Inositol as a Cholesterol-Lowering Agent
By Georges Ramalanjaona, MD, DSc, FACEP, MBA
Coronary heart disease (chd) is the leading cause of death in Western countries, yet its prevalence is low in Japan and developing countries. Primary and secondary prevention clinical trials in persons with elevated cholesterol levels have shown that reducing serum cholesterol levels by diet alone or diet plus drugs results in reduced CHD morbidity and mortality.1 Since the positive association between serum cholesterol level and risk of CHD is well established, it is proposed that dietary fiber may influence the etiology of CHD due to its cholesterol-lowering property.
Inositol or phytic acid (PA), a natural compound found in fiber (seeds and cereal grains), may play a significant role in reducing serum cholesterol by decreasing the zinc:copper ratio.2 A high ratio is associated with hypercholesterolemia.
There is increasing evidence that consumption of non-fermented soy protein, which contains PA, in place of animal protein may lower serum cholesterol levels.
Pharmacokinetics
PA (or myo-inositol hexaphosphate) is a major phosphorus compound. In plants, PA accounts for 70% of the phosphate content and contributes between 1% and 7% of dry weight.
PA has an antinutrient property. It chelates with multivalent cations, such as zinc, calcium, and iron, to form PA-insoluble complexes that are eliminated in the stool, thus reducing the bioavailability of minerals. This inhibitory effect of phytate depends on the degree of phosphorylation of inositol: The higher the degree of phosphorylation, the more significant is the inhibition of cation absorption.
Mechanism of Action
PA has a strong chelating property with minerals. It may have a beneficial effect in lowering serum cholesterol levels by preferential binding of PA to zinc, which results in a decreased zinc:copper ratio.3,4
PA also is considered a natural antioxidant because it inhibits iron-catalyzed hydroxyl radical formation and lipid peroxidation. PA that is endogenous to food may protect against free radical formation within the food and may decrease free radical formation in ingested food in the gastrointestinal tract.5
PA also has been reported to protect against ischemic heart reperfusion injury by chelating iron, eliminating free radical formation, and subsequent lipid peroxidation in vitro.6
Using a rat model, Jariwalla demonstrated the effects of the addition of a natural phytate salt (IP6) on serum lipid and mineral levels in animals fed a cholesterol-enriched and standard diet.1,2 Results showed a significant lowering of serum total cholesterol by IP6 both in animals fed a cholesterol-enriched and standard diet, but a reduction of the zinc:copper ratio only in the cholesterol-enriched group at 11 weeks.
Clinical Studies
To date, there are only limited clinical trials that have studied the effectiveness of PA in reducing serum cholesterol levels in humans.7,8
Dormer and Fisher examined the long-term effects of a widely used form of inositol called inositol hexaniacinate (IHN) on 16 patients who were treated with 400 mg of IHN three times daily for one month, followed by 400 mg four times daily for a total of 40 weeks.8 They reported a statistically significant reduction of serum total cholesterol (P < 0.05) using the pre- and post-treatment analysis (evidence grade I) during the 40 weeks of therapy.
Another trial by Hutt used a sequential control design (evidence grade II) to study the effectiveness of a combination of 900 mg of inositol nicotinate and 1.5 g of Clofibrate daily in 19 patients with hypercholesterolemia during a period of 24 weeks.7 The author reported a statistically significant lowering of low-density lipoprotein (LDL)-cholesterol type IIb (P < 0.05) and an increase of all three types of high-density lipoprotein-cholesterol.
Recently, Anderson et al summarized indirect but strong evidence of the effects of PA in lowering both total and LDL-cholesterol levels using a meta-analysis of 38 controlled clinical trials (evidence grade I).9 They concluded that daily soy protein of 25-50 g (which contained PA and was substituted for animal protein in subjects with higher baseline cholesterol levels), resulted in a 9.3% and 12.9% decrease in total and LDL-cholesterol values, respectively. This hypocholesterolemic benefit of soy was in addition to the effect seen with a diet low in saturated fat and cholesterol.
Several components of soy protein have been implicated in lowering cholesterol levels: PA, isoflavones, and saponins. Although there is an apparent synergy among these components in providing hypocholesterolemic benefit, the exact role of each component and the composition of the soy were not reported in earlier clinical trials.
On-Going Clinical Research
On-going clinical trials in the United States and abroad are testing the nutritional effects of a special corn, which was patented by Victor Raboy in 1997. The corn is low in PA and high in inorganic phosphorus (thus readily absorbable). Clinical trials will examine the effect of the corn on zinc, iron, and calcium absorption, which ultimately affects serum cholesterol in humans.10 These therapeutic trials will continue until statistically significant results are achieved.
Contraindications and Precautions
Diets high in PA may exacerbate malabsorption problems in patients with irritable bowel syndrome and celiac disease. PA supplementation is not recommended in these populations.
Due to its inhibitory effects on minerals, PA consumption should be decreased in people with high calcium or iron requirements (children and pregnant woman) or with low calcium or iron intakes.11
Dosage
Virtually all published clinical trials have used purified PA or dietary PA that is isolated from or a component of a natural product (including seeds, whole grains, and cereals) and comprises between 1% and 7% of the product’s dry weight.11
The oral dose of inositol in its inositol hexaniacinate form is 400 mg three to four times daily.12
Recently, the Food and Drug Administration approved labeling health claims that daily consumption of 25 g of soy protein has a hypocholesterolemic effect as part of a diet low in saturated fat and cholesterol, which may reduce the risk of heart disease.13,14
Conclusion
Current conclusions are derived mainly from in vitro, animal, and epidemiological studies.
Based on these available preliminary data, PA appears to be a safe and effective agent in lowering serum total cholesterol levels. PA could be studied as a reasonable addition to the standard, cholesterol-lowering diet. However, results from human trials studying the effects of dietary PA in preventing heart disease are lacking.
Recommendation
At this time, there is insufficient, direct evidence to recommend PA as a complementary, secondary preventive agent for lowering serum total cholesterol.
PA should not be given to patients with elevated cholesterol levels who have low or marginal zinc, iron, or calcium levels or intakes.
Dr. Ramalanjaona is Associate Chairman for Acad- emic Affairs, Department of Emergency Medicine, Seton Hall University, School of Graduate Medical Educa- tion, South Orange, NJ; and Director of Research, Division of Emergency Medicine, St. Michael’s Hospital, Newark, NJ.
References
1. Jariwalla RJ, et al. Lowering of serum cholesterol and triglycerides and modulation of divalent cations by dietary phytate. J Applied Nutr 1990;42:18-28.
2. Jariwalla RJ. Inositol hexaphosphate (IP6) as an anti-neoplastic and lipid-lowering agent. Anticancer Res 1999;19:3699-3702.
3. Sandberg AS, Anderson H. Effect of dietary phytase on the digestion of phytate in the stomach and small intestine of humans. J Nutr 1988;118:469-473.
4. Klevay LM. Hypocholesterolemia due to sodium phytate. Nutr Rep Int 1997;15:587.
5. Empson KL, et al. Phytic acid as a food antioxidant. J Food Sci 1991;56:560.
6. Ras LS, et al. Protection of ischemic heart from reperfusion injury by myo-inositol hexaphosphate a natural antioxidant. Ann Thor Surg 1991;52:208.
7. Hutt V. Changes in lipids and lipoprotein in patients with hyperlipidemia type IIb, IV, and V treated with different lipid lowering drugs. Artery 1980;8:113-119.
8. Donner V, Fischer FW. The influence of inositol hexaniacinate ester on the serum lipids and lipoproteins. Arzheim-Frosch 1961;11:110-113.
9. Anderson JW, et al. Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 1995; 333:276-282.
10. Marcia W. Therapeutic use of a new corn. Agriculture Res 2000;48:13-17.
11. Zhou JR, Erdman JW. Phytic acid in health and diseases. Gut Rev Food Sci Nutr 1995;35:495-508.
12. Head KA. Inositol hexaniacinate: A safer alternative to niacin. Altern Med Rev 1996:3:176-184.
13. Food labeling: health claims; soy proteins and coronary heart disease. Food and Drug Administration, HHS. Final rule. Federal Reg 1999;57:699-733.
14. Protein Technologies International. Soy Protein and Health: Discovering a Role for Soy Protein in the Fight Against Coronary Heart Disease. Houston, TX: Marimac Communications; 1996.
Ramalanjaona G. Inositol as a cholesterol-lowering agent. Altern Med Alert 2002;5:16-18.Subscribe Now for Access
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