Niacin
Niacin, also known as nicotinic acid, is an organic compound and a form of vitamin B3, an essential human nutrient. Niacin is obtained in the diet from a variety of whole and processed foods, with highest contents in fortified packaged foods, meat, poultry, red fish such as tuna and salmon, lesser amounts in nuts, legumes and seeds. Niacin as a dietary supplement is used to treat pellagra, a disease caused by niacin deficiency. Signs and symptoms include skin and mouth lesions, anemia, headaches, and tiredness. Many countries require its addition to wheat flour or other food grains, thereby reducing the risk of pellagra.
Although niacin and nicotinamide are identical in their vitamin activity, nicotinamide does not have the same pharmacological, lipid-modifying effects or side effects as niacin, i.e., when niacin takes on the -amide group, it does not reduce cholesterol nor cause flushing. Nicotinamide is recommended as a treatment for niacin deficiency because it can be administered in remedial amounts without causing the flushing adverse effect.
Niacin 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 niacin. 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, niacin has not been found useful for decreasing the risk of cardiovascular disease in those already on a statin. A 2010 review had concluded effectiveness of niacin as a mono-therapy, but a 2017 review incorporating twice as many trials concluded that prescription niacin, while affecting lipid levels, did not reduce all-cause mortality, cardiovascular mortality, myocardial infarctions, nor fatal or non-fatal strokes. Prescription niacin was shown to cause hepatotoxicity and increase risk of type 2 diabetes. Niacin prescriptions in the U.S. had peaked in 2009, at 9.4million, declining to 1.3million by 2017.
Niacin has the formula and belongs to the group of the pyridinecarboxylic acid. As the precursor for NAD and NADP, niacin is involved in DNA repair.
Definition
Niacin is both a vitamin and a medicine. As a vitamin, recommendations made by several countries are that for adults, intakes of 14–18 mg/day are sufficient to meet the needs of healthy people. When it is used as a medicine to treat elevated cholesterol and triglycerides, daily doses range from 500 to 3,000 mg/day.As vitamin
Niacin and niacinamide are used for prevention and treatment of pellagra, a disease caused by lack of the vitamin. For treating deficiency, the World Health Organization recommends administering niacinamide instead of niacin, to avoid the flushing side effect commonly caused by niacin. Guidelines suggest using 300 mg/day for three to four weeks. Dementia and dermatitis show improvement within a week. Because deficiencies of other B-vitamins may be present, the WHO recommends a multi-vitamin in addition to the niacinamide.Vitamin deficiency
Severe deficiency of niacin in the diet causes the disease pellagra, which is characterized by diarrhea, sun-sensitive dermatitis involving hyperpigmentation and thickening of the skin, inflammation of the mouth and tongue, delirium, dementia, and if left untreated, death. Common psychiatric symptoms of niacin deficiency include irritability, poor concentration, anxiety, fatigue, loss of memory, restlessness, apathy, and depression. The biochemical mechanism the requirement for nicotinamide adenine dinucleotide inhibition of mitochondrial ATP generation, resulting in cell damage; C), activation of the poly polymerase compromise of expression of neuro-protective brain-derived neurotrophic factor or its receptor tropomyosin receptor kinase B; or E) changes to genome expression directly due to the niacin deficiency.Niacin deficiency is rarely seen in developed countries, and it is more typically associated with poverty, malnutrition or malnutrition secondary to chronic alcoholism. It also tends to occur in less developed areas where people eat maize as a staple food, as maize is the only grain low in digestible niacin. A cooking technique called nixtamalization i.e., pretreating with alkali ingredients, increases the bioavailability of niacin during maize meal/flour production. For this reason, people who consume corn as tortillas or hominy are at less risk of niacin deficiency.
Hartnup disease is a hereditary nutritional disorder resulting in niacin deficiency. It is named after an English family with a genetic disorder that resulted in a failure to absorb the essential amino acid tryptophan, tryptophan beng a precursor for niacin synthesis. The symptoms are similar to pellagra, including red, scaly rash and sensitivity to sunlight. Oral niacin or niacinamide is given as a treatment for this condition in doses ranging from 50-100 mg twice a day, with a good prognosis if identified and treated early. Niacin synthesis is also deficient in carcinoid syndrome, because of metabolic diversion of its precursor tryptophan to form serotonin.
Measuring vitamin status
Plasma concentrations of niacin and niacin metabolites are not useful markers of niacin status. Urinary excretion of the methylated metabolite N1-methyl-nicotinamide is considered reliable and sensitive. The measurement requires a 24-hour urine collection. For adults, a value of less than 5.8 µmol/day represent deficient niacin status and 5.8 to 17.5 µmol/day represents low. According to the World Health Organization, an alternative mean of expressing urinary N1-methyl-nicotinamide is as mg/g creatinine in a 24-hour urine collection, with deficient defined as <0.5, low 0.5-1.59, acceptable 1.6-4.29, and high >4.3 Niacin deficiency occurs before the signs and symptoms of pellagra appear. Erythrocyte nicotinamide adenine dinucleotide concentrations potentially provides another sensitive indicator of niacin depletion, although definitions of deficient, low and adequate have not been established. Lastly, plasma tryptophan decreases on a low niacin diet because tryptophan converts to niacin. However, low tryptophan could also be caused by a diet low in this essential amino acid, so it is not specific to confirming vitamin status.Dietary recommendations
The U.S. Institute of Medicine updated Estimated Average Requirements and Recommended Dietary Allowances for niacin in 1998, also Tolerable upper intake levels. In lieu of an RDA, Adequate Intakes are identified for populations for which there is not sufficient evidence to identify a dietary intake level that is sufficient to meet the nutrient requirements of most people.. The European Food Safety Authority refers to the collective set of information as Dietary Reference Values, with Population Reference Intake instead of RDA, and Average Requirement instead of EAR. For the EU, AIs and ULs have the same definition as in the US, except that units are milligrams per megajoule of energy consumed rather than mg/day. For women, men and children the PRI is 1.6 mg per megajoule. As the conversion is 1 MJ = 239 kcal, an adult consuming 2390 kilocalories should be consuming 16 mg niacin. This is comparable to US RDAs.ULs are established by identifying amounts of vitamins and minerals that cause adverse effects, and then selecting as an upper limit amounts that are the "maximum daily intake unlikely to cause adverse health effects." Regulatory agencies from different countries do not always agree. For the US, 30 or 35 mg for teenagers and adults, less for children. The EFSA UL for adults is set at 10 mg/day - about one-third of the US value. For all of the government ULs, the term applies to niacin as a supplement consumed as one dose, and is intended as a limit to avoid the skin flush reaction. This explains why for EFSA, the recommended daily intake can be higher than the UL.
Both the DRI and DRV describe amounts needed as niacin equivalents, calculated as 1 mg NE = 1 mg niacin or 60 mg of the essential amino acid tryptophan. This is because the amino acid is utilized to synthesize the vitamin.
For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value. For niacin labeling purposes 100% of the Daily Value is 16 mg. Prior to 27 May 2016 it was 20 mg, revised to bring it into agreement with the RDA. Compliance with the updated labeling regulations was required by 1 January 2020, for manufacturers with $10million or more in annual food sales, and by 1 January 2021 for manufacturers with less than $10million in annual food sales. During the first six months following the 1 January 2020 compliance date, the FDA plans to work cooperatively with manufacturers to meet the new Nutrition Facts label requirements and will not focus on enforcement actions regarding these requirements during that time. A table of the old and new adult Daily Values is provided at Reference Daily Intake.
Food preparation
Niacin naturally found in food is susceptible to destruction from high heat cooking, especially in the presence of acidic foods and sauces. It is soluble in water, and so may also be lost from foods boiled in water.Food fortification
The Food Fortification Initiative lists all countries in the world that conduct fortification programs, and within each country, what nutrients are added to which foods, and whether those programs are voluntary or mandatory. As of 2020, 54 countries required food fortification of wheat flour with niacin or niacinamide, 14 also mandate fortification of maize flour, and 6 mandate fortification of rice. From country to country, niacin fortification ranges from 1.3 to 6.0 mg/100 g.Ad a dietary supplement
In the United States, niacin 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 niacin for prescription niacin because of potentially serious side effects, which means that niacin should only be used under the supervision of a health care professional, and because manufacture of dietary supplement niacin is not as well-regulated by the FDA as prescription niacin. More than 30 mg niacin 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 niacin, in immediate-release and slow-release forms, is used to treat primary hyperlipidemia and mixed dyslipidemia. 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 U.S. peaked in 2009, at 9.4million and had declined to 1.3million by 2017. Systematic reviews found no effect of prescription niacin on all-cause mortality, cardiovascular mortality, myocardial infarctions, nor fatal or non-fatal strokes despite raising HDL cholesterol. Reported side effects include an increased risk of new-onset type 2 diabetes.Mechanisms
Niacin 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 niacin are partly mediated through the activation of G protein-coupled receptors, including niacin receptor 1 and niacin receptor 2 which are highly expressed in body fat. NIACR1 and NIACR2 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. Niacin also directly inhibits the action of Acyl-CoA:diacylglycerol acyltransferases 2 a key enzyme for triglyceride synthesis.The mechanism behind niacin increasing HDL-C is not totally understood, but seems to occur in various ways. Niacin increases apolipoprotein A1 levels by inhibiting catabolism, resulting in higher reverse cholesterol transport. 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 niacin was combined with the lovastatin trade-named Advicor, and with simvastatin, trade-named Simcor as prescription drug combinations. Advicor was approved by the U.S. Food and Drug Administration in 2001. Simcor was approved in 2008. Subsequently, large outcome trials using these niacin and statin therapies were unable to demonstrate incremental benefit of niacin 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 agreed to discontinue the drugs.Contraindications
Prescription immediate release and extended release niacin are contraindicated for people with active liver disease, persistent elevated serum transaminases, active peptic ulcer disease, or arterial bleeding. 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 niacin 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. The absence of efficacy and safety testing in children 16 years or younger led to the statement that these drugs not approved for children.Adverse effects
The most common adverse effects of medicinal niacin 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 niacin 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 niacin therapy also include liver failure, hepatitis, and acute liver failure; these hepatotoxic effects of niacin occur more often when extended-release dosage forms are used. The long-term use of niacin 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.
Flushing
- a short-term dilatation of skin arterioles, causing reddish skin color - usually lasts for about 15 to 30 minutes, although sometimes can persist for weeks. Typically, the face is affected, but the reaction can extend to neck and upper chest. The cause is blood vessel dilation due to elevation in prostaglandin GD2 and serotonin. Flushing was often thought to involve histamine, but histamine has been shown not to be involved in the reaction. Flushing is sometimes accompanied by a prickly or itching sensation, in particular, in areas covered by clothing.Prevention of flushing requires altering or blocking the prostaglandin-mediated pathway. Aspirin taken half an hour before the niacin prevents flushing, as does ibuprofen. Taking niacin with meals also helps reduce this side effect. Acquired tolerance will also help reduce flushing; after several weeks of a consistent dose, most people no longer experience flushing. Slow- or "sustained"-release forms of niacin have been developed to lessen these side effects.
Liver damage
Niacin in medicinal doses can cause modest elevations in serum transaminase and unconjugated bilirubin, both biomarkers of liver injury. The changes are reversed if drug treatment is stopped, and usually resolve even when drug intake is continued. However, less commonly, the sustained release form of the drug can lead to serious hepatotoxicity, with onset in days to weeks. Early symptoms of serious liver damage include nausea, vomiting and abdominal pain, followed by jaundice and pruritus. The mechanism is thought to be a direct toxicity of elevated serum niacin. Lowering dose or switching to the immediate release form can resolve symptoms. In rare instances the injury is severe, and progresses to liver failure.Diabetes
The high doses of niacin used to treat hyperlipidemia have been shown to elevate fasting blood glucose in people with type 2 diabetes. Long-term niacin therapy was also associated with an increase in the risk of new-onset type 2 diabetes.Other adverse effects
High doses of niacin can also cause niacin maculopathy, a thickening of the macula and retina, which leads to blurred vision and blindness. This maculopathy is reversible after niacin intake ceases. NIASPAN, the slow-release product, has been associated with a reduction in platelet content and a modest increase in prothrombin time.Pharmacology
Pharmacodynamics
Niacin and nicotinamide are both precursors of the coenzymes nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate in vivo. NAD converts to NADP by phosphorylation in the presence of the enzyme NAD+ kinase. NADP and NAD 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. High energy requirements or high turnover rate organs are usually the most susceptible to their deficiency.Activating HCA2 has non-hypolipidemic effects e.g., antioxidative, anti-inflammatory, antithrombotic, improved endothelial function and plaque stability, which counter development and progression of atherosclerosis.
Niacin inhibits cytochrome P450 enzymes CYP2E1, CYP2D6 and CYP3A4. Niacin produces a rise in serum unconjugated bilirubin in normal individuals and in those with Gilbert's Syndrome. However, in the Gilbert's Syndrome, the rise in bilirubin is higher and clearance is delayed longer than in normal people. One test used to aid in diagnosing Gilbert's Syndrome involves intravenous administration of nicotinic acid in a dose of 50 mg over a period of 30 seconds.
Pharmacokinetics
Both niacin and niacinamide are rapidly absorbed from the stomach and small intestine. Absorption is facilitated by sodium-dependent diffusion, and at higher intakes, via passive diffusion. Unlike some other vitamins, the percent absorbed does not decrease with increasing dose, so that even at amounts of 3-4 grams, absorption is nearly complete. With a one gram dose, peak plasma concentrations of 15 to 30 μg/mL are reached within 30 to 60 minutes. Approximately 88% of an oral pharmacologic dose is eliminated by the kidneys as unchanged niacin or nicotinuric acid, its primary metabolite. The plasma elimination half-life of niacin ranges from 20 to 45 minutes.Niacinamide is the major form in the bloodstream. In the liver, niacinamide is converted to storage nicotinamide adenine dinucleotide. As needed, liver NAD is hydrolyzed to niacinamide and niacin for transport to tissues, there reconverted to NAD to serve as an enzyme cofactor. Excess niacin is methylated in the liver to N1-methylnicotinamide and excreted in urine as such or as the oxidized metabolite N1-methyl-2-pyridone-5-carboxamide. Decreased urinary content of these metabolites is a measure of niacin deficiency. For adults, a urine 2-pyridone value of 5.8 to 17.5 µmol/day represents low niacin status and less than 5.8 µmol/day indicates deficiency.
, and melatonin biosynthesis from tryptophan
Production
Biosynthesis
In all animals the liver can synthesize niacin from the essential amino acid tryptophan, a five-step process with the penultimate compound being quinolinic acid. Some bacteria and plants utilize aspartic acid in a pathway that also goes to quinolinic acid. For humans, the efficiency of conversion is estimated as requiring 60mg of tryptophan to make 1mg of niacin. Riboflavin, vitamin B6 and iron are required for the process. The US Institute of Medicine set a Recommended Dietary Allowance for adults of 5 mg/kg body weight/day for tryptophan, equivalent to 350 mg/day for a 70 kg adult. The RDA for protein is 0.8 g/kg, equivalent to 56 g/day for a 70 kg adult. Dietary protein is approximately 1% tryptophan, so achieving the RDA for protein contributes about 560 mg tryptophan per day. Pellagra, a disease due to niacin deficiency, was observed in Europe and elsewhere when poor people consumed large amounts of corn as part of their protein-poor diet, but not so for those in areas where wheat or rice were the low-cost grain, the reason being that corn protein has a lower tryptophan content.Industrial synthesis
Commercial production for animal feed and other purposes is of nicotinamide, which can be converted to niacin. Nicotinonitrile is produced by ammoxidation of 3-methylpyridine. Nitrile hydratase is then used to catalyze nicotinonitrile to nicotinamide. According to Ullmann's Encyclopedia of Industrial Chemistry, worldwide 31,000 tons of nicotinamide were sold in 2014.Chemistry
This colorless, water-soluble solid is a derivative of pyridine, with a carboxyl group at the 3-position. It is an isomer of picolinic acid and isonicotinic acid, in which the carboxyl group is at the 2- and 4-position, respectively. Other forms of vitamin B3 include the corresponding amide nicotinamide, where the carboxyl group has been replaced by a carboxamide group.Preparations
Niacin is available as a prescription product, and in the United States as a dietary supplement. Prescription products can be immediate release or extended release. Dietary supplement products can be immediate or slow release, the latter including inositol hexanicotinate. The last has questionable clinical efficacy in reducing cholesterol levels.Nicotinamide
may be obtained from the diet where it is present primarily as NAD+ and NADP+. These are hydrolysed in the intestine and the resulting nicotinamide is absorbed either as such, or following its hydrolysis, to niacin. Nicotinamide is used to treat niacin deficiency because it does not cause the flushing adverse reaction seen with niacin. Nicotinamide may be toxic to the liver at doses exceeding 3g/day for adults.Extended release
A prescription extended release niacin, Niaspan, has a film coating that delays release of the niacin, resulting in an absorption over a period of 8–12 hours. The extended release formulations generally reduce vasodilation and flushing side effects, but increase the risk of hepatotoxicity compared to the immediate release forms.Combination products
A combination of niacin and laropiprant had been approved for use in Europe and marketed as Tredaptive. Laropiprant is a prostaglandin D2 binding drug shown to reduce niacin-induced vasodilation and flushing. A clinical trial showed no additional efficacy of Tredaptive in lowering cholesterol when used together with other statin drugs, but did show an increase in other side effects. The study resulted in the withdrawal of Tredaptive from the international market.Extended release niacin was combined with the lovastatin as a prescription drug combination, trade named Advicor, and with simvastatin, trade named Simcor. The FDA withdrew approval of both drugs on 18 April 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."
Inositol hexanicotinate
One form of dietary supplement is inositol hexanicotinate, also called inositol nicotinate, which is inositol that has been esterified with niacin on all six of inositol's alcohol groups. IHN is usually sold as "flush-free" or "no-flush" niacin in units of 250, 500, or 1000 mg/tablets or capsules. In the US, it is sold as an over-the-counter formulation, and often is marketed and labeled as niacin, thus misleading consumers into thinking they are getting an active form of the medication. While this form of niacin does not cause the flushing associated with the immediate-release products, the evidence that it has lipid-modifying functions is disputed. As most of the clinical trials date from the early 1960s or the late 1970s, it is difficult to assess them by today's standards. Thus, so far there is not enough evidence to recommend IHN to treat dyslipidemia.History
Niacin as a chemical compound was first described by chemist Hugo Weidel in 1873 in his studies of nicotine, but that predated by many years the concept of food components other than protein, fat and carbohydrates that were essential for life. Vitamin nomenclature was initially alphabetical, with Elmer McCollum calling these fat-soluble A and water soluble B. Over time, eight chemically distinct, water-soluble B vitamins were isolated and numbered, with niacin as vitamin B3.Corn became a staple food in parts of Europe after its introduction from the Americas. A disease that was characterized by dermatitis of sunlight-exposed skin was described in Spain in 1735 by Gaspar Casal. He attributed the cause to poor diet. It was an endemic disease in northern Italy, where it was named "pellagra" from the Lombard language. Because pellagra outbreaks occurred in regions where maize was a dominant food crop, the most convincing hypothesis during the late nineteenth century, as espoused by Cesare Lombroso, was that the maize either carried a toxic substance or was a carrier of disease. Between 1906 and 1940 more than three million Americans were affected by pellagra, with more than 100,000 deaths. Joseph Goldberger was assigned to study pellagra by the Surgeon General of the United States and produced good results in diet studies conducted at orphanages. Goldberger was nominated four times for the Nobel Prize.
Nicotinic acid was extracted from liver by biochemist Conrad Elvehjem in 1937. He later identified the active ingredient, referring to it as "pellagra-preventing factor" and the "anti-blacktongue factor." It was also referred to as "vitamin PP", "vitamin P-P" and "PP-factor", all derived from the term "pellagra-preventive factor". In the late 1930s, studies by Tom Douglas Spies, Marion Blankenhorn, and Clark Cooper confirmed that niacin cured pellagra in humans. The prevalence of the disease was greatly reduced as a result.
In 1942, when flour enrichment with nicotinic acid began, a headline in the popular press said "Tobacco in Your Bread." In response, the Council on Foods and Nutrition of the American Medical Association approved of the Food and Nutrition Board's new names niacin and niacin amide for use primarily by non-scientists. It was thought appropriate to choose a name to dissociate nicotinic acid from nicotine, to avoid the perception that vitamins or niacin-rich food contains nicotine, or that cigarettes contain vitamins. The resulting name niacin was derived from cotinic id + vitam. Carpenter found in 1951, that niacin in corn is biologically unavailable, and can be released only in very alkaline lime water of pH 11. This explains why a Latin-American culture that used alkali-treated cornmeal to make tortilla was not at risk for niacin deficiency.
In 1955, Altschul and colleagues described large amounts of niacin as having a lipid-lowering property. As such, niacin is the oldest known lipid-lowering drug. Lovastatin, the first 'statin' drug, was first marketed in 1987.