The Effects of Dietary Erythritol on Platelet Reactivity and Vascular Inflammation

Study Overview
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Brief Summary
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The purpose is to conduct a dietary intervention study in which human participants will consume beverages sweetened with erythritol or aspartame, each for 2 weeks, in a randomized crossover design

Detailed Description
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There is a strong correlation between plasma erythritol concentrations and adverse cardiovascular events in high risk individuals. It has also been demonstrated that consumption of dietary erythritol leads to high levels of plasma erythritol. There is in vitro evidence that erythritol at comparable concentrations promotes platelet activation. However, there is no direct evidence that links human consumption of erythritol with the onset of platelet activation and adhesion leading to inflammation. The investigators seek to fill this evidence gap by conducting a randomized crossover dietary intervention study in which human participants will consume beverages sweetened with erythritol or aspartame, each for two weeks.

Official Title
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Randomized Controlled Clinical Trial to Gauge the Effects of Dietary Erythritol on Platelet Reactivity and Vascular Inflammation

Conditions
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Platelet Aggregation, Spontaneous, Vascular Thrombosis

Intervention / Treatment
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* Other: Erythritol
* Other: Aspartame


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI ≥ 27 kg/m2 Exclusion Criteria: • History of blood clot, transient ischemic attack (TIA), stroke, angina, heart attack, or peripheral vascular disease, or current cancer diagnosis. Pregnant or lactating women Current, prior (within 12 months), or anticipated use of medications for treatment of hyperlipidemia, high blood pressure or diabetes, or any medication that in the opinion of the investigators will confound results. Unwilling to forego the use of anti-inflammatory medication during study. Unwilling to forego the use of marijuana during the study. Use of tobacco. Strenuous exerciser (>4 hours/week at a level more vigorous than walking). Surgery or medication for weight loss. Diet exclusions: Food allergies or dietary restrictions that may undermine compliance to dietary protocol, routine ingestion of more than 2 sugar-sweetened beverages or 2 alcoholic beverage/day. Unwillingness to consume artificial or noncaloric sweeteners. Habitual consumption (>10 gram/day) of beverage or foods that contain erythritol. Recent or current weight loss diet.

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized crossover study with 2-week washout
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Erythritol-sweetened beverage<br>1-gram erythritol/kg body weight/day, divided into three beverage servings and fruit-flavored with Kool-Aid® unsweetened drink mix. | Other: Erythritol<br>* Erythritol is a naturally occurring and non-nutritive sugar alcohol that is classified as generally recognized as safe (GRAS)<br>* Other names: Noncaloric sugar alcohol;|
| Placebo Comparator: Aspartame-sweetened beverage<br>Control beverages will be made from a noncaloric aspartame-sweetened, fruit-flavored drink mix at the concentration needed to match the sweetness ( 3 mg aspartame/kg/day) and flavoring of the erythritol beverages on a per volume basis. | Other: Aspartame<br>* Aspartame consists of two amino acids, phenylalanine and aspartic acid, and a methyl group. It does not have metabolic effects and has served as the blinded control beverage in the investigators' completed NIH-funded clinical trials.<br>* Other names: Noncaloric sweetener;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| P-selectin, a platelet surface marker, assessed as median fluorescence intensity | Change in median fluorescence intensity of P-selectin, an index of platelet activation, will be measured by flow cytometry in whole blood collected from subjects before and after consuming erythritol-sweetened beverage for 2 weeks and compared with change in whole blood collected before and after consuming aspartame-sweetened beverage for 2 weeks | 6 weeks | 
| P-selectin, a platelet surface marker, assessed as percentage of P-selectin positive cells | Change in percentage of P-selectin positive cells, an index of platelet activation, will be measured by flow cytometry in whole blood collected from subjects before and after consuming erythritol-sweetened beverage for 2 weeks and compared with change in whole blood collected before and after consuming aspartame-sweetened beverage for 2 weeks | 6 weeks | 
| PAC-1 (GPIIb/IIIa complex), a platelet surface marker, assessed as median fluorescence intensity | Change in median fluorescence intensity of PAC-1, an index of platelet activation, will be measured by flow cytometry in whole blood collected from subjects before and after consuming erythritol-sweetened beverage for 2 weeks and compared with change in whole blood collected before and after consuming aspartame-sweetened beverage for 2 weeks | 6 weeks | 
| PAC-1 (GPIIb/IIIa complex), a platelet surface marker, assessed as percentage of PAC-1 positive cells | Change in percentage of PAC-1 positive cells, an index of platelet activation, will be measured by flow cytometry in whole blood collected from subjects before and after consuming erythritol-sweetened beverage for 2 weeks and compared with change in whole blood collected before and after consuming aspartame-sweetened beverage for 2 weeks | 6 weeks | 
| Annexin V, a platelet surface marker, assessed as median fluorescence intensity | Change in median fluorescence intensity of annexin V, an index of platelet activation, will be measured by flow cytometry in whole blood collected from subjects before and after consuming erythritol-sweetened beverage for 2 weeks and compared with change in whole blood collected before and after consuming aspartame-sweetened beverage for 2 weeks | 6 weeks | 
| Annexin V, a platelet surface marker, assessed as percentage of annexin V positive cells | Change in percentage of annexin V positive cells, an index of platelet activation, will be measured by flow cytometry in whole blood collected from subjects before and after consuming erythritol-sweetened beverage for 2 weeks and compared with change in whole blood collected before and after consuming aspartame-sweetened beverage for 2 weeks | 6 weeks | 
| Platelet reactivity to physiologic agonist, assessed as change in median fluorescence intensity | The change in median fluorescence intensity induced by physiologic agonists, an index of platelet reactivity, will be measured by flow cytometry in whole blood collected from subjects before and after consuming erythritol-sweetened beverage for 2 weeks and compared with change in whole blood collected before and after consuming aspartame-sweetened beverage for 2 weeks | 6 weeks | 
| Platelet aggregation in response to physiologic agonist, assessed as aggregation/min | The change in aggregation/min induced by physiologic agonists will be measured by light transmission aggregometry in whole blood collected from subjects before and after consuming erythritol-sweetened beverage for 2 weeks and compared with change in whole blood collected before and after consuming aspartame-sweetened beverage for 2 weeks | 6 weeks | 
| Platelet aggregation in response to physiologic agonist, assessed as percent of maximum aggregation | The change in % maximum aggregation induced by physiologic agonists will be measured by light transmission aggregometry in whole blood collected from subjects before and after consuming erythritol-sweetened beverage for 2 weeks and compared with change in whole blood collected before and after consuming aspartame-sweetened beverage for 2 weeks | 6 weeks | 
| Platelet-leukocyte interaction, assessed as platelet/leukocyte aggregate size by fluorescence mean intensity | Change in platelet/leukocyte aggregate size, an index of platelet-leukocyte interaction, will be measured by flow cytometry in whole blood collected from subjects before and after consuming erythritol-sweetened beverage for 2 weeks and compared with change in whole blood collected before and after consuming aspartame-sweetened beverage for 2 weeks | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration of E-Selectin | Change in plasma E-Selectin in subjects before and after sustained consumption of erythritol-sweetened beverage compared with change before and after sustained consumption of aspartame-sweetened beverage | 6 weeks | 
| Plasma concentration of sVCAM1 | Change in plasma sVCAM1 in subjects before and after sustained consumption of erythritol-sweetened beverage compared with change before and after sustained consumption of aspartame-sweetened beverage | 6 weeks | 
| Plasma concentration of sICAM1 | Change in plasma sICAM1 in subjects before and after sustained consumption of erythritol-sweetened beverage compared with change before and after sustained consumption of aspartame-sweetened beverage | 6 weeks | 
| Plasma concentration of D-dimer | Change in plasma D-dimer in subjects before and after sustained consumption of erythritol-sweetened beverage compared with change before and after sustained consumption of aspartame-sweetened beverage | 6 weeks | 
| Plasma concentration of Platelet factor 4 | Change in plasma platelet factor 4 in subjects before and after sustained consumption of erythritol-sweetened beverage compared with change before and after sustained consumption of aspartame-sweetened beverage | 6 weeks | 
| Plasma concentration of Fibrinogen | Change in plasma fibrinogen in subjects before and after sustained consumption of erythritol-sweetened beverage compared with change before and after sustained consumption of aspartame-sweetened beverage | 6 weeks | 
| Plasma concentration of Prothrombin fragment 1+2 | Change in plasma prothrombin fragment 1+2 in subjects before and after sustained consumption of erythritol-sweetened beverage compared with change before and after sustained consumption of aspartame-sweetened beverage | 6 weeks | 
| Plasma concentration of Plasmin-antiplasmin complex | Change in plasma plasmin-antiplasmin complex in subjects before and after sustained consumption of erythritol-sweetened beverage compared with change before and after sustained consumption of aspartame-sweetened beverage | 6 weeks | 
| Plasma concentration of Lp(a) | Change in plasma Lp(a) in subjects before and after sustained consumption of erythritol-sweetened beverage compared with change before and after sustained consumption of aspartame-sweetened beverage | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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platelet activation, vascular inflammation, erythritol, aspartame, dietary intervention