Olea europaea in hypertension & metabolic syndrome

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1 Olea europaea in hypertension & metabolic syndrome Cardio 017 The Hotel Michel P. HERMANS MD (UCL) PhD (UCL & Oxford, UK) Dip. Natural Sciences (Open University, Milton Keynes, UK) Dip. Earth Sciences (Open University, Milton Keynes, UK) Dip. Human Geography (Open University, Milton Keynes, UK) Dip. Environment (Open University, Milton Keynes, UK) PG Certificate in Social Sciences (Open University, Milton Keynes, UK) Endocrinologie & Nutri0on Cliniques universitaires St-Luc Université Catholique de Louvain

2 1. Hypertension & endothelial dysfunction 2. Tensiofytol : composition & MOA 3. Metabolic syndrome 4. Efficacy studies 5. PREDIMED study 6. Patient s profile & ongoing study

3 Physiopathology of Hypertension The blood pressure is the pressure of circulating blood on the walls of the arteries, it depends on the flexibility and the size of the arteries Constriction é Vascular Resistance When the diameter of the artery diminishes, the blood pressure increases Flexible blood vessel (dilatation & vasoconstriction) Rigid blood vessel (endothelial dysfunction) Endothelial dysfunction causes hypertension

Endothelium Endothelium Smooth Muscle cells The vascular endothelium is the inner layer (monocellular) of the blood vessels, the one in contact with the blood.

the vessel wall / leucocytes, platelets Regulation of the vasomotion: can liberate nitric oxide(no) which provokes vasodilatation The major cardiovascular pathologies like

4 Endothelium Endothelium Smooth Muscle cells The vascular endothelium is the inner layer (monocellular) of the blood vessels, the one in contact with the blood. Functions: Keeps the blood inside the blood vessels Regulation of the vascular permeability Molecular filter (exchange of nutrients) Regulation of the interaction between the vessel wall / leucocytes, platelets Regulation of the vasomotion: can liberate nitric oxide(no) which provokes vasodilatation The major cardiovascular pathologies like atherosclerosis, hypertension, diabetes are characterized by the dysfunction of the endothelial cells (often oxidative stress) with a reduction of the dependant relaxations of the endothelium.

5 1. Wolf-Maier et al Van Wijk et al Poorly-controlled Hypertension Badly controlled hypertension increases the risk of stroke, myocardial infarctions, auricular fibrillation, heart failure or kidney disease Control: Only 3 out of 10 patients with antihypertensive treatments 1 are monitored on the target values (<140/90 mmhg) > 2, the number of antihypertensive drugs needed to reach the target BP, in most of the clinical studies Low treatment compliance (bad adherence to treatment): Side effects/ cost of treatment / dosage 1 patient out of 2 stops the antihypertensive treatment after 3 years 2 Only 1 patient out of 5 resorting to specialized medical care for a resistant hypertension has been found to take all prescribed medicines during a test held in the Netherlands (Sympathy Study).

6 1. Hypertension & endothelial dysfunction 2. Tensiofytol : composition & MOA 3. Metabolic syndrome 4. Efficacy studies 5. PREDIMED study 6. Patient s profile & ongoing study

Daily dose 2 capsules: 334mg standardized olive leaf extract à 100mg oleuropein + EFSA: helps maintaining a normal blood pressure 106mg standardized olive extract à 20mg hydroxytyrosol EFSA:

7 Daily dose 2 capsules: 334mg standardized olive leaf extract à 100mg oleuropein + EFSA: helps maintaining a normal blood pressure 106mg standardized olive extract à 20mg hydroxytyrosol EFSA: contributes to decreasing the oxidation of LDL cholesterol IMPROVES THE ENDOTHELIAL FUNCTION AND DECREASES THE BLOOD PRESSURE RECOMMENDED USE From 18 years : 2 capsules per day The first in the morning before breakfast and the second in the evening with a large glass of water

8 Active ingredients & metabolism Unique composition The best of 2 parts of the plant LEAF: Extract standardized in Oleuropein + FRUIT: Extract standardized in Hydroxytyrosol Oleuropein metabolizes à Hydroxytyrosol + other active metabolites Hydroxytyrosol immediately available through the fruit extract + Active substances in the extracts: phenolic derivatives, triterpenes (oleanolic acid) Fast and effective action, maximum concentrations after 2h for Oleuropein

9 Tensiofytol Mode of action Oleuropein & Hydroxytyrosol Rigid blood vessel (endothelial dysfunction) Flexible blood vessel (dilatation & vasoconstriction)

Treatment of Dyslipidemia Consumption of olive oil polyphenols contributes to the

effect relationship has been established between the consumption of olive oil polyphenols

10 Treatment of Dyslipidemia Consumption of olive oil polyphenols contributes to the protection of LDL particles from oxidative damage The Panel concludes that a cause and effect relationship has been established between the consumption of olive oil polyphenols (standardized by their content of hydroxytyrosol and its derivatives) and protection of LDL particles from oxidative damage. The Panel considers that in order to bear the claim, 5 mg of hydroxytyrosol and its derivatives (e.g. oleuropein complex and tyrosol) should be consumed daily.

Tensiofytol Mode of action Focus on an endothelial cell : Oleuropein Hydroxytyrosol OXIDATIVE STRESS endothelial cell CAPTION: O2 : Superoxide NO : Nitric Oxide enos : Endothelial Nitric Oxide

11 Tensiofytol Mode of action Focus on an endothelial cell : Oleuropein Hydroxytyrosol OXIDATIVE STRESS endothelial cell CAPTION: O2 : Superoxide NO : Nitric Oxide enos : Endothelial Nitric Oxide Synthase ONOO - : Peroxynitrite smooth muscle Oleuropein/Hydroxytyrosol : DOUBLE ACTION : diminishes the destruction of NO & increases the production of NO : IMPROVES THE ENDOTHELIAL FUNCTION AND THE FLEXIBILITY OF THE WALL Endothelial reactivity 2 Flexibility of blood vessels 2

12 1. Hypertension & endothelial dysfunction 2. Tensiofytol : composition & MOA 3. Metabolic syndrome 4. Efficacy studies 5. PREDIMED study 6. Patient s profile & ongoing study

Fatty tissue expansion Proinflammatory state muscle insulin resistance

dysregulation IR-inducing secretory products and NEFAs; adiponectin

insulin resistance glucose transport and uptake glycogen synthesis hepatic

13 Fatty tissue expansion Proinflammatory state muscle insulin resistance insulin signalling (PIP3 PKB/Akt) Atherogenic dyslipidemia adipocyte dysregulation IR-inducing secretory products and NEFAs; adiponectin apob-vldl-tg lipoproteins GLUT4 translocation glucose output hepatic insulin resistance glucose transport and uptake glycogen synthesis hepatic lipogenesis NAFL, NAFLD, NASH chronic hyperinsulinaemia IFG-IGT / T2DM in predisposed individuals

14 Selective IR & hyperinsulinemia hepatocyte HGO & hyperglycemia Steatosis and VLDL export vascular endotheliocyte Decreased NO Increased endothelin

dysregulation IR-inducing secretory products and NEFAs; adiponectin Atherogenic dyslipidemia apob-vldl-tg lipoproteins glucose

15 muscle insulin resistance Nutritional-physical activity imbalance Proinflammatory state genetic &/or acquired mitochondrial defects (density/ function/biogenesis) oxidation capacity: sarcopenia, fiber type & distribution, ageing, obesity adipocyte dysregulation IR-inducing secretory products and NEFAs; adiponectin Atherogenic dyslipidemia apob-vldl-tg lipoproteins glucose output hepatic insulin resistance hepatic lipogenesis NAFL, NAFLD, NASH chronic hyperinsulinaemia IFG-IGT / T2DM in predisposed individuals

17 1. Hypertension & endothelial dysfunction 2. Tensiofytol : composition & MOA 3. Metabolic syndrome 4. Efficacy studies 5. PREDIMED study 6. Patient s profile & ongoing study

18 Efficiency + Mode of action Olive oil polyphenols decrease blood pressure and improve endothelial function in young women with mild hypertension. Moreno-luna et al. Am. J. Hypertension, dec. 2012, Double blind cross-over on 24 women, 1 st diagnostic 11 women, prehypertension: SBP mmhg and/or DBP mmhg 13 women, mild hypertension: SBP mmhg and/or DBP mmhg Baseline after 4 months Mediterranean diet: Average Systolic Blood Pressure (SBP) 134,1 mmhg, average Diastolic Blood Pressure (DBP) 84.6 mmhg Treatment: virgin olive oil (VOO) vs. Placebo (olive oil without polyphenols) VOO: 60ml oil à 30 mg total polyphenols /day Duration: 2 months treatment 1 month wash out Switch 2 months treatment SBP= Systolic Blood Pressure DBP=Diastolic Blood Pressure Moreno-luna et al. Am. J. Hypertension, dec. 2012,

Efficiency + Mode of action Olive oil polyphenols decrease blood pressure and improve endothelial function in young women with mild hypertension. Moreno-luna et al.

2012, Baseline after 4 months Mediterranean diet: Average Systolic Blood Pressure (SBP) 134,1 mmhg, average Diastolic Blood Pressure (DBP) 84.6 mmhg Results 1.

19 Efficiency + Mode of action Olive oil polyphenols decrease blood pressure and improve endothelial function in young women with mild hypertension. Moreno-luna et al. Am. J. Hypertension, dec. 2012, Baseline after 4 months Mediterranean diet: Average Systolic Blood Pressure (SBP) 134,1 mmhg, average Diastolic Blood Pressure (DBP) 84.6 mmhg Results 1. Decrease SBP: -7,9 mmhg and DBP -6,7 mmhg, p< 0.01 vs. Baseline 2. Ox- LDL = - 28 μg/l p < CRP = mg/l p < Improvement of endothelial function; flexibility of the blood vessel wall. p < Increase in NO metabolites 60ml VOO(30mg Polyphenols): 134.1mmHg à 126.2mmHg 7.9mmHg p< 0.01

20 Efficiency Olive leaf extract Susalit 2011 Phytomedicine 18 (2011) Olive (Olea europaea) leaf extract effective in patients with stage-1 hypertension: Comparison with Captopril Double blind study, olive leaf extract vs. Antihypertensive N=162 (148 evaluated), Patients with mild Hypertension (stage 1) SBP mmhg Baseline average SBP: ±5.58mmHg group olive leaf extract and ±5.56mmHg group Captopril; Baseline average DBP: 93.9 ±4.51and 93.8 ±4.88mmHg respectively Treatment: 500 mg leaf extract à 100 mg oleuropein (OE) 2x/d vs mg Captopril 2x/d. Captopril: the 1 st inhibitor of angiotensin-converting enzyme (ACE) Duration: 2 months

Efficiency Olive leaf extract Susalit 2011 Phytomedicine 18 (2011) 251 258 Olive (Olea europaea) leaf extract effective in patients with stage-1 hypertension: Comparison with Captopril Results:

21 Efficiency Olive leaf extract Susalit 2011 Phytomedicine 18 (2011) Olive (Olea europaea) leaf extract effective in patients with stage-1 hypertension: Comparison with Captopril Results: Decrease SBP/DBP= 11.5 / -4.8 mmhg with olive leaf extract -13.7/-6.4 mmhg with Captopril As efficient as Captopril (50mg/day) on the decrease of SBP and DBP Significant reduction of triglycerides: -23% (p<0.01) No effect on the triglycerides in the group of Captopril 1000mg OLE (200 OE): 149mmHg à mmhg 11.5mmHg

Efficiency Results Blood pressure 10mg Hydroxytyrosol

disease -35 % -50 % Lethal Cerebrovascular accident >

studies (on 1 million adult patients) 7% Systolic Blood

statistical difference measured on the side effects between

22 Efficiency Results Blood pressure 10mg Hydroxytyrosol 1x/day N=50 patients with metabolic syndrome Ischemic heart disease -35 % -50 % Lethal Cerebrovascular accident > Decrease of the cardiovascular risk LLewington S et al., Lancet. 2002;360: Meta-analysis on 61 observational studies (on 1 million adult patients) 7% Systolic Blood Pressure (mmhg) Diastolic Blood Pressure (mmhg) No statistical difference measured on the side effects between the treated group and placebo Decrease of 2 mmhg Coronary artery disease Systolic Blood pressure 10% Decrease of mortality due to a stroke

23 Efficiency Olive oil, in combination with antihypertensive drugs Perona 2004 Clinical Nutrition (2004) Virgin olive oil reduces blood pressure in hypertensive elderly subjects Randomized studies on elderly subjects with hypertension and treated since at least 5 years with beta blockers and diuretics N =62 : 31 Hypertensive + 31 Normotensive / 42 women 20 men Average age 84 years Treatment: 60g/day Virgin olive oil (VOO) vs. Sunflower oil Duration: 1 month treatment 1 month wash out Switch 1 month treatment

Efficiency Olive oil, in combination with antihypertensive drugs Perona 2004 Clinical Nutrition (2004) Virgin olive oil reduces blood pressure in hypertensive elderly subjects Results: Virgin olive

24 Efficiency Olive oil, in combination with antihypertensive drugs Perona 2004 Clinical Nutrition (2004) Virgin olive oil reduces blood pressure in hypertensive elderly subjects Results: Virgin olive oil (VOO), reduces the BP and normalizes the BP (136 mmhg) vs. Sunflower oil (150 ±8 mmhg). Virgin olive oil (VOO) reduced the total Cholesterol and the LDL-Cholesterol in the Normotensive patients (P<0:01) vs. Sunflower oil NT: Normotensive HT: Hypertensive SIGNIFICANT ACTION ON THE BLOOD PRESSURE IN ADDITION TO AN ANTIHYPERTENSIVE TREATMENT! VOO: 150 mmhg à 136 mmhg 14mmHg P<0.01 vs Sunflower oil VOO: Virgin Olive Oil SO: Sunflower oil

25 1. Hypertension & endothelial dysfunction 2. Tensiofytol : composition & MOA 3. Metabolic syndrome 4. Efficacy studies 5. PREDIMED & Mediterranean diet 6. Patient s profile & ongoing study

26 Prevention PREDIMED STUDY LONG-TERM EFFECT 7447 subjects during 4,8 years a. Mediterranean diet + Virgin olive oil: 1 liter/week b. Mediterranean diet + Nuts: 30g/ day (walnuts, hazelnuts, almonds) c. Control: low fat diet PREDIMED Study : 7447 subjects have followed one of these 3 diets during 4,8 years 9 Number of myocardial infarctions, strokes and deaths due to cardiovascular causes : Incidence of the cardiovascular events Control group Mediterranean diet + nuts Mediterranean diet + Extra Virgin olive oil -30% cardiovascular events (p<0,003) Years

Effect of a Traditional Mediterranean Diet on Lipoprotein Oxidation. JAMA Internal Medicine, 2007.

27 Effect of a Traditional Mediterranean Diet on Lipoprotein Oxidation. JAMA Internal Medicine, individuals from the PREDIMED study who were at a high cardiovascular risk were assessed after 3 months The Mediterranean diet caused reductions in oxidized LDL cholesterol, along with improvements in several other heart disease risk factors VOO: Virgin Olive Oil

28 Olive oil Medina Remon 2015 Effects of total dietary polyphenols on plasma nitric oxide and blood pressure in a high cardiovascular risk cohort. The PREDIMED randomized trial 1 year intervention with two Mediterranean diets (Med-diet) could decrease blood pressure (BP) due to a high polyphenol consumption N= 200 high CV risk (elderly) 1 year EVOO vs. Med-nuts / randomized controlled clinical trial Measure: BP, NO, Total Polyphenol Excretion (TPE) Systolic and diastolic BP decreased significantly after a one-year dietary intervention with Med-EVOO and Med-nuts. These changes were associated with a significant increase in TPE and plasma NO. Additionally, a significant positive correlation was observed between changes in urinary TPE, a biomarker of TP intake, and in plasma NO.

Hydroxytyrosol Reduction in Incidence of T2DM with Mediterranean Diet Results of the PREDIMED-Reus nutrition intervention randomized trial This was a three-arm randomized trial in 418 non-diabetic

29 Hydroxytyrosol Reduction in Incidence of T2DM with Mediterranean Diet Results of the PREDIMED-Reus nutrition intervention randomized trial This was a three-arm randomized trial in 418 non-diabetic subjects aged years recruited in one center Participants were randomly assigned to education on a low-fat diet (control group) or to one of two MedDiets, supplemented with either free virgin olive oil (1 liter/week) or nuts (30 g/day), for 4 years diabetes incidence reduced by 52% A = olive oil C = control P<0.047

30 Mode of action Meta-analyse Olive oil Schwingshackl 2015 nutrients Effects of Olive Oil on Markers of Inflammation and Endothelial Function A Systematic Review and Meta-Analysis Action olive oil : Inflammation Marker and Endothelial Function 30 studies / 3106 patients Dosage: 1 50 mg /day ê significant CRP (C-Reactive Protein)(p<0.0001) n=15 studies ê significant IL-6 (Interleukin-6) (p<0.04 Improvement of the endothelial function (NO)/ (p<0.002) n=8 é flow-mediated dilation(fmd ) Olive oil exerts beneficial effects on the endothelial functions and on the inflammation markers à contributes to the cardiovascular protection linked to the Mediterranean diet

31 Mode of action Meta-analyse Olive oil Schwingshackl 2015 nutrients Effects of Olive Oil on Markers of Inflammation and Endothelial Function A Systematic Review and Meta-Analysis Improvement of the endothelial function (NO)/ n=8 studies 335 patients é flow-mediated dilation (FMD) p<0.002

32 1. Hypertension & endothelial dysfunction 2. Tensiofytol : composition & MOA 3. Metabolic syndrome 4. Efficacy studies 5. PREDIMED study 6. Patient s profile & ongoing study

evaluation Study of associated CVRF + evaluation of complications + Etiology Control 1/year Control every 6 months Check regularly Study of associated CVRF + evaluation of complications

33 To whom advice early natural medical care? Measure the BP (mmhg) Optimal BP Pre-hypertension Normal HT HT stage 1 Tensiofytol vs. Antihypertensive drugs + Action on the other risk factors: Triglycerides, oxldl, HDL, glycemia (glucose intolerance) Symptomatic Asymptomatic Symptomatic Prevention advice Lifestyle Medical evaluation Study of associated CVRF + evaluation of complications + Etiology Control 1/year Control every 6 months Check regularly Study of associated CVRF + evaluation of complications Pharmacological treatment Profiles of patients at risk? > 45 years > 50 years Regular BP > 130/80 mmhg In pre- or post-menopause n Family history of hypertension n high cholesterol level n Overweight n Sedentary n Keen on salt - prepared dishes n Metabolic syndrome Dietary supplement targeted standardized at : n 100 mg oleuropein n 20 mg hydroxytyrosol Dietary supplement targeted* standardized at : n 100 mg oleuropein n 20 mg hydroxytyrosol *If the targeted blood pressure remains difficult to reach with the pharmacologocal treatment and lifestyle

34 Morten and Vidiendal Olsen Evaluation of endothelial function by peripheral arterial tonometry and relation with the nitric oxide pathway. Nitric Oxide 2014 Reactive Ischemia Hyperemia (RIH) EndoPat 2000, Itamar

35 EndoPat 2000 system 6 minutes rest 5 minutes of ischemia Left arm 6 minutes post ischemia Right arm

36 On going study at ULG/Cardio service : vasodilating effect of Tensiofytol evaluated with the EndoPat T0 T 1 hour 2 caps (100 mg oleuropéine 20 mg hydroxytyrosol)

Managing High Blood Pressure Naturally. Michael A. Smith, MD Life Extension s Healthy Talk Series

Managing High Blood Pressure Naturally Michael A. Smith, MD Life Extension s Healthy Talk Series Part 1 What is Blood Pressure? Blood Pressure Systole Systolic Forward Pressure 110 mmhg 70 mmhg Diastole