Randomized double blind clinical trial on the effect of oral α-cyclodextrin on serum lipids

Marcelo J A Amar, Maryann Kaler, Amber B Courville, Robert Shamburek, Maureen Sampson, Alan T Remaley, Marcelo J A Amar, Maryann Kaler, Amber B Courville, Robert Shamburek, Maureen Sampson, Alan T Remaley

Abstract

Background: This single center, double-blinded, cross-over, placebo controlled clinical trial investigated the effect of oral α-cyclodextrin (α-CD), a soluble dietary fiber, on blood lipid and lipoprotein levels in healthy human subjects. α-CD, a cyclical polymer containing 6 glucose subunits, is currently sold as an over the counter food supplement and is also a common additive in many foods. α-CD forms a hydrophobic central cavity that binds lipids and has been shown in animal studies and in previous clinical trials to alter plasma lipid levels.

Methods: We screened for healthy subjects, males and females, between ages 18 to 75. Out of total 103 subjects interviewed, 75 subjects completed the study. Qualified individuals in each gender group were randomized into two groups in terms of which treatment arm they received first (placebo vs. α-CD, receiving 6 grams P.O. a day, for 12-14 weeks with a 7 day wash out between arms). The primary outcome variable, plasma total cholesterol, as well as other tests related to lipids and lipoprotein and glucose metabolism, were measured at baseline and at the end of each arm of the study.

Results: α-CD was well tolerated; no serious adverse events related to α-CD were observed. Approximately 8 % of the subjects on α-CD complained of minor gastrointestinal symptoms versus 3 % on placebo (p = 0.2). Small-LDL particle number decreased 10 % (p < 0.045) for subjects on α-CD versus placebo. Fasting plasma glucose (1.6 %, p < 0.05) and Insulin resistance index (11 %, p < 0.04) were also decreased when on α-CD versus placebo.

Conclusion: α-CD treatment appears to be safe and well tolerated in healthy individuals and showed a modest reduction in small LDL particles, and an improvement in glucose related parameters.

Trial registration: NCT01131299.

Keywords: BAS; Bile acid sequestrants; HDL-C; High density lipoprotein cholesterol; LDL-C; LIRI; Lipoprotein Insulin Resistance Index; Low density lipoprotein cholesterol; TC; TG; Total cholesterol; Triglycerides; α-cyclodextrin.

Figures

Fig. 1
Fig. 1
Experimental design of the study

References

    1. Fedder DO, Koro CE, L'Italien GJ. New national cholesterol education program III guidelines for primary prevention lipid-lowering drug therapy: projected impact on the size, sex, and age distribution of the treatment-eligible population. Circulation. 2002;105:152–6. doi: 10.1161/hc0202.101971.
    1. Lewis SJ. Lipid-lowering therapy: who can benefit? Vasc Health Risk Manag. 2011;7:525–34. doi: 10.2147/VHRM.S23113.
    1. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–504. doi: 10.1056/NEJMoa040583.
    1. Bays HE, Goldberg RB. The 'forgotten' bile acid sequestrants: is now a good time to remember? Am J Ther. 2007;14:567–80. doi: 10.1097/MJT.0b013e31815a69fc.
    1. Out C, Groen AK, Brufau G. Bile acid sequestrants: more than simple resins. Curr Opin Lipidol. 2012;23:43–55. doi: 10.1097/MOL.0b013e32834f0ef3.
    1. Nakamura T, Matsuzawa Y. [Drug treatment of hyperlipoproteinemia: bile acid-binding resins] Nihon Rinsho. 1994;52:3266–70.
    1. Rosenthal RL. Effectiveness of altering serum cholesterol levels without drugs. Proc (Bayl Univ Med Cent) 2000;13:351–5.
    1. Bhargava A. Fiber intakes and anthropometric measures are predictors of circulating hormone, triglyceride, and cholesterol concentrations in the women’s health trial. J Nutr. 2006;136:2249–54.
    1. Brown L, Rosner B, Willett WW, Sacks FM. Cholesterol-lowering effects of dietary fiber: a meta-analysis. Am J Clin Nutr. 1999;69:30–42.
    1. Lajos Szente JS. Cyclodextrins as food ingredients. Trends Food Scie Technol. 2004;15:137–42. doi: 10.1016/j.tifs.2003.09.019.
    1. Bar A. Preface. Cyclodextrins. Regul Toxicol Pharmacol. 2004;39(Suppl 1):S1–2. doi: 10.1016/j.yrtph.2004.05.002.
    1. Lina BA, Bar A. Subchronic oral toxicity studies with alpha-cyclodextrin in rats. Regul Toxicol Pharmacol. 2004;39(Suppl 1):S14–26. doi: 10.1016/j.yrtph.2004.05.006.
    1. Grunberger G, Jen KL, Artiss JD. The benefits of early intervention in obese diabetic patients with FBCx: a new dietary fibre. Diabetes Metab Res Rev. 2007;23:56–62. doi: 10.1002/dmrr.687.
    1. Karcagi RG, Gaal T, Wagner L, Husveth F. Effect of various dietary fat supplementations on liver lipid and glycogen of high-yielding dairy cows in the peripartal period. Acta Vet Hung. 2008;56:57–70. doi: 10.1556/AVet.56.2008.1.6.
    1. Wagner EM, Jen KL, Artiss JD, Remaley AT. Dietary alpha-cyclodextrin lowers low-density lipoprotein cholesterol and alters plasma fatty acid profile in low-density lipoprotein receptor knockout mice on a high-fat diet. Metabolism. 2008;57:1046–51. doi: 10.1016/j.metabol.2008.02.020.
    1. Lina BA, Bar A. Subchronic (13-week) oral toxicity study of alpha-cyclodextrin in dogs. Regul Toxicol Pharmacol. 2004;39(Suppl 1):S27–33. doi: 10.1016/j.yrtph.2004.05.005.
    1. Kaewprasert S, Okada M, Aoyama Y. Nutritional effects of cyclodextrins on liver and serum lipids and cecal organic acids in rats. J Nutr Sci Vitaminol (Tokyo) 2001;47:335–9. doi: 10.3177/jnsv.47.335.
    1. Comerford KB, Artiss JD, Jen KL, Karakas SE. The beneficial effects of alpha-cyclodextrin on blood lipids and weight loss in healthy humans. Obesity (Silver Spring) 2011;19:1200–4. doi: 10.1038/oby.2010.280.
    1. Buckley JD, Thorp AA, Murphy KJ, Howe PR. Dose-dependent inhibition of the post-prandial glycaemic response to a standard carbohydrate meal following incorporation of alpha-cyclodextrin. Ann Nutr Metab. 2006;50:108–14. doi: 10.1159/000090498.
    1. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9. doi: 10.1007/BF00280883.
    1. Jeyarajah EJ, Cromwell WC, Otvos JD. Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy. Clin Lab Med. 2006;26:847–70. doi: 10.1016/j.cll.2006.07.006.
    1. Stampfer MJ, Krauss RM, Ma J, Blanche PJ, Holl LG, Sacks FM, Hennekens CH. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA. 1996;276:882–8. doi: 10.1001/jama.1996.03540110036029.
    1. Gardner CD, Fortmann SP, Krauss RM. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA. 1996;276:875–81. doi: 10.1001/jama.1996.03540110029028.
    1. Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Despres JP. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men - Prospective results from the Quebec Cardiovascular Study. Circulation. 1997;95:69–75. doi: 10.1161/01.CIR.95.1.69.
    1. Shalaurova I, Connelly MA, Garvey WT, Otvos JD. Lipoprotein insulin resistance index: a lipoprotein particle-derived measure of insulin resistance. Metab Syndr Relat Disord. 2014;12:422–9. doi: 10.1089/met.2014.0050.
    1. Antlsperger G, Schmid G. Toxicological comparison of cyclodextrins. Dordrecht. Boston, Mass: Kluwer Academic Publishers; 1996.
    1. Williams KJ, Tabas I. The response-to-retention hypothesis of atherogenesis reinforced. Curr Opin Lipidol. 1998;9:471–4. doi: 10.1097/00041433-199810000-00012.
    1. Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol. 1995;15:551–61. doi: 10.1161/01.ATV.15.5.551.
    1. Guevara MA, Bauer LL, Garleb KA, Fahey GC, de Godoy MR. Serum lipid profiles, total tract nutrient digestibility, and gastrointestinal tolerance by dogs of alpha-cyclodextrin. J Anim Sci. 2015;93:2201–7. doi: 10.2527/jas.2014-8442.
    1. Guevara MA. Nutritional evaluation of α-cyclodextrin using canine, hamster, and in vitro models. Unpublished. 2011.
    1. Younes H, Levrat MA, Demigne C, Remesy C. Resistant starch is more effective than cholestyramine as a lipid-lowering agent in the rat. Lipids. 1995;30:847–53. doi: 10.1007/BF02533961.
    1. Levrat MA, Favier ML, Moundras C, Remesy C, Demigne C, Morand C. Role of dietary propionic acid and bile acid excretion in the hypocholesterolemic effects of oligosaccharides in rats. J Nutr. 1994;124:531–8.
    1. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19:576–85. doi: 10.1038/nm.3145.
    1. Tang WH, Hazen SL. The contributory role of gut microbiota in cardiovascular disease. J Clin Invest. 2014;124:4204–11. doi: 10.1172/JCI72331.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi