Vitamin B3: Disease Prevention & Treatment

Cancer

Studies of cultured cells in vitro provide evidence that NAD content influences the cellular response to DNA damage, an important risk factor for cancer. Cellular NAD is consumed in the synthesis of ADP-ribose polymers, which play a role in DNA repair, and cyclic ADP-ribose may mediate cell-signaling pathways important in the prevention of cancer. Additionally, cellular NAD content has been found to influence levels of the tumor suppressor protein, p53, in human breast, skin, and lung cells. Neither the cellular NAD content nor the dietary intake of NAD precursors (niacin and tryptophan) necessary for optimizing protective responses following DNA damage has been determined, but they are likely to be higher than required for the prevention of pellagra. Niacin deficiency was found to decrease bone marrow NAD and poly-ADP-ribose levels and increase the risk of chemically induced leukemia, and niacin supplementation decreased the risk of ultraviolet light-induced skin cancers in mice. However, little is known regarding cellular NAD levels and the prevention of DNA damage or cancer in humans. Elevation of NAD levels in blood lymphocytes after supplementation of two healthy individuals with 100 mg/day of nicotinic acid for eight weeks reduced DNA strand breaks in lymphocytes exposed to free radicals in a test tube assay compared to those of non-supplemented individuals. More recently, nicotinic acid supplementation of up to 100 mg/day in 21 healthy smokers failed to provide any evidence of a decrease in cigarette smoke-induced genetic damage in blood lymphocytes compared to placebo.

Generally, relationships between dietary factors and cancer are established first in epidemiologic studies and followed up by basic cancer research on the cellular level. In the case of niacin, research on biochemical and cellular aspects of DNA repair have stimulated an interest in the relationship between niacin intake and cancer risk in human populations. Recently, a large case-control study found increased consumption of niacin, along with antioxidant nutrients, to be associated with decreased incidence of oral (mouth), pharyngeal (throat), and esophageal cancers in northern Italy and Switzerland. An increase in niacin intake of 6.2 mg was associated with about a 40% decrease in cases of cancers of the mouth and throat, while a 5.2 mg increase in niacin intake was associated with a similar decrease in cases of cancer of the esophagus.

Insulin-dependent diabetes mellitus (IDDM)

Insulin-dependent diabetes mellitus in children is known to result from the autoimmune destruction of insulin-secreting beta (b)-cells in the pancreas. Prior to the onset of symptomatic diabetes, specific antibodies, including islet cell antibodies (ICA) can be detected in the blood of high-risk individuals. The ability to detect individuals at high risk for the development of IDDM has led to the enrollment of high-risk siblings of children diagnosed with IDDM into trials designed to prevent its onset. Evidence from in vitro and animal research indicates that high levels of nicotinamide protect b-cells from damage by toxic chemicals, inflammatory white blood cells, and reactive oxygen species. Pharmacologic doses of nicotinamide (up to 3 grams/day) were first used to protect b-cells in patients shortly after the onset of IDDM. An analysis of ten published trials (five placebo-controlled) found evidence of improved b-cell function after one year of treatment with nicotinamide, but failed to find any clinical evidence of improved glycemic (blood glucose) control. Recently, high doses of nicotinamide were found to decrease insulin sensitivity in high-risk relatives of IDDM patients, which might explain the finding of improved b-cell function without concomitant improvement in glycemic control. Several pilot studies for the prevention of IDDM in ICA-positive relatives of patients with IDDM yielded conflicting results, while a large randomized trial in school children that was not placebo-controlled found a significantly lower incidence of IDDM in the nicotinamide-treated group. A large multi-center randomized controlled trial of nicotinamide in ICA-positive siblings of IDDM patients between 3 and 12 years of age recently failed to find a difference in the incidence of IDDM after 3 years. Another large multicenter trial of nicotinamide in high-risk relatives of IDDM patients is presently in progress. Unlike nicotinamide, nicotinic acid has not been found effective in the prevention of IDDM.

DISEASE TREATMENT

High cholesterol and cardiovascular diseases

Pharmacologic doses of nicotinic acid, but not nicotinamide, have been known to reduce serum cholesterol since 1955 . Only one randomized placebo-controlled multicenter trial examined the effect of nicotinic acid therapy alone (3 grams daily) on outcomes of cardiovascular disease. The Coronary Drug Project (CDP) followed over 8,000 men with a previous myocardial infarction (heart attack) for 6 years . In the group that took 3 grams of nicotinic acid daily, total blood cholesterol decreased by an average of 10%, triglycerides decreased by 26%, recurrent nonfatal myocardial infarction decreased by 27%, and cerebrovascular events (stroke + transient ischemic attacks) decreased by 26% compared to the placebo group. Though nicotinic acid therapy did not decrease total deaths or deaths from cardiovascular disease during the 6-year study period, post-trial follow up 9 years later revealed a 10% reduction in total deaths. Four out of five major cardiovascular outcome trials found nicotinic acid in combination with other therapies to be of statistically significant benefit in men and women. Nicotinic acid therapy has been found to result in markedly increased HDL-cholesterol levels, as well as decreased serum Lp(a) lipoprotein concentrations, and a shift from small dense LDL particles to large, buoyant LDL particles, all of which are considered cardioprotective changes in blood lipid profiles. Because of the adverse side effects associated with high doses of nicotinic acid (see Safety), it has most recently been used in combination with other lipid-lowering medications in slightly lower doses. A recent randomized controlled trial found that a combination of nicotinic acid (2 to 3 grams/day) and a cholesterol-lowering drug (simvastatin) resulted in greater benefits on serum HDL levels and cardiovascular events, such as heart attack and stroke, than placebo in patients with coronary artery disease and low HDL levels. However, an antioxidant combination (vitamin E, vitamin C, selenium, and b-carotene) appeared to blunt the beneficial effects of niacin plus simvastatin.

Although it is a nutrient, at the pharmacologic dose required for cholesterol-lowering effects, the use of nicotinic acid should be approached as if it were a drug. Individuals should only undertake cholesterol-lowering therapy with nicotinic acid under the supervision of a qualified health care provider, so that the potential for adverse effects may be minimized and treatment benefit maximized.

HIV/AIDS

It has been hypothesized that infection with human immunodeficiency virus (HIV), the virus that causes acquired immmunodeficiency syndrome (AIDS), increases the risk of niacin deficiency. Interferon-gamma (IF-g) is a cytokine produced by cells of the immune system in response to infection. IF-g levels are elevated in individuals infected with HIV, and higher IF-g levels have been associated with poorer prognosis. By stimulating the enzyme, indoleamine 2,3 dioxygenase (IDO), IF-g is known to increase the breakdown of tryptophan, a niacin precursor, supporting the idea that infection with HIV increases the risk of niacin deficiency. In a very small, uncontrolled study, treatment of four HIV positive individuals with 1,000 to 1,500 mg/day of nicotinamide for 2 months resulted in 40% increases in plasma tryptophan levels. An observational study of 281 HIV-positive men found that higher levels of niacin intake were associated with decreased progression rate to AIDS and improved survival.