Published On: Thu, Apr 18th, 2013

Dietary Supplements for Cholesterol Reduction

cholesterol meterDietary Supplements for Cholesterol Reduction

by Gene Bruno, MS, MHS (Dean of Academics, Huntington College of Health Sciences)

Heart and blood vessel (cardiovascular) disease is the No. 1 killer of Americans, and study after study points to elevated cholesterol as a major contributor to the problem. Some authorities have indicated that for every one percentage point that cholesterol levels are reduced, the risk for cardiovascular disease is reduced by 2 points. The current conventional medical treatment is cholesterol-lowering prescription drugs, along with low saturated fat diets. Although these drugs do lower serum cholesterol, they also have potential side-effects. Consequently, it may make sense to work with your doctor in trying one or more of the following relatively risk-free dietary supplement approaches before taking drugs.

Artichoke extract

You may have enjoyed steamed or grilled artichokes dipped in butter, but this culinary treat also has medicinal properties. Aside from its well-established effects for promoting liver health and popular use in Europe for the treatment of mild indigestion (particularly following a high fat meal) artichoke leaf extract also has the ability to reduce total and LDL cholesterol, and the LDL/HDL ratio over 6 to 12 weeks of treatment. In one double-blind, placebo-controlled study, those using artichoke leaf extract experienced an 18.5% decrease in total cholesterol, compared to 8.6% in the placebo group. The LDL-cholesterol decreased 22.9% in the artichoke group and 6.3% for placebo; and LDL/HDL ratio showed a decrease of 20.2% in the artichoke group and 7.2% in the placebo group. i Other research has shown similar results, and artichoke extract may work better in people with higher cholesterol levels.ii Orally, artichoke extract might increase flatulence in some patients. The typical dose used in research is 1800-1920 mg per day in 2 to 3 divided doses.

Chromium

Chromium supplementation has reduced total cholesterol,iii ivLDL cholesterolv vi and increased HDL cholesterolvii viii in double-blind and other controlled trials, although other trials have not found these effects.ix x One double-blind trial found that high amounts of chromium (500 mcg per day) in combination with daily exercise was highly effective, producing nearly a 20% decrease in total cholesterol levels in just 13 weeks.xi Not surprisingly, people with higher blood levels of chromium appear to be at lower risk for heart disease.xii

Inositol hexanicotinate

High amounts (several grams per day) of niacin lower cholesterol; an effect recognized in the approval of niacin as a prescription medication for high cholesterol.xiii At such intakes, however, acute symptoms (flushing, headache, stomachache) may be severe. In an attempt to avoid the side effects of niacin, alternative health practitioners increasingly use inositol hexaniacinate, recommending 500 to 1,000 mg, taken three times per day, instead of niacin.xiv xv This special form of niacin has been reported to lower serum cholesterol but so far has not been found to cause significant toxicity.xvi

Guggul

Guggul, a mixture of substances taken from a plant, is an approved treatment for elevated cholesterol in India and has been a mainstay of the Ayurvedic approach to preventing atherosclerosis. One double-blind trial studying the effects of guggul reported that serum cholesterol dropped by 17.5%.xvii In another double-blind trial comparing guggul to the drug clofibrate, the average fall in serum cholesterol was slightly greater in the guggul group; moreover, HDL cholesterol rose in 60% of people responding to guggul, while clofibrate did not elevate HDL.xviii A third double-blind trial found significant changes in total and LDL cholesterol levels, but not in HDL.xix Guggul extract, providing 75 to 150 mg of guggulsterones daily, has been given in research 2 to 3 times daily for up to 8 weeks.

Plant Sterols & Stanols

Beta-sitosterol is a plant sterol. Plant sterols are natural substances found in small quantities in many fruits, vegetables, nuts, seeds, cereals, legumes, vegetable oils, and other plant sources. Research has demonstrated that taking beta-sitosterol orally significantly reduces total and low-density lipoprotein (LDL) cholesterol levels, but has little or no effect on high-density lipoprotein (HDL) cholesterol levels. LDL is considered to be the “bad cholesterol”, while HDL is considered to be the “good cholesterol”. The way it works is that beta-sitosterol blocks cholesterol absorption in the intestines, which in turn results in lowered LDL cholesterol in the bloodstream. For the most part, the consumption of about 2 grams daily has been reported to decrease LDL cholesterol levels 9% to 20%, although usual doses have ranged between 800 mg to 6 grams per day and given before meals. Beta-sitosterol is typically given in conjunction with a low-fat diet.xx xxi xxii xxiii xxiv xxv xxvi xxvii xxviii xxix Orally, beta-sitosterol is usually well tolerated. Ezetimibe (Zetia), a medication used to lower cholesterol levels, inhibits intestinal absorption of beta-sitosterol. For most people, 800-2000 mg beta-sitosterol, in divided doses taken before meals, is a good amount.

Similar to sterols, plant stanols are natural substances that occur in even smaller quantities in many of the same sources. Like sterols, stanols block the absorption of cholesterol in the intestines. One stanol, sitostanol, has been extensively researched for its effect upon cholesterol. Specifically, taking sitostanol orally is effective for reducing total and LDL- cholesterol in about 88% of adult patients when used alone or in combination with a low-fat diet or statin drug (drug that inhibits the production of cholesterol in the body).xxx xxxi xxxii xxxiii xxxiv xxxv xxxvi xxxvii xxxviii xxxix xl xli xlii xliii xliv xlv When used alone it can reduce total and LDL cholesterol levels by 10% to 15%. When added to statin drugs, sitostanol reduces total cholesterol and LDL cholesterol by an additional 3% to 11% and 7% to 16%, respectively. Clinical studies have used from 800 mg to 4 grams per day.xlvi The best cholesterol lowering effects occur at about 2 grams per day, but doses above 2 grams per day do not seem to provide additional benefit.xlvii Sitostanols are not currently found in dietary supplements, but they can be found in certain margarine-type spreads and salad dressings. Read product labels in your supermarket and see which of these products provide sitostanol. Orally, sitostanol seems to be very well tolerated. Sitostanol can reduce absorption and blood levels of beta-carotene, so it should be used at a different time if you are taking beta-carotene supplements. For best results, use 2000 mg sitostanol in divided doses taken before meals.

Green Tea Leaf Extract

Although made from the leaves of the same plant that brings us ordinary black tea, green tea differs in that it is less fermented and so contains far more polyphenol catechins and theaflavins, natural ingredients that give green tea its medicinal properties. In double-blind research, green tea extract (GTE) taken orally lowered cholesterol and triglycerides. In one such study the GTE group had significant reduction in LDL-cholesterol and triglyceride, and marked increase in the level of HDL-cholesterol from 1200 mg GTE daily.xlviii In another study, a 10% decrease in systolic blood pressure and a 9% reduction in LDL cholesterol was seen with 583 mg of catechins from GTE compared to no change is systolic blood pressure and a 1% increase in LDL cholesterol in the control group.xlix Likewise, a 375 mg daily of a theaflavin-enriched GTE resulted in an 11.3% reduction in total cholesterol, a 16.4% deduction in LDL-cholesterol, and a 2.3% increase in HDL-cholesterol, while cholesterol levels did not change significantly in the placebo group.l Epidemiological research also indicates that adults who consume 6 or more cups/day of green tea have a 33% lower risk of developing type 2 diabetes compared to those who consume one cup/day or less.li

High doses of green tea extract may cause gastrointestinal upset and/or central nervous system stimulation in some people. Theoretically, the caffeine in green tea might increase the risk of additive CNS effects with amphetamines, although GTE only provides about 10 to 30 mg of caffeine (compared to 100 mg in a cup of moderately brewed coffee). Catechins in green tea and caffeine are reported to have antiplatelet activity, so theoretically green tea might increase the risk of bleeding when used with antiplatelet or anticoagulant drugs (although this interaction has not been reported in humans). The doses used in research ranged between 375 to 1200 mg of GTE. Consuming 375 mg of green tea extract (providing 60% polyphenols) would be equivalent to drinking about 6-8 cups of green tea.

Pantethine

Pantethine is a form of the pantothenic acid, also known as vitamin B5. Taking 900 mg of pantethine in three divided doses daily was shown to reduce triglycerides by 30%, reduce LDL cholesterol 13.5% and raise HDL cholesterol 10% in patients with high cholesterol and triglycerides during a double-blind study.lii Three other double-blind studies showed similar results.liii liv lv In addition, several open studies have specifically examined the use of 600 to 1200 mg pantethine daily to improve cholesterol and triglyceride levels in diabetics and found it to be safe and effective.lvi lvii lviii In one of those studies, 900 mg of pantethine daily resulted in a 16% reduction in total cholesterol, a 30% reduction in very-low-density lipoprotein (VLDL)-cholesterol and a 45% reduction in triglycerides at 2 months.lix Pantethine seems to be well-tolerated. It may cause minor gastrointestinal complaints in some people. Some evidence suggests that pantethine reduces platelet aggregation. When taken concurrently with drugs that affect platelets or coagulation, it might have an additive effect. The most frequently used amount in research seems to be 900 mg daily, in divided doses (e.g., 300 mg, three times daily).

References

i Englisch W, Beckers C, Unkauf M, et al. Efficacy of Artichoke dry extract in patients with hyperlipoproteinemia. Arzneimittelforschung 2000;50:260-5.

ii Pittler MH, Thompson CO, Ernst E. Artichoke leaf extract for treating hypercholesterolaemia. Cochrane Database Syst Rev 2002;3:CD003335.

iii Anderson RA, Cheng N, Bryden NA, et al. Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes. Diabetes 1997; 46:1786-91.

 iv Offenbacher EG, Pi-Sunyer FX. Beneficial effect of chromium-rich yeast on glucose tolerance and blood lipids in elderly subjects. Diabetes 1980; 29:919-25.

 v Press RI, Geller J, Evans GW. The effect of chromium picolinate on serum cholesterol and apolipoprotein fractions in human subjects. West J Med 1990; 152:41-5.

 vi Hermann J, Chung H, Arquitt A, et al. Effects of chromium or copper supplementation on plasma lipids, plasma glucose and serum insulin in adults over age fifty. J Nutr Elderly 1998; 18:27-45.

 vii Riales R, Albrink MJ. Effect of chromium chloride supplementation on glucose tolerance and serum lipids including high-density lipoprotein of adult men. Am J Clin Nutr 1981; 34:2670-8.

 viii Roeback JR, Hla KM, Chambless LE, Fletcher RH. Effects of chromium supplementation on serum high-density lipoprotein cholesterol levels in men taking beta-blockers. Ann Intern Med 1991; 115:917-24.

 ix Uusitupa MI, Kumpulainen JT, Voutilainen E, et al. Effect of inorganic chromium supplementation on glucose tolerance, insulin response, and serum lipids in noninsulin-dependent diabetics. Am J Clin Nutr 1983; 38:404-10.

 x Uusitupa MI, Mykkanen L, Siitonen O, et al. Chromium supplementation in impaired glucose tolerance of elderly: effects on blood glucose, plasma insulin, C-peptide and lipid levels. Br J Nutr 1992; 68:209-16.

 xi Boyd SG, Boone BE, Smith AR, et al. Combined dietary chromium picolinate supplementation and an exercise program leads to a reduction of serum cholesterol and insulin in college-aged subjects. J Nutr Biochem 1998; 9:471-5.

 xii Newman HA, Leighton RF, Lanese RR, Freedland NA. Serum chromium and angiographically determined coronary artery disease. Clin Chem 1978; 541-4.

 xiii Guyton JR, Blazing MA, Hagar J, et al. Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Niaspan-Gemfibrozil Study Group. Arch Intern Med 2000;160:1177–84.

 xiv Head KA. Inositol hexaniacinate: a safer alternative to niacin. Alt Med Rev 1996; 1:176-84.

 xv Murray M. Lipid-lowering drugs vs. Inositol hexaniacinate. Am J Natural Med 1995; 2:9-12.

 xvi Dorner Von G, Fisher FW. Zur Beinflussung der Serumlipide und-lipoproteine durch den Hexanicotinsaureester des m-Inositol. Arzneimittel Forschung 1961; 11:110-3.

 xvii Agarwal RC, Singh SP, Saran RK, et al. Clinical trial of gugulipid new hypolipidemic agent of plant origin in primary hyperlipidemia. Indian J Med Res 1986; 84:626-34.

 xviii Nityanand S, Srivastava JS, Asthana OP. Clinical trials with Gugulipid—a new hypolipidemic agent. J Assoc Phys India 1989; 37:323-8.

 xix Singh RB, Niaz MA, Ghosh S. Hypolipidemic and antioxidant effects of Commiphora mukul as an adjunct to dietary therapy in patients with hypercholesterolemia. Cardiovasc Drugs Ther 1994; 8:659-64.

 xx Becker M, Staab D, Von Bergmann K. Treatment of severe familial hypercholesterolemia in childhood with sitosterol and sitostanol. J Pediatr 1993;122:292-6.

xxi Oster P, Schlierf G, Heuck CC, et al. [Sitosterol in familial hyperlipoproteinemia type II. A randomized, double-blind, cross-over study]. [Article in German]. Dtsch Med Wochenschr 1976;101:1308-11.

xxii Schlierf G, Oster P, Heuck CC, et al. Sitosterol in juvenile type II hyperlipoproteinemia. Atherosclerosis 1978;30:245-8.

xxiii Schwartzkopff W, Jantke HJ. [Dose-effect of beta-sitosterin in type IIa and IIb hypercholesterolemias]. [Article in German]. MMW Munch Med Wochenschr 1978;120:1575-8.

xxiv Becker M, Staab D, Von Bergman K. Long-term treatment of severe familial hypercholesterolemia in children: effect of sitosterol and bezafibrate. Pediatrics 1992;89:138-42.

xxv Weststrate JA, Meijer GW. Plant sterol-enriched margarines and reduction of plasma total- and LDL-cholesterol concentrations in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr 1998;52:334-43.

xxvi Anon. FDA authorizes new coronary heart disease health claim for plant sterol and plant stanol esters. FDA. 2000. Available at: www.fda.gov/bbs/topics/ANSWERS/ANS01033.html.

xxvii Lichtenstein AH, Deckelbaum RJ. Stanol/sterol ester-containing foods and blood cholesterol levels: a statement for healthcare professionals from Nutrition Committee, Council on Nutrition, Physical Activity, Metabolism of American Heart Association. Circulation 2001;103:1177-9.

xxviii Matvienko OA, Lewis DS, Swanson M, et al. A single daily dose of soybean phytosterols in ground beef decreases serum total cholesterol and LDL cholesterol in young, mildly hypercholesterolemic men. Am J Clin Nutr 2002;76:57-64.

xxix Neil HA, Meijer GW, Roe LS. Randomised controlled trial of use by hypercholesterolaemic patients of a vegetable oil sterol-enriched fat spread. Atherosclerosis 2001;156:329-37.

xxx Nguyen TT, Dale Pittler MH, Thompson CO, Ernst E. Artichoke leaf extract for treating hypercholesterolaemia. Cochrane Database Syst Rev 2002;3:CD003335.

 Anderson RA, Cheng N, Bryden NA, et al. Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes. Diabetes 1997; 46:1786-91.

 Offenbacher EG, Pi-Sunyer FX. Beneficial effect of chromium-rich yeast on glucose tolerance and blood lipids in elderly subjects. Diabetes 1980; 29:919-25.

 Press RI, Geller J, Evans GW. The effect of chromium picolinate on serum cholesterol and apolipoprotein fractions in human subjects. West J Med 1990; 152:41-5.

 Hermann J, Chung H, Arquitt A, et al. Effects of chromium or copper supplementation on plasma lipids, plasma glucose and serum insulin in adults over age fifty. J Nutr Elderly 1998; 18:27-45.

 Riales R, Albrink MJ. Effect of chromium chloride supplementation on glucose tolerance and serum lipids including high-density lipoprotein of adult men. Am J Clin Nutr 1981; 34:2670-8.

 Roeback JR, Hla KM, Chambless LE, Fletcher RH. Effects of chromium supplementation on serum high-density lipoprotein cholesterol levels in men taking beta-blockers. Ann Intern Med 1991; 115:917-24.

 Uusitupa MI, Kumpulainen JT, Voutilainen E, et al. Effect of inorganic chromium supplementation on glucose tolerance, insulin response, and serum lipids in noninsulin-dependent diabetics. Am J Clin Nutr 1983; 38:404-10.

 Uusitupa MI, Mykkanen L, Siitonen O, et al. Chromium supplementation in impaired glucose tolerance of elderly: effects on blood glucose, plasma insulin, C-peptide and lipid levels. Br J Nutr 1992; 68:209-16.

 Boyd SG, Boone BE, Smith AR, et al. Combined dietary chromium picolinate supplementation and an exercise program leads to a reduction of serum cholesterol and insulin in college-aged subjects. J Nutr Biochem 1998; 9:471-5.

 Newman HA, Leighton RF, Lanese RR, Freedland NA. Serum chromium and angiographically determined coronary artery disease. Clin Chem 1978; 541-4.

 Guyton JR, Blazing MA, Hagar J, et al. Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Niaspan-Gemfibrozil Study Group. Arch Intern Med 2000;160:1177–84.

 Head KA. Inositol hexaniacinate: a safer alternative to niacin. Alt Med Rev 1996; 1:176-84.

 Murray M. Lipid-lowering drugs vs. Inositol hexaniacinate. Am J Natural Med 1995; 2:9-12.

 Dorner Von G, Fisher FW. Zur Beinflussung der Serumlipide und-lipoproteine durch den Hexanicotinsaureester des m-Inositol. Arzneimittel Forschung 1961; 11:110-3.

 Agarwal RC, Singh SP, Saran RK, et al. Clinical trial of gugulipid new hypolipidemic agent of plant origin in primary hyperlipidemia. Indian J Med Res 1986; 84:626-34.

 Nityanand S, Srivastava JS, Asthana OP. Clinical trials with Gugulipid—a new hypolipidemic agent. J Assoc Phys India 1989; 37:323-8.

 Singh RB, Niaz MA, Ghosh S. Hypolipidemic and antioxidant effects of Commiphora mukul as an adjunct to dietary therapy in patients with hypercholesterolemia. Cardiovasc Drugs Ther 1994; 8:659-64.

 Becker M, Staab D, Von Bergmann K. Treatment of severe familial hypercholesterolemia in childhood with sitosterol and sitostanol. J Pediatr 1993;122:292-6.

 Oster P, Schlierf G, Heuck CC, et al. [Sitosterol in familial hyperlipoproteinemia type II. A randomized, double-blind, cross-over study]. [Article in German]. Dtsch Med Wochenschr 1976;101:1308-11.

 Schlierf G, Oster P, Heuck CC, et al. Sitosterol in juvenile type II hyperlipoproteinemia. Atherosclerosis 1978;30:245-8.

 Schwartzkopff W, Jantke HJ. [Dose-effect of beta-sitosterin in type IIa and IIb hypercholesterolemias]. [Article in German]. MMW Munch Med Wochenschr 1978;120:1575-8.

 Becker M, Staab D, Von Bergman K. Long-term treatment of severe familial hypercholesterolemia in children: effect of sitosterol and bezafibrate. Pediatrics 1992;89:138-42.

 Weststrate JA, Meijer GW. Plant sterol-enriched margarines and reduction of plasma total- and LDL-cholesterol concentrations in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr 1998;52:334-43.

 Anon. FDA authorizes new coronary heart disease health claim for plant sterol and plant stanol esters. FDA. 2000. Available at: www.fda.gov/bbs/topics/ANSWERS/ANS01033.html. LC, von Bergmann K, Croghan IT. Cholesterol-lowering effect of stanol ester in a US population of mildly hypercholesterolemic men and women: a randomized controlled trial. Mayo Clin Proc 1999;74:1198-206.

xxxi Vuorio AF, Gylling H, Turtola H, et al. Stanol ester margarine alone and with simvastatin lowers serum cholesterol in families with familial hypercholesterolemia caused by the FH-north karelia mutation. Arterioscler Thromb Vasc Biol 2000;20:500-6.

xxxii Weststrate JA, Meijer GW. Plant sterol-enriched margarines and reduction of plasma total- and LDL-cholesterol concentrations in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr 1998;52:334-43.

xxxiii Gylling H, Miettinen TA. Cholesterol reduction by different plant stanol mixtures and with variable fat intake. Metabolism 1999;48:575-80.

xxxiv Gylling H, Puska P, Vartiainen E, et al. Serum sterols during stanol ester feeding in a mildly hypercholesterolemic population. J Lipid Res 1999;40:593-600.

xxxv Gylling H, Radhakrishnan R, Miettinen TA. Reduction of serum cholesterol in postmenopausal women with previous myocardial infarction and cholesterol malabsorption induced by dietary sitostanol ester margarine: women and dietary sitostanol. Circulation 1997;96:4226-31.

xxxvi Gylling H, Miettinen TA. Serum cholesterol and cholesterol and lipoprotein metabolism in hypercholesterolaemic NIDDM patients before and during sitostanol ester-margarine treatment. Diabetologia 1994;37:773-80.

xxxvii Gylling H, Miettinen TA. Effects of inhibiting cholesterol absorption and synthesis on cholesterol and lipoprotein metabolism in hypercholesterolemic non-insulin-dependent diabetic men. J Lipid Res 1996;37:1776-85.

xxxviii Gylling H, Puska P, Vartiainen E, et al. Retinol, vitamin D, carotenes and alpha-tocopherol in serum of a moderately hypercholesterolemic population consuming sitostanol ester margarine. Am J Cardiol 1999;145:279-85.

xxxix Hallikainen MA, Uusitupa MI. Effects of 2 low-fat stanol ester-containing margarines on serum cholesterol concentrations as part of a low-fat diet in hypercholesterolemic subjects. Am J Clin Nutr 1999;69:403-10.

xl Jones PJ, Ntanios FY, Raeini-Sarjaz M, et al. Cholesterol-lowering efficacy of a sitostanol-containing phytosterol mixture with a prudent diet in hyperlipidemic men. Am J Clin Nutr 1999;69:1144-50.

xli Gylling H, Siimes MA, Miettinen TA. Sitostanol ester margarine in dietary treatment of children with familial hypercholesterolemia. J Lipid Res 1995;36:1807-12.

xlii Miettinen TA, Puska P, Gylling H, et al. Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population. N Engl J Med 1995;333(20):1308-12.

xliii Vanhanen HT, Kajander J, Lehtovirta H. Serum levels, absorption efficiency, faecal elimination and synthesis of cholesterol during increasing doses of dietary sitostanol esters in hypercholesterolaemic subjects. Clin Sci (Colch) 1994;87:61-7.

xliv Plat J, van Onselen EN, van Heugten MM, Mensink RP. Effects on serum lipids, lipoproteins and fat soluble antioxidant concentrations of consumption frequency of margarines and shortenings enriched with plant stanol esters. Eur J Clin Nutr 2000;54:671-7.

xlv Hallikainen MA, Sarkkinen ES, Gylling H, et al. Comparison of the effects of plant sterol ester and plant stanol ester-enriched margarines in lowering serum cholesterol concentrations in hypercholesterolaemic subjects on a low-fat diet. Eur J Clin Nutr 2000;54:715-25.

xlvi Law M. Plant sterol and stanol margarines and health. BMJ 2000;320:861-4.

xlvii Lichtenstein AH, Deckelbaum RJ. Stanol/sterol ester-containing foods and blood cholesterol levels: a statement for healthcare professionals from Nutrition Committee, Council on Nutrition, Physical Activity, Metabolism of American Heart Association. Circulation 2001;103:1177-9.

xlviii Hsu CH, Tsai TH, Kao YH, Hwang KC, Tseng TY, Chou P. Effect of green tea extract on obese women: a randomized, double-blind, placebo-controlled clinical trial. Clin Nutr 2008; 27(3):363-70.

xlix Nagao T, Hase T, Tokimitsu I. A green tea extract high in catechins reduces body fat and cardiovascular risks in humans. Obesity (Silver Spring) 2007;15(6):1473-83.

l Maron DJ, Lu GP, Cai NS, et al. Cholesterol-lowering effect of a theaflavin-enriched green tea extract: a randomized controlled trial. Arch Intern Med 2003;163:1448-53

li Iso H, Date C, Wakai K, et al; JACC Study Group. The relationship between green tea and total caffeine intake and risk for self-reported type 2 diabetes among Japanese adults. Ann Intern Med 2006;144:554-62.

lii Gaddi A, Descovich GC, Noseda G, et al. Controlled evaluation of pantethine, a natural hypolipidemic compound, in patients with different forms of hyperlipoproteinemia. Atherosclerosis 1984;50:73-83.

liii Gaddi A, Descovich GC, Noseda G, et al. Controlled evaluation of pantethine, a natural hypolipidemic compound, in patients with different forms of hyperlipoproteinemia. Atherosclerosis 1984;50:73-83.

liv Angelico M, Pinto G, Ciaccheri C, et al. Improvement in serum lipid profile in hyperlipoproteinaemic patients after treatment with pantethine: a crossover, double-blind trial versus placebo. Curr Ther Res 1983;33:1091-1097.

lv Bertolini S, Donati C, Elicio N, et al. Lipoprotein changes induced by pantethine in hyperlipoproteinemic patients: adults and children. Int J Clin Pharmacol Ther Toxicol 1986;24:630-637.

lvi Arsenio L, Caronna S, Lateana M, et al. Hyperlipidemia, diabetes and atherosclerosis: Efficacy of treatment with pantethine [in Italian, English abstract]. Acta Biomed Ateneo Parmense 1984;55:25-42.

lvii Donati C, Barbi G, Cairo G, et al. Pantethine improves the lipid abnormalities of chronic hemodialysis patients: Results of a multicenter clinical trial. Clin Nephrol 1986;25:70-74.

lviii Donati C, Bertieri RS, Barbi G. Pantethine, diabetes mellitus and atherosclerosis. Clinical study of 1045 patients [in Italian, English abstract]. Clin Ter 1989;128:411-422.

lix Coronel G, Tornero F, Torrente J, et al. Treatment of hyperlipidemia in diabetic patients on dialysis with a physiological substance. Am J Nephrol 1991;11:32-36.

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