Impact of Extra Virgin Olive Oil (EVOO) With Health Properties in Metabolic Syndrome

Study Overview
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Brief Summary
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Metabolic syndrome (MS), defined according to the revised Adult Treatment Panel III - National Cholesterol Education Program (ATP III - NCEP) criteria, represents a widespread condition in Western populations (prevalence ranging from 22% to about 33%) and with a trend that increases with time and age. MS, not differently from each of the components that characterize it, is a known risk factor for cardiovascular and metabolic diseases. To date, national and international panels indicate lifestyle modification as the only indication for treating MS and reducing the risk of cardiovascular and metabolic diseases. The increase in daily physical activity and the modification of the diet are therefore the cornerstones of the treatment. The Mediterranean Diet (MD) represents a traditional value of the Italian population which has shown in several studies a protective effect on mortality and survival free from cardiovascular events. The added value of MD is the presence of extra virgin olive oil (EVOO), a healthy food with high content of monounsaturated fatty acids, especially oleic acid, and variable concentrations (range 50-800 mg/kg) of phenols (oleuropein, ligstroside, and oleocanthal, and their derivatives phenolic alcohols, such as hydroxytyrosol and tyrosol). Olive oil is defined as healthy according to EC Reg. 432/2012. A good EVOO contains about 75% of oleic acid although a variability between 55% and 83% of all fatty acids is expected according to the World Health Organization. The polyphenols content plays a key role in the choice of the type and quantity of oil with health objectives, with particular reference to the unsaturated and polyunsaturated component (oleic acid, linoleic acid, alpha linolenic acid). Phenolic compounds not only determine EVOO main organoleptic qualities (oxidative stability and specific flavor and taste features) but, theoretically, make it a substance with antioxidant, antiinflammatory, insulin-sensitizing, cardioprotective, antiatherogenic, neuroprotective, immunomodulatory and anticancer activity. The study aims to use a polyphenols enriched EVOO with health properties, derived from different cultivation variants of olives (cultivars), chosen on the basis of preliminary research, coming from Sicilian harvesting campaigns, to evaluate its potential to modify 'in vivo', in subjects with MS, some clinical and laboratory parameters inferring cardiovascular risk, metabolism and inflammation.

Detailed Description
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Metabolic syndrome (MS), defined according to the to the revised Adult Treatment Panel III - National Cholesterol Education Program (ATP III - NCEP) criteria,, represents a widespread condition in Western populations (absolute prevalence ranging from 22% to about 33%) and with a trend that increases with time and age (it is expected that its prevalence will increase by about 53% by 2035). MS, not differently from each of the components that characterize it, is a known risk factor for cardiovascular diseases (relative risk (RR) 1.53-2.18) and type 2 diabetes mellitus (RR 3.53-5.17). To date, national and international panels indicate lifestyle modification as the only indication for treating MS and reducing the risk of cardiovascular and metabolic diseases. The increase in daily physical activity and the modification of the diet are therefore the cornerstones of the treatment. The Mediterranean Diet (MD) represents a traditional value of the Italian population which has shown in several studies a protective effect on mortality and survival free from cardiovascular events. The added value of MD is the presence of extra virgin olive oil (EVOO), a healthy food with high content of monounsaturated fatty acids, especially oleic acid, and variable concentrations (range 50-800 mg/kg) of phenols (oleuropein, ligstroside, and oleocanthal, and their derivatives phenolic alcohols, such as hydroxytyrosol and tyrosol). Olive oil is defined as healthy according to European Commission (EC) Reg. 432/2012. A good EVOO contains about 75% of oleic acid although a variability between 55% and 83% of all fatty acids is expected according to the World Health Organization. The polyphenols content plays a key role in the choice of the type and quantity of oil with health objectives, with particular reference to the unsaturated and polyunsaturated component (oleic acid, linoleic acid, alpha linolenic acid). Phenolic compounds not only determine EVOO main organoleptic qualities (oxidative stability and specific flavor and taste features) but, theoretically, make it a substance with antioxidant, antiinflammatory, insulin-sensitizing, cardioprotective, antiatherogenic, neuroprotective, immunomodulatory and anticancer activity. Any beneficial substance, including olive oil, goes through a series of biochemical processes before reaching the target organ, by the digestive enzymes and bacteria of the gut microbiota, or the eventual formation of active metabolites after the first liver passage; thus, an exclusively 'in vitro' evaluation of a substance on target cells does not always represent the physiological model of the interaction of these substances with the organism. The study aims to use a polyphenols enriched EVOO with health properties, derived from different cultivation variants of olives (cultivars), chosen on the basis of preliminary research, coming from Sicilian harvesting campaigns, to evaluate its potential to modify 'in vivo', in subjects with MS, some clinical and laboratory parameters inferring cardiovascular risk, metabolism and inflammation. Preliminarily, in the phase of the olive harvesting campaigns (three different harvesting periods carried out between November and December: green, mature and advanced ripening), the different indigenous cultivars coming from the same area of Western Sicily (precisely from Val di Mazara, Valle del Belice, Trapani valleys and called Biancolilla, Nocellara, Cerasuolo) will be subjected to biochemical analyses which will aim to identify those with the highest oleic acid and polyphenols content, which will contribute to the enhancement of the specific territory and to the maintenance of biodiversity. The general objective of the study is to strengthen and enhance the research chain in the nutraceutical and health food sector and the cooperation between the research system and local companies, to support the maximum diffusion and use of new therapeutic substances and advanced technologies for treatment and prevention, and, at the same time, contributing to competitiveness and economic growth by raising the level of scientific-technical skills and knowledge in the production system and in Institutions. The main objectives of the research, therefore, will be the following: Identification and selection of specific autochthonous cultivar able to provide a high quality and polyphenols enriched EVOO. Establish potential benefits of a polyphenols enriched EVOO-MD assessing the improvement over metabolic (lipidic and glycemic status), inflammatory (cytokines) and cardiovascular (cIMT and endothelial dysfunction) parameters. Establish potential benefits of a polyphenols enriched EVOO-MD assessing the improvement over liver steatosis. Analysis of polyphenols enriched EVOO effects on peripheral blood mononuclear cells (PBMC) gene expression exploring their potential use as diagnostic and therapeutic response tool.

Official Title
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Impact of Extra Virgin Olive Oil (EVOO) With Health Properties in Improving the Overall Health Status and Preventing Cardiovascular Risk in Metabolic Syndrome

Conditions
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Metabolic Syndrome

Intervention / Treatment
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* Dietary Supplement: EVOO polyphenols enriched
* Dietary Supplement: EVOO standard


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: diagnosis of metabolic syndrome according the revised NCEP ATP III criteria; three or more of the following five criteria are met: waist circumference over 102 cm/40 inches (men) or 88 cm/35 inches (women), blood pressure over 130/85 mmHg, fasting triglyceride level over 150 mg/dl, fasting high-density lipoprotein cholesterol level less than 40 mg/dl (men) or 50 mg/dl (women) and fasting blood sugar over 100 mg/dl. Hepatitis B virus (HBV) and hepatitis C virus (HCV) negativity. Exclusion Criteria: alcohol intake (>30 g/day for men and >20 g/day for women); acute or chronic hepatic and/or cardiac failure; acute or chronic kidney disease (stage G4 Kidney Disease: Improving Global Outcomes (KDIGO) revised classification, glomerular filtration rate <30 mL/min/1.73 m2); neoplasms; autoimmune or acute and chronic inflammatory diseases; acute or chronic infective diseases; pregnancy and/or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind placebo-controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: EVOO polyphenols enriched<br>Fifteen subjects with metabolic syndrome will be randomly enrolled each year (3 years of study planned), to the addition of 40 ml daily of healthy polyphenols enriched EVOO to their mediterranean diet for the duration of six months | Dietary Supplement: EVOO polyphenols enriched<br>* Addition of 40 ml daily of healthy polyphenols enriched EVOO to mediterranean diet for 6 months<br>|
| Placebo Comparator: EVOO standard<br>Fifteen subjects with metabolic syndrome will be randomly enrolled each year (3 years of study planned), to the addition of 40 ml daily of standard EVOO to their mediterranean diet for the duration of six months | Dietary Supplement: EVOO standard<br>* Addition of 40 ml daily of standard EVOO to mediterranean diet for 6 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of glycemic control induced by polyphenols enriched EVOO-MD. | Statistically significant change (p<0.05) from baseline (T0) to end of intervention (T1) of glycated hemoglobin levels. | From baseline to end of intervention (6 months) | 
| Change of insulin resistance induced by polyphenols enriched EVOO-MD. | Statistically significant change (p<0.05) from baseline (T0) to end of intervention (T1) of (HOMA-IR) index. | From baseline to end of intervention (6 months) | 
| Change of high density lipoproteins levels induced by polyphenols enriched EVOO-MD. | Statistically significant change (p<0.05) from baseline (T0) to end of intervention (T1) of high density lipoproteins (HDL) levels. | From baseline to end of intervention (6 months) | 
| Change of triglycerides levels induced by polyphenols enriched | Statistically significant change (p<0.05) from baseline (T0) to end of intervention (T1) of triglycerides levels. | From baseline to end of intervention (6 months) | 
| Change of inflammatory parameter tumor necrosis factor (TNF)-α induced by polyphenols enriched EVOO-MD. | Statistically significant change (p<0.05) from baseline (T0) to end of intervention (T1) of TNF-α levels. | From baseline to end of intervention (6 months) | 
| Change of inflammatory parameter interleukine (IL)-6, induced by polyphenols enriched EVOO-MD. | Statistically significant change (p<0.05) from baseline (T0) to end of intervention (T1) of tumor necrosis factor IL-6 levels. | From baseline to end of intervention (6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in liver steatosis ultrasound pattern induced by polyphenols enriched EVOO-MD. | Statistically significant change from baseline (T0) to end of intervention (T1) of liver ultrasound steatosis pattern by ultrasonography. | From baseline to end of intervention (6 months) | 
| Change in visceral fat thickness induced by polyphenols enriched EVOO-MD. | Statistically significant change (p<0.05) from baseline (T0) to end of intervention (T1) of visceral fat thickness by ultrasonography. | From baseline to end of intervention (6 months) | 
| Change in carotid intima-media thickness (cIMT) induced by polyphenols enriched EVOO-MD. | Statistically significant change (p <0.05) from baseline (T0) to end of intervention (T1) of cIMT by ultrasonography. | From baseline to end of intervention (6 months) | 
| Change in endothelial disfunction induced by polyphenols enriched EVOO-MD. | Statistically significant change (p <0.05) from baseline (T0) to end of intervention (T1) in endothelial dysfunction, by flow-mediated dilatation technique of the brachial artery. | From baseline to end of intervention (6 months) | 
| EVOO effects on PBMC stress response gene expression | Statistically significant change (p <0.05) from baseline (T0) to end of intervention (T1) of expression of nuclear protein 1 (NUPR1) | From baseline to end of intervention (6 months) | 
| EVOO effects on PBMC lipid metabolism gene expression | Statistically significant change (p <0.05) from baseline (T0) to end of intervention (T1) of expression of Acetyl-Coenzyme A Carboxylase 1 (ACC1). | From baseline to end of intervention (6 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Extra Virgin Olive Oil (EVOO), Metabolic syndrome, Mediterranean diet, Polyphenols, Cardiovascular risk, Liver steatosis, Inflammation