Inositol Hexaniacinate: A Safer Alternative to Niacin
Abstract
Niacin has long been prescribed for the treatment of various cardiovascular conditions, particularly the hyperlipidemias. It has been proven effective at lowering VLDL, LDL, total cholesterol and triglyceride levels while raising HDL levels. The side effects of niacin which may occur at the dosages often required for therapeutic efficacy, ranging from flushing and pruritus to hepatoxicity and impaired glucose tolerance, often prove troubling for both patient and practitioner. The need for a safer approach to niacin supplementation has resulted in the investigation of niacin esters. One of the most widely studied of these is inositol hexaniacinate (IHN). In numerous trials it has been found to be virtually free of the side effects associated with conventional niacin therapy. Extensive research has found IHN to be effective in the treatment of hyperlipidemia, Raynaud's disease and intermittent claudication. A number of other conditions which respond favorably to niacin therapy such as hypertension, diabetes, dysmennorhea and alcoholism bear further investigation. (Alt Med Rev 1996;1(3):176-184.)
--------------------------------------------------------------------------------
Importance of Niacin to Human Health:
Niacin (B3, nicotinic acid) is vital to cellular metabolism, principally through its role in the coenzymes, nicotine-adenine dinucleotide (NAD) and nicotine-adenine dinucleotide phosphatate (NADP), in oxidation-reduction reactions. Niacin is primarily metabolized in the liver to niacinamide (nicotinamide) and other derivatives. Niacinamide is, in turn, a precursor to NAD and NADP.1 Due to its vasodilatory effects, niacin (but not niacinamide) has, for decades, been prescribed by orthodox and alternative practitioners alike for the treatment of cardiovascular disease, particularly the hyperlipidemias.1-2 In addition, the use of niacin for the treatment of peripheral vascular disorders including Raynaud's disease and intermittent claudication has been widely studied.3-6 Besides the use of niacin in therapeutic doses, there are certain fractions of the general population that may be deficient in niacin, requiring supplementation to prevent pellagra (the disease of niacin deficiency). These groups include alcoholics7 and the elderly.8
Adverse Effects of Niacin:
Although niacin has numerous therapeutic benefits, it may also result in a considerable number of side effects both acute and chronic, subjective and objective. The acute, subjective symptoms include flushing, particularly of the face and neck with pruritis and burning skin, GI complaints and weakness.9 These effects are due to histamine release from the mast cells, starting approximately 20 minutes after ingestion and lasting from one to one and a half hours. Side effects are often minimized by the addition of aspirin which may create further problems. Although there may also be a reduction of symptoms after several days by increasing the dose gradually and by taking the niacin with meals, many people discontinue its use before ever reaching optimal therapeutic doses. Sustained-release niacin preparations may minimize flushing but result in more gastrointestinal complaints, according to at least one study.1 Chronic conditions may also result from the use of niacin. These may include hepatoxicity, hyperuricemia, glucose intolerance, ocular effects, exacerbation of peptic ulcer, postural hypotension, particularly in patients taking antihypertensive agents, and skin disorders including acanthosis nigricans.1-2 The ocular effects may include decreased vision, cystoid macular edema, periorbital edema, loss of eyebrows or eyelashes and superficial punctate keratitis. These may occur with the use of niacin in high doses and are reversible if it is discontinued.10 Niacin competes with uric acid for renal excretion with subsequent elevation of serum uric acid levels. On rare occasions, this may lead to the development of gout or uric acid kidney stones.11
The hepatotoxic effects are perhaps of the most concern to those administering this therapy on a long-term basis. Abnormalities noted on liver function tests may include dose related increases in aspartate aminotransferase and alkaline phosphatase. Liver pathology may include cholestasis, hepatocellular disarray and nodular formation by fibrous tissue. Severe liver toxicity with regular niacin is quite rare.1 Coppola and Brady12 reported on four cases of niacin-induced hepatotoxicity. All four were taking sustained-release niacin. Fulminant liver failure may occur with the use of high doses of sustained-release niacin as evidenced by the case of a 44-year-old male who developed liver failure after three days on 6 grams daily of timed-release niacin, reported by Mullin et al.13 He had previously consumed up to 6 grams daily of regular crystalline niacin. After 16 months on this regime his liver enzymes had remained normal. Gibbons et al14 reported on the prevalence of side-effects of both sustained-release and regular niacin in a clinical setting. 110 patients in 133 separate trials were given nicotinic acid during a five year period. The results were that 43% of individuals given regular nicotinic acid and 42% of those receiving the sustained-release form were forced to discontinue treatment because of side-effects.14
Inositol Hexaniacinate:
Biochemistry and Metabolism Because of the therapeutic importance of this vitamin it is imperative that we explore safer and perhaps more effective forms of administration. One such form, and probably the most studied, is the hexanicotinic acid ester of meso-inositol, inositol hexaniacinate (IHN), also called inositol hexanicotinate or inositol nicotinate. The compound consists of six molecules of nicotinic acid and one molecule of inositol (See Figure 1).15
It is metabolized in the body into its component parts, niacin and inositol (hexahydroxycyclohexane). In the United States it was first described by Badgett et al. in 1945.15 It appears that the compound is slowly metabolized, not reaching maximum serum levels for approximately 10 hours after ingestion.15 When IHN is administered orally to humans, the result is a sustained increase in the level of free nicotinic acid in blood and plasma.16 Pharmacokinetic studies have indicated that these esters are, at least in part, absorbed intact and hydrolyzed in the body with release of free niacin and inositol. The rise in niacin levels was more than could be explained by observation of the rate of hydrolysis of these esters in buffered solutions of various pHs, designed to simulate the gastric and intestinal juices. Therefore, it was assumed that another mechanism was involved. This was demonstrated by Harthon and Brattsand16 to be an active, enzymatic hydrolysis in the bloodstream.
Safety of Inositol Hexaniacinate
IHN appears to be safe and free of side effects at doses up to 4 grams. Welsh and Ede studied a group of 153 patients with a variety of conditions ranging from RaynaudÕs disease to psoriasis and reported not a single side effect, with doses ranging from 600 to 1800 mg daily. They compared this to patients with the same conditions receiving nicotinic acid. Approximately 1/3 of them reported one or more of the following symptoms: flushing, nausea, vomiting, giddiness and weakness. Furthermore, the IHN patients tolerated without side effects dosages 3 or 4 times larger than the nicotinic acid group.15 Numerous other investigators, studying the use of dosages of IHN in the range of 4 grams daily, reported not a single adverse reaction.3,17-19
Therapeutic Applications of IHN
IHN has a fairly broad range of therapeutic applications. The most well researched conditions include the hyperlipidemias, Raynaud's disease and intermittent claudication. Promising applications which bear further investigation include its use for stasis ulcers, dysmenorrhea, dermatitis herpetiformis, alcoholism, diabetes, cancer prevention and hypertension. These will each be addressed below.
Hyperlipidemia:
Numerous epidemiological studies, both prospective and retrospective, have demonstrated that hyperlipidemia is a major risk factor for the development of atherosclerosis. High levels of very low density lipoproteins (VLDL), low density lipoproteins (LDL), total cholesterol and triglycerides correlate positively with an increased risk for cardiovascular disease (CVD) while elevated levels of high density lipoproteins (HDL) convey cardioprotection.2,20
Niacin, in doses up to 6 grams daily, has long been known to effectively reduce triglycerides, total cholesterol, and LDL cholesterol while at the same time elevating HDL levels1,2,21,22 Supplemental niacin will also reduce the risk of MI in patients with a previous history.23 Niacin appears to effect blood lipids by a number of different mechanisms. It lowers LDL and triglyceride levels by decreasing VLDL synthesis in the liver. This decrease occurs as a chain reaction, beginning with the activation of the enzyme, phosphodiesterase and inhibition of adenylate cyclase activity by nicotinic acid. This in turn inhibits cAMP production in adipocytes.. There is a subsequent decrease in release of free fatty acids (FFA) from peripheral adipose tissue resulting in a decrease in FFA transport to the liver followed by a reduction of VLDL formation which results in a decrease in the LDL cholesterol fraction. The decrease in VLDL and LDL then leads to a decrease in serum triglycerides, phospholipids and cholesterol which generally combine with these lipoproteins.24
Niacin also inhibits cholesterol synthesis from acetate in the liver and appears to increase its degradation as well.24 In addition, elevated blood levels of lipoprotein A have been studied as an independent risk factor for CVD.25 Niacin appears to play a role by altering the function of lipoprotein A-I and reducing synthesis of lipoprotein A-II.2 This is believed to result in an elevation of HDL levels.2
Another interesting effect of niacin is discussed by OÕKeefe, Lavis and McCallister. The susceptibility of LDL to oxidative stress appears to be as or more important than actual levels of LDL cholesterol. It appears that LDL particles must be oxidized by free radicals before they become atherogenic. Relatively small, dense LDL particles seem to be more easily oxidized than their larger, more buoyant counterparts. Niacin has been found to convert the smaller easily oxidized particles to the larger, oxidation-resistant LDL particles.26
The wonders of niacin aside, the problem of side-effects in the doses often necessary to effect a change is significant. The prescription medications available for treatment of hyperlipidemia are also not without side effects. For a brief summary of these medications, mechanisms of action and potential side effects, see Table 1.
Table1. Hypolipidemic Drugs:
Mechanism of Action and Adverse ReactionCategoryMechanism of ActionAdverse Reactions
Bile Acid Sequestrants:
(cholestyramine;colestipol)decreases LDL by binding bile acids and increasing activity of LDL receptorsGI distrubances; may bind certain medications and fat soluble vitamins; decreased prothrombin
Nicotinic Acid
decreases FFA mobilization; decreases LDL and triglycerides by decreasing VLDL synthesis; increases HDL by decreased catabolismflushing; pruritus; GI complaints; hepatotoxicity; hyperuricemia; impaired glucose tolerance
Inositol Hexaniacinate
assumed to be same mechanism as nicotinic acid with the addition of the lipotropic effects of inositolNo side effects reported
HMG-CoA reductase inhibitors: (fluvastatin; lovastatin; mevastatin; pravastatin; simvastatin)
decreases LDL by inhibition of HMC-CoA reductase; increases activity of LDL receptorscarcinogenicity; hepatotoxicity; elevation of creatine kinase; rhabdomyolysis; myositis; stomach ulcers
Fibric Acid derivatives; (bezafibrate; ciprofibrate; clofibrate; fenofibrate; gemfibrozil)
decreases triglycerides by increasing lipoprotein lipase activity; increases HDLcarcinogenicity; bdominal discomfort; gallstones; impaired glucose tolerance; hepatotoxicity; creatine kinase elevation
Probucol
decreases LDL by increasing non-receptor mediated LDL clearanceincrease in QT interval; nonspecific GI complaints; reduced HDL; anemia
Abstract
Niacin has long been prescribed for the treatment of various cardiovascular conditions, particularly the hyperlipidemias. It has been proven effective at lowering VLDL, LDL, total cholesterol and triglyceride levels while raising HDL levels. The side effects of niacin which may occur at the dosages often required for therapeutic efficacy, ranging from flushing and pruritus to hepatoxicity and impaired glucose tolerance, often prove troubling for both patient and practitioner. The need for a safer approach to niacin supplementation has resulted in the investigation of niacin esters. One of the most widely studied of these is inositol hexaniacinate (IHN). In numerous trials it has been found to be virtually free of the side effects associated with conventional niacin therapy. Extensive research has found IHN to be effective in the treatment of hyperlipidemia, Raynaud's disease and intermittent claudication. A number of other conditions which respond favorably to niacin therapy such as hypertension, diabetes, dysmennorhea and alcoholism bear further investigation. (Alt Med Rev 1996;1(3):176-184.)
--------------------------------------------------------------------------------
Importance of Niacin to Human Health:
Niacin (B3, nicotinic acid) is vital to cellular metabolism, principally through its role in the coenzymes, nicotine-adenine dinucleotide (NAD) and nicotine-adenine dinucleotide phosphatate (NADP), in oxidation-reduction reactions. Niacin is primarily metabolized in the liver to niacinamide (nicotinamide) and other derivatives. Niacinamide is, in turn, a precursor to NAD and NADP.1 Due to its vasodilatory effects, niacin (but not niacinamide) has, for decades, been prescribed by orthodox and alternative practitioners alike for the treatment of cardiovascular disease, particularly the hyperlipidemias.1-2 In addition, the use of niacin for the treatment of peripheral vascular disorders including Raynaud's disease and intermittent claudication has been widely studied.3-6 Besides the use of niacin in therapeutic doses, there are certain fractions of the general population that may be deficient in niacin, requiring supplementation to prevent pellagra (the disease of niacin deficiency). These groups include alcoholics7 and the elderly.8
Adverse Effects of Niacin:
Although niacin has numerous therapeutic benefits, it may also result in a considerable number of side effects both acute and chronic, subjective and objective. The acute, subjective symptoms include flushing, particularly of the face and neck with pruritis and burning skin, GI complaints and weakness.9 These effects are due to histamine release from the mast cells, starting approximately 20 minutes after ingestion and lasting from one to one and a half hours. Side effects are often minimized by the addition of aspirin which may create further problems. Although there may also be a reduction of symptoms after several days by increasing the dose gradually and by taking the niacin with meals, many people discontinue its use before ever reaching optimal therapeutic doses. Sustained-release niacin preparations may minimize flushing but result in more gastrointestinal complaints, according to at least one study.1 Chronic conditions may also result from the use of niacin. These may include hepatoxicity, hyperuricemia, glucose intolerance, ocular effects, exacerbation of peptic ulcer, postural hypotension, particularly in patients taking antihypertensive agents, and skin disorders including acanthosis nigricans.1-2 The ocular effects may include decreased vision, cystoid macular edema, periorbital edema, loss of eyebrows or eyelashes and superficial punctate keratitis. These may occur with the use of niacin in high doses and are reversible if it is discontinued.10 Niacin competes with uric acid for renal excretion with subsequent elevation of serum uric acid levels. On rare occasions, this may lead to the development of gout or uric acid kidney stones.11
The hepatotoxic effects are perhaps of the most concern to those administering this therapy on a long-term basis. Abnormalities noted on liver function tests may include dose related increases in aspartate aminotransferase and alkaline phosphatase. Liver pathology may include cholestasis, hepatocellular disarray and nodular formation by fibrous tissue. Severe liver toxicity with regular niacin is quite rare.1 Coppola and Brady12 reported on four cases of niacin-induced hepatotoxicity. All four were taking sustained-release niacin. Fulminant liver failure may occur with the use of high doses of sustained-release niacin as evidenced by the case of a 44-year-old male who developed liver failure after three days on 6 grams daily of timed-release niacin, reported by Mullin et al.13 He had previously consumed up to 6 grams daily of regular crystalline niacin. After 16 months on this regime his liver enzymes had remained normal. Gibbons et al14 reported on the prevalence of side-effects of both sustained-release and regular niacin in a clinical setting. 110 patients in 133 separate trials were given nicotinic acid during a five year period. The results were that 43% of individuals given regular nicotinic acid and 42% of those receiving the sustained-release form were forced to discontinue treatment because of side-effects.14
Inositol Hexaniacinate:
Biochemistry and Metabolism Because of the therapeutic importance of this vitamin it is imperative that we explore safer and perhaps more effective forms of administration. One such form, and probably the most studied, is the hexanicotinic acid ester of meso-inositol, inositol hexaniacinate (IHN), also called inositol hexanicotinate or inositol nicotinate. The compound consists of six molecules of nicotinic acid and one molecule of inositol (See Figure 1).15
It is metabolized in the body into its component parts, niacin and inositol (hexahydroxycyclohexane). In the United States it was first described by Badgett et al. in 1945.15 It appears that the compound is slowly metabolized, not reaching maximum serum levels for approximately 10 hours after ingestion.15 When IHN is administered orally to humans, the result is a sustained increase in the level of free nicotinic acid in blood and plasma.16 Pharmacokinetic studies have indicated that these esters are, at least in part, absorbed intact and hydrolyzed in the body with release of free niacin and inositol. The rise in niacin levels was more than could be explained by observation of the rate of hydrolysis of these esters in buffered solutions of various pHs, designed to simulate the gastric and intestinal juices. Therefore, it was assumed that another mechanism was involved. This was demonstrated by Harthon and Brattsand16 to be an active, enzymatic hydrolysis in the bloodstream.
Safety of Inositol Hexaniacinate
IHN appears to be safe and free of side effects at doses up to 4 grams. Welsh and Ede studied a group of 153 patients with a variety of conditions ranging from RaynaudÕs disease to psoriasis and reported not a single side effect, with doses ranging from 600 to 1800 mg daily. They compared this to patients with the same conditions receiving nicotinic acid. Approximately 1/3 of them reported one or more of the following symptoms: flushing, nausea, vomiting, giddiness and weakness. Furthermore, the IHN patients tolerated without side effects dosages 3 or 4 times larger than the nicotinic acid group.15 Numerous other investigators, studying the use of dosages of IHN in the range of 4 grams daily, reported not a single adverse reaction.3,17-19
Therapeutic Applications of IHN
IHN has a fairly broad range of therapeutic applications. The most well researched conditions include the hyperlipidemias, Raynaud's disease and intermittent claudication. Promising applications which bear further investigation include its use for stasis ulcers, dysmenorrhea, dermatitis herpetiformis, alcoholism, diabetes, cancer prevention and hypertension. These will each be addressed below.
Hyperlipidemia:
Numerous epidemiological studies, both prospective and retrospective, have demonstrated that hyperlipidemia is a major risk factor for the development of atherosclerosis. High levels of very low density lipoproteins (VLDL), low density lipoproteins (LDL), total cholesterol and triglycerides correlate positively with an increased risk for cardiovascular disease (CVD) while elevated levels of high density lipoproteins (HDL) convey cardioprotection.2,20
Niacin, in doses up to 6 grams daily, has long been known to effectively reduce triglycerides, total cholesterol, and LDL cholesterol while at the same time elevating HDL levels1,2,21,22 Supplemental niacin will also reduce the risk of MI in patients with a previous history.23 Niacin appears to effect blood lipids by a number of different mechanisms. It lowers LDL and triglyceride levels by decreasing VLDL synthesis in the liver. This decrease occurs as a chain reaction, beginning with the activation of the enzyme, phosphodiesterase and inhibition of adenylate cyclase activity by nicotinic acid. This in turn inhibits cAMP production in adipocytes.. There is a subsequent decrease in release of free fatty acids (FFA) from peripheral adipose tissue resulting in a decrease in FFA transport to the liver followed by a reduction of VLDL formation which results in a decrease in the LDL cholesterol fraction. The decrease in VLDL and LDL then leads to a decrease in serum triglycerides, phospholipids and cholesterol which generally combine with these lipoproteins.24
Niacin also inhibits cholesterol synthesis from acetate in the liver and appears to increase its degradation as well.24 In addition, elevated blood levels of lipoprotein A have been studied as an independent risk factor for CVD.25 Niacin appears to play a role by altering the function of lipoprotein A-I and reducing synthesis of lipoprotein A-II.2 This is believed to result in an elevation of HDL levels.2
Another interesting effect of niacin is discussed by OÕKeefe, Lavis and McCallister. The susceptibility of LDL to oxidative stress appears to be as or more important than actual levels of LDL cholesterol. It appears that LDL particles must be oxidized by free radicals before they become atherogenic. Relatively small, dense LDL particles seem to be more easily oxidized than their larger, more buoyant counterparts. Niacin has been found to convert the smaller easily oxidized particles to the larger, oxidation-resistant LDL particles.26
The wonders of niacin aside, the problem of side-effects in the doses often necessary to effect a change is significant. The prescription medications available for treatment of hyperlipidemia are also not without side effects. For a brief summary of these medications, mechanisms of action and potential side effects, see Table 1.
Table1. Hypolipidemic Drugs:
Mechanism of Action and Adverse ReactionCategoryMechanism of ActionAdverse Reactions
Bile Acid Sequestrants:
(cholestyramine;colestipol)decreases LDL by binding bile acids and increasing activity of LDL receptorsGI distrubances; may bind certain medications and fat soluble vitamins; decreased prothrombin
Nicotinic Acid
decreases FFA mobilization; decreases LDL and triglycerides by decreasing VLDL synthesis; increases HDL by decreased catabolismflushing; pruritus; GI complaints; hepatotoxicity; hyperuricemia; impaired glucose tolerance
Inositol Hexaniacinate
assumed to be same mechanism as nicotinic acid with the addition of the lipotropic effects of inositolNo side effects reported
HMG-CoA reductase inhibitors: (fluvastatin; lovastatin; mevastatin; pravastatin; simvastatin)
decreases LDL by inhibition of HMC-CoA reductase; increases activity of LDL receptorscarcinogenicity; hepatotoxicity; elevation of creatine kinase; rhabdomyolysis; myositis; stomach ulcers
Fibric Acid derivatives; (bezafibrate; ciprofibrate; clofibrate; fenofibrate; gemfibrozil)
decreases triglycerides by increasing lipoprotein lipase activity; increases HDLcarcinogenicity; bdominal discomfort; gallstones; impaired glucose tolerance; hepatotoxicity; creatine kinase elevation
Probucol
decreases LDL by increasing non-receptor mediated LDL clearanceincrease in QT interval; nonspecific GI complaints; reduced HDL; anemia