Nicotinic acid

Nicotinic acid, or niacin, is an organic compound and a vitamer ofvitamin B₃, an essential human nutrient. It is produced by plants and animals from the amino acid tryptophan.
Nicotinic acid is also a prescription medication. Amounts far in excess of the recommended dietary intake for vitamin functions will lower blood triglycerides and low density lipoprotein cholesterol, and raise blood high density lipoprotein cholesterol. There are two forms: immediate-release and sustained-release nicotinic acid. Initial prescription amounts are 500 mg/day, increased over time until a therapeutic effect is achieved. Immediate-release doses can be as high as 3,000 mg/day; sustained-release as high as 2,000 mg/day. Despite the proven lipid changes, nicotinic acid has not been found useful for decreasing the risk of cardiovascular disease in those already prescribed a statin drug. A 2010 review had concluded that nicotinic acid was effective as a mono-therapy, but a 2017 review incorporating twice as many trials concluded that prescription nicotinic acid, while affecting lipid levels, did not reduce all-cause mortality, cardiovascular mortality, myocardial infarctions, nor fatal or non-fatal strokes. Prescription nicotinic acid was shown to cause hepatotoxicity and increase risk of type 2 diabetes. Nicotinic acid prescriptions in the United States had peaked in 2009 at 9.4million, declining to 800thousand by 2020. In 2023, it was the 288th most commonly prescribed medication in the US, with more than 500,000 prescriptions.
Nicotinic acid has the formula and belongs to the group of the pyridinecarboxylic acids. As the precursor for nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate, it is involved in DNA repair.
Extra-terrestrial nicotinic acid has been found in carbonaceous chondrite meteorites and in sample-returns from the asteroids 162173 Ryugu and 101955 Bennu.

Definition

The term "niacin" was originally coined from "nicotinic acid vitamin", with the goal of distancing the nutrient B3 from the drug nicotine in tobacco. As a result, it originally referred to the nutritional entity of vitamin B₃. However, in American English, the term has also come to mean "nicotinic acid" in the context of high-dose use as a prescription medicine. In other varieties of English, the medicine is only ever called "nicotinic acid". The term "nicotinic acid" unambiguously refers to the substance and the prescription medicine containing it, which treats elevated cholesterol and triglycerides. When used as a drug, daily doses range from 500 to 3,000 mg/day. High-dose nicotinamide does not have this medicinal effect.
Vitamin B₃ has several vitamers that can act in place of each other, including nicotinic acid and nicotinamide. It is precursor of the coenzymes nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate. These compounds are coenzymes for many dehydrogenases, participating in many hydrogen transfer processes. NAD is important in catabolism of fat, carbohydrate, protein, and alcohol, as well as cell signaling and DNA repair, and NADP mostly in anabolism reactions such as fatty acid and cholesterol synthesis. Vitamin intake recommendations made by several countries are that intakes of 14–18 mg/day are sufficient to meet the needs of healthy adults.
Nicotinic acid and nicotinamide are both used for prevention and treatment of pellagra, a disease caused by lack of the vitamin.

As a dietary supplement

In the United States, nicotinic acid is sold as a non-prescription dietary supplement with a range of 100 to 1000 mg per serving. These products often have a Structure/Function health claim allowed by the US Food & Drug Administration. An example would be "Supports a healthy blood lipid profile." The American Heart Association strongly advises against the substitution of dietary supplement nicotinic acid for prescription nicotinic acid because of potentially serious side effects, which means that nicotinic acid should only be used under the supervision of a health care professional, and because manufacture of dietary supplement nicotinic acid is not as well-regulated by the FDA as prescription nicotinic acid. More than 30 mg nicotinic acid consumed as a dietary supplement can cause skin flushing. Face, arms and chest skin turns a reddish color because of vasodilation of small subcutaneous blood vessels, accompanied by sensations of heat, tingling and itching. These signs and symptoms are typically transient, lasting minutes to hours; they are considered unpleasant rather than toxic.

As lipid-modifying medication

Prescription nicotinic acid, commonly labeled as niacin in the United States, is available in immediate-release and slow-release formulations. It is used to treat primary hyperlipidemia and hypertriglyceridemia. It is used either as a monotherapy or in combination with other lipid-modifying drugs. Dosages start at 500 mg/day and are often gradually increased to as high as 3000 mg/day for immediate release or 2000 mg/day for slow release to achieve the targeted lipid changes. Prescriptions in the US peaked in 2009, at 9.4million and had declined to 800thousand by 2020. In 2023, it was the 288th most commonly prescribed medication in the United States, with more than 500,000 prescriptions.
Systematic reviews found no effect of prescription nicotinic acid on all-cause mortality, cardiovascular mortality, myocardial infarctions, nor fatal or non-fatal strokes despite raising HDL cholesterol in patients already taking statins. Reported side effects include an increased risk of new-onset type 2 diabetes.

Mechanisms

Nicotinic acid reduces synthesis of low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, lipoprotein and triglycerides, and increases high-density lipoprotein cholesterol. The lipid-therapeutic effects of nicotinic acid are partly mediated through the activation of G protein-coupled receptors, including hydroxycarboxylic acid receptor 2 and hydroxycarboxylic acid receptor 3, which are highly expressed in body fat. HCA₂ and HCA₃ inhibit cyclic adenosine monophosphate production and thus suppress the release of free fatty acids from body fat, reducing their availability to the liver to synthesize the blood-circulating lipids in question. A decrease in free fatty acids also suppresses liver expression of apolipoprotein C3 and PPARg coactivator-1b, thus increasing VLDL-C turnover and reducing its production. Nicotinic acid also directly inhibits the action of diacylglycerol O-acyltransferase 2 a key enzyme for triglyceride synthesis.
The mechanism behind nicotinic acid increasing HDL-C is not totally understood, but seems to occur in various ways. Nicotinic acid increases apolipoprotein A1 levels by inhibiting the breakdown of this protein, which is a component of HDL particles. It also inhibits HDL-C hepatic uptake by suppressing production of the cholesterol ester transfer protein gene. It stimulates the ABCA1 transporter in monocytes and macrophages and upregulates peroxisome proliferator-activated receptor gamma, resulting in reverse cholesterol transport.

Combined with statins

Extended release nicotinic acid was combined with lovastatin, and with simvastatin, as prescription drug combinations. The combination niacin/lovastatin was approved by the US Food and Drug Administration in 2001. The combination niacin/simvastatin was approved by the FDA in 2008. Subsequently, large outcome trials using these nicotinic acid and statin therapies were unable to demonstrate incremental benefit of nicotinic acid beyond statin therapy alone. The FDA withdrew approval of both drugs in 2016. The reason given: "Based on the collective evidence from several large cardiovascular outcome trials, the Agency has concluded that the totality of the scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL-cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events." The drug company discontinued the drugs.

Contraindications

Prescription immediate release and extended release nicotinic acid are contraindicated for people with either active or a history of liver disease because both, but especially Niaspan, have been associated with instances of serious, on occasion fatal, liver failure. Both products are contraindicated for people with existing peptic ulcer disease, or other bleeding problems because nicotinic acid lowers platelet count and interferes with blood clotting. Both products are also contraindicated for women who are pregnant or expecting to become pregnant because safety during pregnancy has not been evaluated in human trials. These products are contraindicated for women who are lactating because it is known that nicotinic acid is excreted into human milk, but the amount and potential for adverse effects in the nursing infant are not known. Women are advised to either not nurse their child or discontinue the drug. High-dose nicotinic acid has not been tested or approved for use in children under 16 years.

Adverse effects

The most common adverse effects of medicinal nicotinic acid are flushing of the face, neck and chest, headache, abdominal pain, diarrhea, dyspepsia, nausea, vomiting, rhinitis, pruritus and rash. These can be minimized by initiating therapy at low dosages, increasing dosage gradually, and avoiding administration on an empty stomach.
The acute adverse effects of high-dose nicotinic acid therapy - which is commonly used in the treatment of hyperlipidemias - can further include hypotension, fatigue, glucose intolerance and insulin resistance, heartburn, blurred or impaired vision, and macular edema. With long-term use, the adverse effects of high-dose nicotinic acid therapy also include liver failure, hepatitis, and acute liver failure; these hepatotoxic effects of nicotinic acid occur more often when extended-release dosage forms are used. The long-term use of nicotinic acid at greater than or equal to 2 grams per day also significantly increases the risk of cerebral hemorrhage, ischemic stroke, gastrointestinal ulceration and bleeding, diabetes, dyspepsia, and diarrhea.