevalence and the high risk of CVD with MS make this a very large population of persons who would benefit from NA therapy, especially those persons with normal or modest elevations of LDL-C.

The problem of treating MS with NA as monotherapy is achieving the LDL-C goal for that person. Since cardiovascular risk assessment views MS as the equivalent of having a prior coronary event the LDL-C goal is usually more aggressive (e.g.70 mg/dl) and that can be difficult to achieve on NA alone. A meta-analysis in 2010 of NA studies using NA alone or in combination with other agents showed a 26% reduction in coronary events. In addition, they showed a decrease in coronary atherosclerosis in 92% of persons treated with NA, as well as a reduction in carotid intimal thickness of 17 mm per year of NA treatment [2]. Most of these studies were conducted prior to the introduction of statins for lipid management. The compliment of the lipid benefits of NA and the effective LDL-C lowering benefit of statin drugs led to clinical trials using PG-ERNA with statins which did demonstrate broad improvement of lipid profiles (decreased LDL-C, TG, Lp(a), and increased HDL-C) [19, 20]. Modeling of lipid therapy from these studies indicated that an ERNA with a statin would produce optimal lipid values for reducing coronary disease [21].

The early success in lipid profile improvement of combination trials of PG-ERNA/statin led to the development of two very large clinical trials of combination PG-ERNA/statin therapy that were intended to demonstrate conclusively the benefit of combined treatment on the reduction of cardiovascular events and mortality (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes [AIM-HIGH] and Second Heart Protection Study—Treatment of HDL to Reduce the Incidence of Vascular Events [HPS-2 THRIVE]) [22, 23]. The much-anticipated results of those trials were very disappointing and not only failed to demonstrate reduction in vascular events but also appeared to show increased adverse events and side effects with that combination. Critics of these two trials pointed out major design flaws in both studies that raise serious questions about the validity of any conclusions drawn from study results. The AIM-HIGH trial was terminated early because of what was thought to be an increase in cerebrovascular accidents in the PG-ERNA/statin treatment group, which in later analysis was found to be an artifact [22]. The main conclusion of the AIM-HIGH trial was that the combined PG-ERNA/statin treatment group did not show a decrease in cardiovascular events. This, in fact, was not true for the subgroup who were in the highest tertile of baseline TG and the lowest tertile of baseline HDL-C, both lipid fractions that benefitted from the NA addition to treatment [24]. Another AIM-HIGH post-hoc analysis of remnant lipoproteins and HDL-C2 showed that the PG-ERNA/statin treatment group did demonstrate improvements that could confer benefit in prevention of cardiovascular events, but perhaps this was not able to be demonstrated because of early termination [25]. Others also point out that the Coronary Drug Project took 6 years to demonstrate a reduction in coronary events with NA therapy, so the failure of AIM-HIGH and HPS-2 THRIVE to demonstrate the same may have been due to early termination of these studies [26]. Also, one of the lipid benefits of adding NA to a statin is the additional lowering of LDL-C which did occur in the AIM-HIGH trial. However, this benefit was muted since the control group had a second LDL-C lowering drug (ezetimibe) added to their treatment to match any LDL-C lowering by NA in the treatment group [22].

The HPS-2 THRIVE trial was actually PG-ERNA in combination with Laropiprant, a prostaglandin DP1 receptor inhibitor that reduces the NA flushing side effect, and together this combination was added to statin therapy. The investigators had no idea when designing the study that the PG-ERNA/Laropiprant combination would cause such an increase in myopathies especially in Chinese subjects. Of the 25,673 study subjects over 11,000 were Chinese, and their annual incidence of myopathy was 800% greater than that European subjects on the same treatment [27]. Critics of the HPS-2 THRIVE trial felt the addition of Laropiprant to the NA treatment group confounded the outcomes and thus they do not accept it as a legitimate study of the combination of NA and statin therapy [26]. The main conclusion of the HPS-2 THRIVE study was similar to the AIM-HIGH study; that is, the addition of NA to statin therapy did not improve cardiovascular outcomes, and, in fact, resulted in an increase in serious adverse effects [23]. Despite the design flaws in these large trials, the consensus is that adding NA to statin therapy in persons who are already at their LDL-C goal does not improve clinical outcomes. These two large studies raised serious questions about what is the appropriate combination therapy with statins in persons who have not reached their LDL-C goal. While this controversy still lingers, many feel the effectiveness of NA in reducing LDL-C (especially small dense LDL-C particles) as well as the other lipid benefits as shown in earlier studies continues to make NA an appropriate combination with statins to achieve lipid goals and desired clinical endpoints [26].

Recent changes in recommendations of national cholesterol treatment guidelines in the United States have increased the number who are considered eligible to start statin therapy (absolute risk of cardiac event >7.5% over 10 years) to over 50 million persons [28]. The rate of statin intolerance (stopping therapy) in general population cholesterol intervention is 18–20% or about 10 million persons (statin intolerant) in the United States who are candidates for other lipid therapy interventions [29]. This represents another large target group that is appropriate for NA therapy since none of the other agents available have abroad range of lipid and non-lipid benefits for prevention of CVD [8, 26]. Some have suggested that proprotein-convertase subtilisin/kexin type 9 (PCSK-9) inhibitors be used when statin intolerance is encountered. At a cost of $15,000/year for PCSK-9 inhibitors and an estimated incremental cost of$330,000 per quality-adjusted life-years (QALYs), this option is very limited [30].

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Joseph M. Keenan (November 5th 2018). The Role of Niacin in the Management of Dyslipidemia, Dyslipidemia, Samy I. McFarlane, IntechOpen, DOI: 10.5772/intechopen.81725. Available from:

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