Statin dose reduction with complementary diet therapy: A pilot study of personalized medicine

Bianca Scolaro, Marina S Nogueira, Aline Paiva, Adriana Bertolami, Lucia P Barroso, Tomas Vaisar, Sean P Heffron, Edward A Fisher, Inar A Castro, Bianca Scolaro, Marina S Nogueira, Aline Paiva, Adriana Bertolami, Lucia P Barroso, Tomas Vaisar, Sean P Heffron, Edward A Fisher, Inar A Castro

Abstract

Objective: Statin intolerance, whether real or perceived, is a growing issue in clinical practice. Our aim was to evaluate the effects of reduced-dose statin therapy complemented with nutraceuticals.

Methods: First phase: Initially, 53 type 2 diabetic statin-treated patients received a supplementation with fish oil (1.7 g EPA + DHA/day), chocolate containing plant sterols (2.2 g/day), and green tea (two sachets/day) for 6 weeks. Second phase: "Good responders" to supplementation were identified after multivariate analysis (n = 10), and recruited for a pilot protocol of statin dose reduction. "Good responders" were then provided with supplementation for 12 weeks: standard statin therapy was kept during the first 6 weeks and reduced by 50% from weeks 6-12.

Results: First phase: After 6 weeks of supplementation, plasma LDL-C (-13.7% ± 3.7, P = .002) and C-reactive protein (-35.5% ± 5.9, P = .03) were reduced. Analysis of lathosterol and campesterol in plasma suggested that intensity of LDL-C reduction was influenced by cholesterol absorption rate rather than its synthesis. Second phase: no difference was observed for plasma lipids, inflammation, cholesterol efflux capacity, or HDL particles after statin dose reduction when compared to standard therapy.

Conclusions: Although limited by the small sample size, our study demonstrates the potential for a new therapeutic approach combining lower statin dose and specific dietary compounds. Further studies should elucidate "good responders" profile as a tool for personalized medicine. This may be particularly helpful in the many patients with or at risk for CVD who cannot tolerate high dose statin therapy.

Trial registration: ClinicalTrials.gov, NCT02732223.

Keywords: Atherosclerosis; Omega-3 fatty acids; Plant sterols; Polyphenols; Responders.

Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.

Figures

Figure 1
Figure 1
Baseline sterol profile (Mean ± SEM) of subgroups divided according to the intensity of LDL-C reduction (above or below the median; MED = −13%) after treatment with nutraceuticals. P values were obtained by T-test for independent groups. n = 23 in each group.

References

    1. Gotto A.M., Moon J.E. Pharmacotherapies for lipid modification: beyond the statins. Nature Reviews Cardiology. 2013;10:560–570.
    1. Libby P., Ridker P.M., Hansson G.K. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473:317–325.
    1. Sabatine M.S., Giugliano R.P., Keech A.C., Honarpour N., Wiviott S.D., Murphy S.A. Evolocumab and clinical outcomes in patients with cardiovascular disease. New England Journal of Medicine. 2017;376:1713–1722.
    1. Nicholls S.J., Puri R., Anderson T., Ballantyne C.M., Cho L., Kastelein J.J.P. Effect of evolocumab on progression of coronary disease in statin-treated patients. JAMA. 2016;316(22):2373.
    1. Parathath S., Grauer L., Huang L.-S., Sanson M., Distel E., Goldberg I.J. Diabetes adversely affects macrophages during atherosclerotic plaque regression in mice. Diabetes. 2011;60:1759–1769.
    1. Kingwell B.A., Chapman M.J., Kontush A., Miller N.E. HDL-targeted therapies: progress, failures and future. Nature Reviews Drug Discovery. 2014;13(6):445–464.
    1. Davidson M.H. Reducing residual risk for patients on statin therapy: the potential role of combination therapy. The American Journal of Cardiology. 2005;96(Suppl):3K–13K.
    1. Stoekenbroek R.M., Kastelein J.J.P. Dyslipidaemia: statin-associated muscle symptoms — really all in the mind? Nature Reviews Cardiology. 2017;14(8):445–446.
    1. Serban M., Colantonio L.D., Manthripragada A.D., Monda K.L., Bittner V.A., Banach M. Statin intolerance and risk of coronary heart events and all-cause mortality following myocardial infarction. Journal of the American College of Cardiology. 2017;69(11):1386–1395.
    1. Rideout T.C., Harding S.V., Marinangeli C.P.F., Jones P.J.H. Combination drug-diet therapies for dyslipidemia. Translational Research. 2010;155(5):220–227.
    1. Moss J.W.E., Ramji D.P. Nutraceutical therapies for atherosclerosis. Nature Reviews Cardiology. 2016;13(9):513–532.
    1. Jacobson T.A. Role of n-3 fatty acids in the treatment of hypertriglyceridemia and cardiovascular disease. American Journal of Clinical Nutrition. 2008;87:1981S–1990S.
    1. De Smet E., Mensink R.P., Plat J. Effects of plant sterols and stanols on intestinal cholesterol metabolism: suggested mechanisms from past to present. Molecular Nutrition & Food Research. 2012;56:1058–1072.
    1. Manach C., Mazur A., Scalbert A. Polyphenols and prevention of cardiovascular diseases. Current Opinion in Lipidology. 2005;16(1):77–84.
    1. Scolaro B., Soo Jin Kim H., de Castro I.A. Bioactive compounds as an alternative for drug co-therapy: overcoming challenges in cardiovascular disease prevention. Critical Reviews in Food Science and Nutrition. 2016 (Article in Press)
    1. Mozaffarian D., Wu J.H.Y. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. Journal of the American College of Cardiology. 2011;58(20):2047–2067.
    1. Katan M.B., Grundy S.M., Jones P., Law M., Miettinen T., Paoletti R. Efficacy and safety of plant stanols and sterols in the management of blood cholesterol levels. Mayo Clinic Proceedings. 2003;78:965–978.
    1. Moss J.W.E., Davies T.S., Garaiova I., Plummer S.F., Michael D.R., Ramji D.P. A unique combination of nutritionally active ingredients can prevent several key processes associated with atherosclerosis in vitro. PLoS One. 2016;11(3):e0151057.
    1. Botelho P.B., Galasso M., Dias V., Mandrioli M., Lobato L.P., Rodriguez-Estrada M.T. Oxidative stability of functional phytosterol-enriched dark chocolate. LWT – Food Science and Technology. 2014;55(2):444–451.
    1. García-Llatas G., Vidal C., Cilla A., Barberá R., Lagarda M.J. Simultaneous quantification of serum phytosterols and cholesterol precursors using a simple gas chromatographic method. European Journal of Lipid Science and Technology. 2012;114(5):520–526.
    1. Shirai N., Suzuki H., Wada S. Direct methylation from mouse plasma and from liver and brain homogenates. Analytical Biochemistry. 2005;343(1):48–53.
    1. Hong Y., Yeh S., Chang C., Hu M. Total plasma malondialdehyde levels in 16 Taiwanese college students determined by various thiobarbituric acid tests and an improved high-performance liquid chromatography-based method. Clinical Biochemistry. 2000;33(8):619–625.
    1. De La Llera-Moya M., Drazul-Schrader D., Asztalos B.F., Cuchel M., Rader D.J., Rothblat G.H. The ability to promote efflux via ABCA1 determines the capacity of serum specimens with similar high-density lipoprotein cholesterol to remove cholesterol from macrophages. Arteriosclerosis, Thrombosis, and Vascular Biology. 2010;30:796–801.
    1. Hutchins P.M., Ronsein G.E., Monette J.S., Pamir N., Wimberger J., He Y. Quantification of HDL particle concentration by calibrated ion mobility analysis. Clinical Chemistry. 2014;60(11):1393–1401.
    1. Kleiner A.C., Cladis D.P., Santerre C.R. A comparison of actual versus stated label amounts of EPA and DHA in commercial omega-3 dietary supplements in the United States. Journal of the Science of Food and Agriculture. 2015;95:1260–1267.
    1. Albert B.B., Derraik J.G.B., Cameron-Smith D., Hofman P.L., Tumanov S., Villas-Boas S.G. Fish oil supplements in New Zealand are highly oxidised and do not meet label content of n-3 PUFA. Scientific Reports. 2015;5:7928.
    1. Albert B.B., Cameron-Smith D., Hofman P.L., Cutfield W.S. Oxidation of marine omega-3 supplements and human health. BioMed Research International. 2013;2013:464921.
    1. Nogueira M.S., Kessuane M.C., Lobo Ladd A.A.B., Lobo Ladd F.V., Cogliati B. Effect of long-term ingestion of weakly oxidised flaxseed oil on biomarkers of oxidative stress in LDL-receptor knockout mice. British Journal of Nutrition. 2016;116(2):258–269.
    1. Ng T.W.K., Ooi E.M.M., Watts G.F., Chan D.C., Barrett P.H.R. Atorvastatin plus omega-3 fatty acid ethyl ester decreases very-low-density lipoprotein triglyceride production in insulin resistant obese men. Diabetes, Obesity and Metabolism. 2014;16:519–526.
    1. Scholle J.M., Baker W.L., Talati R., Coleman C.I. The effect of adding plant sterols or stanols to statin therapy in hypercholesterolemic patients: systematic review and meta-analysis. Journal of the American College of Nutrition. 2009;28:517–524.
    1. Bertolami A., Botelho P.B., Macedo L.F.L., Abdalla D.S.P., Faludi A.A., Galasso M. Effect of plant sterols compared with ezetimibe on oxidative stress in patients treated with statins. Journal of Functional Foods. 2014;10:178–186.
    1. Rideout T.C., Harding S.V., Mackay D., Abumweis S.S., Jones P.J.H. High basal fractional cholesterol synthesis is associated with nonresponse of plasma LDL cholesterol to plant sterol therapy. American Journal of Clinical Nutrition. 2010;92:41–46.
    1. Mackay D.S., Gebauer S.K., Eck P.K., Baer D.J., Jones P.J.H. Lathosterol-to-cholesterol ratio in serum predicts cholesterol-lowering response to plant sterol consumption in a dual-center, randomized, single-blind placebo-controlled trial. The American Journal of Clinical Nutrition. 2015;101:432–439.
    1. Hallikainen M., Kurl S., Laakso M., Miettinen T.A., Gylling H. Plant stanol esters lower LDL cholesterol level in statin-treated subjects with type 1 diabetes by interfering the absorption and synthesis of cholesterol. Atherosclerosis. 2011;217:473–478.
    1. Van Himbergen T.M., Matthan N.R., Resteghini N.A., Otokozawa S., Ai M., Stein E.A. Comparison of the effects of maximal dose atorvastatin and rosuvastatin therapy on cholesterol synthesis and absorption markers. Journal of Lipid Research. 2009;50:730–739.
    1. Calder P.C. The role of marine omega-3 (n-3) fatty acids in inflammatory processes, atherosclerosis and plaque stability. Molecular Nutrition & Food Research. 2012;56:1073–1080.
    1. Li K., Huang T., Zheng J., Wu K., Li D. Effect of marine-derived n-3 polyunsaturated fatty acids on C-reactive protein, interleukin 6 and tumor necrosis factor α: a meta-analysis. PLoS One. 2014;9(2):e88103.
    1. Rangel-Huerta O.D., Aguilera C.M., Mesa M.D., Gil A. Omega-3 long-chain polyunsaturated fatty acids supplementation on inflammatory biomakers: a systematic review of randomised clinical trials. The British Journal of Nutrition. 2012;107:S159–S170.
    1. Ballantyne C.M., Bays H.E., Kastelein J.J., Stein E., Isaacsohn J.L., Braeckman R.A. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study) American Journal of Cardiology. 2012;110(7):984–992.
    1. Naruszewicz M., Łaniewska I., Millo B., Dłuzniewski M. Combination therapy of statin with flavonoids rich extract from chokeberry fruits enhanced reduction in cardiovascular risk markers in patients after myocardial infraction (MI) Atherosclerosis. 2007;194:179–184.
    1. Pang J., Zhang Z., Zheng T., Bassig B.A., Ge J., Yang Y. Green tea consumption and the risk of the related factors of cardiovascular diseases and ischemic related diseases: a meta-analysis. International Journal of Cardiology. 2016;202:967–974.
    1. Murray M., Walchuk C., Suh M., Jones P.J. Green tea catechins and cardiovascular disease risk factors: should a health claim be made by the United States Food and Drug Administration? Trends in Food Science & Technology. 2015;41(2):188–197.
    1. Ridker P.M. How common is residual inflammatory risk? Circulation Research. 2017;120(4):617–619.
    1. Reiner Z. Combined therapy in the treatment of dyslipidemia. Fundamental & Clinical Pharmacology. 2010;24(1):19–28.
    1. Ronsein G.E., Hutchins P.M., Isquith D., Vaisar T., Zhao X.Q., Heinecke J.W. Niacin therapy increases high-density lipoprotein particles and total cholesterol efflux capacity but not ABCA1-specific cholesterol efflux in statin-treated subjects. Arteriosclerosis, Thrombosis, and Vascular Biology. 2016;36(2):404–411.
    1. Nicholls S.J., Ruotolo G., Brewer H.B., Kane J.P., Wang M.D., Krueger K.A. Cholesterol efflux capacity and pre-beta-1 HDL concentrations are increased in dyslipidemic patients treated with evacetrapib. Journal of the American College of Cardiology. 2015;66(20):2201–2210.
    1. Kini A.S., Vengrenyuk Y., Shameer K., Maehara A., Purushothaman M., Yoshimura T. Intracoronary imaging, cholesterol efflux, and transcriptomes after intensive statin treatment. Journal of the American College of Cardiology. 2017;69(6):628–640.
    1. Khera A.V., Demler O.V., Adelman S.J., Collins H.L., Glynn R.J., Ridker P.M. Cholesterol efflux capacity, high-density lipoprotein particle number, and incident cardiovascular events: an analysis from the JUPITER trial (Justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin) Circulation. 2017;135(25):2494–2504.
    1. Duprez D.A., Otvos J., Tracy R.P., Feingold K.R., Greenland P., Gross M.D. High-Density lipoprotein subclasses and noncardiovascular, noncancer chronic inflammatory-related events versus cardiovascular events: the Multi-ethnic study of atherosclerosis. Journal of the American Heart Association. 2015;4(9):e002295.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere