Can red yeast rice & olive extract improve lipid profile and cardiovascular risk in metabolic syndrome? A double blind randomized controlled trial Prof. Dr. N. Hermans Department of Pharmaceutical Sciences, Research Group NatuRA Prof. Dr. V. Verhoeven Faculty of Medicine, Research Group ELIZA
Introduction 1
Outline • Introduction • Aim • Material & methods - Study design - Biomarkers of metabolic stress - Biomarkers of oxidative stress • Results • Discussion • Conclusion 2
Introduction 3 Alberti et al., Circulation,120,2009
Introduction 1. 2. 3. 4
Introduction • STATINS → HMGCoA-reductase inhibitors 5 Rang and Dale’s Pharmacology, 6th ed., 2007
Aim Double blind placebo controlled randomized trial to study the efficacy of red yeast rice (RYR)– olive fruit extract on 1. LDL and oxidative stress 2. serum lipid parameters, blood pressure, cardiovascular risk, side effects 6
Outline • Introduction • Aim • Material & methods - Study design - Biomarkers of metabolic stress - Biomarkers of oxidative stress • Results • Discussion • Conclusion 7
Material & Methods Study design Double blind Placebo- controlled N=50 Metabolic syndrome: NCEP ATP III + LDL > 160 mg/ dL RYR-olive Placebo 8 weeks N=24 N=26 • Biomarkers of metabolic syndrome • Biomarkers of oxidative stress 8
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Material & Methods Study design • Clinical parameters • Waist circumference • BMI • Blood pressure • Biochemical parameters • Total Cholesterol • LDL • HDL • apoA1 • apoB • Triglycerides • HbA1c 11
Material & Methods Study design • Parameters of oxidative stress • Oxidised LDL (OxLDL) • Malondialdehyde (MDA) • Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) 12
Material & Methods Biomarkers of oxidative stress MDA • Oxidative degradation PUFA • Plasma λ (ex) = 532 nm λ (em) = 553 nm 13
Material & Methods Biomarkers of oxidative stress OxLDL • Plasma OxLDL ELISA (Mercodia) Lp-PLA 2 • Plasma Lp-PLA 2 activity (PLAC-test) 14
Material & Methods RYR-olive fruit extract Red yeast rice (RYR) • Asia - traditional medicine - used in food as food colorant, flavour enhancer • Fermentation of rice by Monascus purpureus: secondary metabolites : monacolins 15
Material & Methods RYR-olive fruit extract Red yeast rice (RYR) • 10 mg monacolin K → Inhibition HMG-CoA reductase → 2 forms BIOLOGICAL ACTIVITY 16 lovastatin
Material & Methods RYR-olive fruit extract Olive fruit extract • Main polyphenolic constituents: → Antioxidative activity → ê oxidation of LDL • 10 mg hydroxytyrosol 17
Material & Methods RYR-olive fruit extract Olive fruit extract • ê oxidation of LDL EFSA, EFSA Journal, 9, 2033 (2011) 18
Material & Methods RYR-olive fruit extract • ≠ Randomised Controlled Trials - 1 RCT, cross-over, multicenter, 3 weeks (200 men) 25 ml/day of olive oil: LOW PC: 2.7 mg/kg polyphenols Quantified on no HO-tyrosol main MEDIUM PC: 164 mg/kg polyphenols polyphenols 28.5 mg/kg HO-tyrosol HIGH PC: 366 mg/kg polyphenols 63.5 mg/kg HO-tyrosol • Biomarkers of lipid peroxidation • Dose-effect relationship Weinbrenner et al., J Nutr, 134, 2314-2321 (2004); Covas et al., Ann Intern Med, 145. 333-341 (2006) 19
Material & Methods RYR-olive fruit extract Dose-effect relationship • LOW PC: 2.7 mg/kg polyphenols no HO-tyrosol MEDIUM PC: 164 mg/kg polyphenols 28.5 mg/kg HO-tyrosol HIGH PC: 366 mg/kg polyphenols 63.5 mg/kg HO-tyrosol ↑ polyphenols, ↑ HO-tyrosol ⇓ ↑ antioxidant activity ↓ Lipid peroxidation 20
Material & Methods RYR-olive fruit extract Dose-effect relationship • VOO (Virgin olive oil): 629 mg/l polyphenols - 24,4 mg/l tyrosol; 63,5 mg/l hydroxytyrosol; 327,2 mg/l oleuropein derivatives ROO (Refined olive oil): 0 mg/l polyphenols 21 de la Torre-Carbot et al., J Nutr, 140, 501-508 (2010)
Material & Methods Analysis of test product Lovastatin Monacolin K HPLC-UV analysis of RYR – 10.82 ± 0.84 mg monacolins/caps 22
Material & Methods Analysis of test product Hydroxytyrosol HPLC-UV analysis of hydroxytyrosol – 9.32 ± 0.54 mg / caps hydroxytyrosol 23
Outline • Introduction • Aim • Material & methods - Study design - Biomarkers of metabolic stress - Biomarkers of oxidative stress • Results • Discussion • Conclusion 24
Results - biochemical Table 1: Comparison between alterations in biochemical parameters in intervention and control group 25
Results – Clinical Table 2: Comparison between alterations in clinical parameters in intervention and control group 26 Verhoeven et al., BMC Complem. Altern. Med., 2015
Results Biomarkers of oxidative stress • MDA Plasma MDA-levels at baseline & after 8 weeks of treatment in RYR-olive treated & placebo groups. 27 Hermans et al., J Funct Foods,submitted for public (2015)
Results Biomarkers of oxidative stress • OxLDL 20% Plasma OxLDL-levels at baseline & after 8 weeks of treatment in RYR- olive treated & placebo groups. ***: p<0,001 mean difference placebo-intervention groups. 28 Hermans et al., J Funct Foods,submitted for public (2015)
Results Biomarkers of oxidative stress • Lp-PLA 2 7% Plasma Lp-PLA 2 -levels at baseline & after 8 weeks of treatment in RYR-olive treated & placebo groups. ***: p<0,001 mean difference placebo-intervention groups. 29 Hermans et al., J Funct Foods,submitted for public (2015)
Results Biomarkers of oxidative stress r=0,740 n=26 p<0,001 30 Correlation between the absolute difference in OxLDL & Lp-PLA2.
Results – Cardiovascular risk • Median CV risk in both groups: 2% • Intervention group: 1-18% Control group: 1-46% • After the intervention: lower risk in 8/26 in RYR-olive (mainly blood pressure) lower risk in 1/24 higher risk in 2/24 in control group 31
Outline • Introduction • Aim • Material & methods - Study design - Biomarkers of metabolic stress - Biomarkers of oxidative stress • Results • Discussion • Conclusion 32
Discussion RYR - olive (Monakolin K 10 mg; Hyroxytyrosol 10 mg) daily – 8 weeks • Total cholesterol ê 17 % • LDL ê 24 % • Triglyceride ê 9 % • Blood pressure ê 7 % (10 mmHg) systolic 9 % (7 mmHg)diastolic • OxLDL ê 20 % • Lp-PLA 2 ê 7 % 33
Discussion Study Type Aim N Dose Results Conclusion Heber et RCT-DB, Cholesterol- 83 2,4 g/dg RYR Reduction of Significant al., Am J 12 w lowering (~ 10mg MK) LDL, TC, TG reduction of Clin Nutr effects of TC, TG en LDL. 1999 RYR compared to diet Lin et al., RCT Lipid 79 1,2 g/dg RYR LDL: -28% Significant Eur J DB, lowering (~11,5 mg TC: -22% reduction of MK) Endocrinol 8 w effects and TG: -16% LDL, TC en TG. 2005 safety of HDL: NS Well tolerated RYR Tetsuo et RCT Dose-effect 60 100mg RYR 100mg RYR: 100 mg RYR al. DB, study of (= 2 mg MK) , LDL: -17% (2mg MK)/day: 2008 8 w RYR 200mg RYR TC: -9% reduction of (= 4 mg MK) 200mg RYR: LDL en TC . LDL: -17% TC: -12% 34
Discussion Study Type Aim N Dose Results Conclusion Gheith Open Efficacy and 72 0,6 g RYR TC fluva: Safe and et al., label, safety of RYR 2x/day -31% effective in Ind J 12 m compared to TC RYR: treatment of Nephrol fluvastatin in 20 mg -54% nephrotic 2008 treatment of statin/day ↓ Proteinuria dyslipidemia nephrotic dyslipidemia Liu et RCT Effect of XZK in 4870 0,3 g XZK TC: -11% XZK: reduced al., Am J 4,5 j secondary (= 2,5 – LDL: -18% cholesterol 3,2 mg MK) Cardiol, prevention of (8w) level, 30% 2008 AMI coronary events and mortality Mitchell RCT Cholesterol 79 0,6 g/dg drink with RYR containing et al., J DB, lowering effects RGR RYR: drink lowers LDL Clin 12 m of nutritional (2,4 mg at 8w, TC: en TC. Well MK) Lipidol drink with or -14% tolerated. 2012 without RYR at 8w, LDL: 35 -8%
Discussion Statin intolerant (SAM) patients Study Type Aim N Dose Results Conclusion Venero et > 4 w Dose-effect 25 1,2 g/day TC: -15% Mild reduction al., Am J study and RYR LDL: -21% of TC and LDL. Cardiol, tolerance of TGs: -6% well-tolerated 2010 RYR HDL: -0,5% Becker et RCT Effectivity and 62 3,6 g/dg LDL: -21% vs Therapeutic al., Ann DB tolerance RYR placebo option for Intern 24 w (3,6 mg MK) patients with Med, 2009 SAM 36
Discussion- side effects • 20/26 in intervention group: no side effects • 21/24 participants in placebo group: no side effects Side effects Intervention group Placebo group (26) (24) Muscle ache 3 1 Muscle cramps 1 1 Muscle weakness 1 1 Arthralgia 1 2 • Mild CK elevation (less than twice the cut off) was present in 4/26 vs 2/24. 37
Discussion - Challenges • Treatment > 8 weeks • > study population / statin intolerant patients • Effect due to combination RYR-olive extract ? synergistic,…?? à Biomarkers of oxidative stress • Quality: Batch control !! - monacolin K levels – monacolin K/lovastatin ratio - hydroxytyrosol levels - citrinin 38
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