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The principal goal for the study is to examine whether ingestion of a beverage containing artificial sweeteners alters in vitro platelet aggregation.
Because of the increasing number of cardiometabolic diseases, such as diabetes mellitus, in the population, the use of artificial sweeteners to replace free sugars has been gaining popularity. Two popular artificial sweeteners are erythritol and xylitol. Erythritol and xylitol are both naturally occurring polyols found in fruits and vegetables. They are potent artificial sweeteners with a higher sweetening intensity and lower calorie content than table sugar.
Previous research has shown that the higher levels of sugar alcohols, like those used as artificial sweeteners, in the blood are related to a higher risk of cardiovascular complications, like heart attacks and strokes, and death. This may be because higher levels of sugar alcohols in one's blood may increase the activity of platelets, which would then increase the risk of heart attack and stroke. The investigators therefore want to find if consuming a single beverage that contains an artificial sweetener can raise the levels of sugar alcohols in the blood and if it can alter platelet function or aggregation.
The purpose of this study is to examine if drinking a single beverage that contains an artificial sweetener can perceptibly alter the activity of platelets in the body. Platelets are a component of blood that are primarily responsible for helping to stop bleeding and repair damaged blood vessels by grouping together, a process known as aggregation, to form clots.
Artificial sweeteners are popular because they have a lower calorie content than table sugar while still making food and beverages sweet. Their use as a sugar substitute is especially attractive for people with heart disease or diabetes, or for people who are trying to lose weight.
Two popular artificial sweeteners are erythritol and xylitol. Erythritol and xylitol are both naturally occurring polyols, also called sugar alcohols, found in fruits and vegetables. They are potent artificial sweeteners with a higher sweetening intensity and lower calorie content than table sugar.This makes them attractive for the use as sugar substitutes or alternatives, particularly for patients with type 2 diabetes.
Up to now, there is no prospective data available about polyols with respect to their impact on event outcomes in cardiovascular patients, despite their extensive use in the food industry. Moreover, little is known about plasma levels and metabolic changes following food intake of artificial sweeteners, in particular polyols.
The investigators have previously measured fasting levels of various polyols in a large clinical cohort of cardiovascular patients and found that some candidate polyols are related to a higher risk of cardiovascular complications and death. In vitro data using human platelets revealed that the polyols xylitol and erythritol at the levels observed in fasting patients induce platelet aggregation potential. The investigator's data shows that erythritol and xylitol impact platelet function and may, therefore, contribute to cardiovascular mortality.
In preliminary studies the investigators found that when ingesting either erythritol or xylitol, the levels of these sweeteners in the plasma rise within the first hour after consumption. With this study the investigators wish to examine whether the postprandial levels are capable of altering platelet function in vitro. The investigators hypothesize that postprandial polyol concentrations following ingestion increase platelet aggregation in the blood.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Xylitol, 30g | Experimental | oral xylitol, a potent artificial sweetener |
|
| Erythritol, 30g | Experimental | oral erythritol, a potent artificial sweetener |
|
| Xylitol, 5g | Experimental | oral xylitol, a potent artificial sweetener |
|
| Glucose, 30g | Active Comparator | oral glucose, delivered as dextrose |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| xylitol, 30g | Dietary Supplement | Intervention is a drink consisting of 300mL of water containing 30g of xylitol as a single oral dose. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Platelet Aggregation After Polyol Ingestion | Measuring platelet function 30 minutes after polyol ingestion, using established in vitro platelet assays. Platelet aggregation responses, based on changes in light transmission after adding different concentrations of the agonists ADP and TRAP6 are reported. A higher percentage of light transmission indicates an increased aggregation response, with maximum amplitude (100%) indicating total aggregation. | 30 minutes |
| Change From Baseline in Platelet Aggregation at 30 Minutes Post Polyol Ingestion | Measuring changes in platelet function before versus after xylitol or erythritol ingestion, using established in vitro platelet assays. Platelet aggregation responses, based on changes in light transmission after adding different concentrations of the agonists ADP and TRAP6 are reported. A higher percentage of light transmission indicates an increased aggregation response, with maximum amplitude (100%) indicating total aggregation. | Baseline and 30 minutes post ingestion of polyol intervention |
| Plasma Polyol Levels After Polyol Ingestion | Measuring plasma levels (uM) of polyols (xylitol or erythritol) 30 minutes after xylitol or erythritol ingestion, using established techniques by mass spectrometry. Xylitol was measured, and is reported below, in the two xylitol intervention arms and erythritol was measured, and is reported below, in the erythritol and glucose intervention arms. | 30 minutes |
| Change From Baseline in Plasma Polyol Levels at 30 Minutes Post Polyol Ingestion | Measuring changes in levels of plasma polyols before versus after xylitol or erythritol ingestion, using established techniques by mass spectrometry. Xylitol concentrations are reported in the two xylitol intervention arms. Erythritol concentrations are reported in the erythritol and glucose intervention arms. | Baseline and 30 minutes post ingestion of polyol intervention |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Plasma Lipid Profile at 1 Day Post Polyol Ingestion | Measuring changes in lipid levels as markers of changes in metabolism before versus after xylitol or erythritol ingestion. | Baseline and 1 day post ingestion of polyol intervention |
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Cohort 1 Inclusion Criteria:
Cohort 1 Exclusion Criteria:
Cohort 2 Inclusion Criteria:
Cohort 2 Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Wilson Tang, MD | The Cleveland Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cleveland Clinic | Cleveland | Ohio | 44195 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27840639 | Background | Makinen KK. Gastrointestinal Disturbances Associated with the Consumption of Sugar Alcohols with Special Consideration of Xylitol: Scientific Review and Instructions for Dentists and Other Health-Care Professionals. Int J Dent. 2016;2016:5967907. doi: 10.1155/2016/5967907. Epub 2016 Oct 20. | |
| Background | Oku T, Okazaki M. Laxative threshold of sugar alcohol erythritol in human subjects. Nutrition Research. 1996;16(4):577-89. | ||
| 36849732 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Xylitol, 30g | oral xylitol, a potent artificial sweetener xylitol, 30g: Intervention is a drink consisting of 300mL of water containing 30g of xylitol as a single oral dose. |
| FG001 | Erythritol, 30g | oral erythritol, a potent artificial sweetener erythritol, 30g: Intervention is a drink consisting of 300mL of water containing 30g of erythritol as a single oral dose. |
| FG002 | Xylitol, 5g | oral xylitol, a potent artificial sweetener xylitol, 5g: Intervention is a drink consisting of 300mL of water containing 5g of xylitol as a single oral dose. |
| FG003 | Glucose, 30g | oral glucose, delivered as dextrose glucose, 30g: Intervention is a drink consisting of 300mL of water containing 30g of glucose (dextrose) as a single oral dose. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Xylitol, 30g | oral xylitol, a potent artificial sweetener xylitol, 30g: Intervention is a drink consisting of 300mL of water containing 30g of xylitol as a single oral dose. |
| BG001 | Erythritol, 30g |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Platelet Aggregation After Polyol Ingestion | Measuring platelet function 30 minutes after polyol ingestion, using established in vitro platelet assays. Platelet aggregation responses, based on changes in light transmission after adding different concentrations of the agonists ADP and TRAP6 are reported. A higher percentage of light transmission indicates an increased aggregation response, with maximum amplitude (100%) indicating total aggregation. | Only 10 of the 23 subjects consuming 30g of erythritol had aggregometry measurements performed. These were the last 10 subjects enrolled in this arm. The earlier subjects were only used to assess levels of erythritol following ingestion (pharmacokinetics studies) without looking at platelet function. The pharmacokinetics studies informed the subsequent aggregometry experiments in the final 10 subjects. | Posted | Median | Inter-Quartile Range | % of maximum amplitude | 30 minutes |
|
Adverse events data was collected duration of enrollment period (1-12 days for each subject depending on arm assignment).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Xylitol, 30g | oral xylitol, a potent artificial sweetener xylitol, 30g: Intervention is a drink consisting of 300mL of water containing 30g of xylitol as a single oral dose. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Stanley Hazen, MD | Cleveland Clinic Foundation | 216-444-9426 | hazens@ccf.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jun 29, 2023 | Nov 14, 2024 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Mar 25, 2022 | Nov 14, 2024 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D014993 | Xylitol |
| D004896 | Erythritol |
| D005947 | Glucose |
| ID | Term |
|---|---|
| D013402 | Sugar Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
| D002241 | Carbohydrates |
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| erythritol, 30g | Dietary Supplement | Intervention is a drink consisting of 300mL of water containing 30g of erythritol as a single oral dose. |
|
| xylitol, 5g | Dietary Supplement | Intervention is a drink consisting of 300mL of water containing 5g of xylitol as a single oral dose. |
|
| glucose, 30g | Dietary Supplement | Intervention is a drink consisting of 300mL of water containing 30g of glucose (dextrose) as a single oral dose. |
|
|
| Urinary Polyol Levels After Polyol Ingestion | Measuring the urinary levels of polyols (xylitol or erythritol) 30 minutes after xylitol or erythritol ingestion, using established techniques by mass spectrometry. Xylitol was measured, and is reported below, in the two xylitol intervention arms and erythritol was measured, and is reported below, in the erythritol and glucose intervention arms. | 30 minutes |
| Change From Baseline in Urinary Polyol Levels at 30 Minutes Post Polyol Ingestion | Measuring changes in levels of urinary polyols before versus after xylitol or erythritol ingestion, using established techniques by mass spectrometry. Xylitol was measured, and is reported below, in the two xylitol intervention arms and erythritol was measured, and is reported below, in the erythritol and glucose intervention arms. | Baseline and 30 minutes post ingestion of polyol intervention |
| Result |
| Witkowski M, Nemet I, Alamri H, Wilcox J, Gupta N, Nimer N, Haghikia A, Li XS, Wu Y, Saha PP, Demuth I, Konig M, Steinhagen-Thiessen E, Cajka T, Fiehn O, Landmesser U, Tang WHW, Hazen SL. The artificial sweetener erythritol and cardiovascular event risk. Nat Med. 2023 Mar;29(3):710-718. doi: 10.1038/s41591-023-02223-9. Epub 2023 Feb 27. |
| 38842092 | Result | Witkowski M, Nemet I, Li XS, Wilcox J, Ferrell M, Alamri H, Gupta N, Wang Z, Tang WHW, Hazen SL. Xylitol is prothrombotic and associated with cardiovascular risk. Eur Heart J. 2024 Jul 12;45(27):2439-2452. doi: 10.1093/eurheartj/ehae244. |
| 39114916 | Result | Witkowski M, Wilcox J, Province V, Wang Z, Nemet I, Tang WHW, Hazen SL. Ingestion of the Non-Nutritive Sweetener Erythritol, but Not Glucose, Enhances Platelet Reactivity and Thrombosis Potential in Healthy Volunteers-Brief Report. Arterioscler Thromb Vasc Biol. 2024 Sep;44(9):2136-2141. doi: 10.1161/ATVBAHA.124.321019. Epub 2024 Aug 8. |
| Physician Decision |
|
oral erythritol, a potent artificial sweetener
erythritol, 30g: Intervention is a drink consisting of 300mL of water containing 30g of erythritol as a single oral dose.
| BG002 | Xylitol, 5g | oral xylitol, a potent artificial sweetener xylitol, 5g: Intervention is a drink consisting of 300mL of water containing 5g of xylitol as a single oral dose. |
| BG003 | Glucose, 30g | oral glucose, delivered as dextrose glucose, 30g: Intervention is a drink consisting of 300mL of water containing 30g of glucose (dextrose) as a single oral dose. |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
oral xylitol, a potent artificial sweetener xylitol, 30g: Intervention is a drink consisting of 300mL of water containing 30g of xylitol as a single oral dose. |
| OG001 | Erythritol, 30g | oral erythritol, a potent artificial sweetener erythritol, 30g: Intervention is a drink consisting of 300mL of water containing 30g of erythritol as a single oral dose. |
| OG002 | Xylitol, 5g | oral xylitol, a potent artificial sweetener xylitol, 5g: Intervention is a drink consisting of 300mL of water containing 5g of xylitol as a single oral dose. |
| OG003 | Glucose, 30g | oral glucose, delivered as dextrose glucose, 30g: Intervention is a drink consisting of 300mL of water containing 30g of glucose (dextrose) as a single oral dose. |
|
|
| Primary | Change From Baseline in Platelet Aggregation at 30 Minutes Post Polyol Ingestion | Measuring changes in platelet function before versus after xylitol or erythritol ingestion, using established in vitro platelet assays. Platelet aggregation responses, based on changes in light transmission after adding different concentrations of the agonists ADP and TRAP6 are reported. A higher percentage of light transmission indicates an increased aggregation response, with maximum amplitude (100%) indicating total aggregation. | Only 10 of the 23 subjects consuming 30g of erythritol had aggregometry measurements performed. These were the last 10 subjects enrolled in this arm. The earlier subjects were only used to assess levels of erythritol following ingestion (pharmacokinetics studies) without looking at platelet function. The pharmacokinetics studies informed the subsequent aggregometry experiments in the final 10 subjects. | Posted | Median | Inter-Quartile Range | % of maximum amplitude | Baseline and 30 minutes post ingestion of polyol intervention |
|
|
|
| Primary | Plasma Polyol Levels After Polyol Ingestion | Measuring plasma levels (uM) of polyols (xylitol or erythritol) 30 minutes after xylitol or erythritol ingestion, using established techniques by mass spectrometry. Xylitol was measured, and is reported below, in the two xylitol intervention arms and erythritol was measured, and is reported below, in the erythritol and glucose intervention arms. | Posted | Median | Inter-Quartile Range | uM | 30 minutes |
|
|
|
| Primary | Change From Baseline in Plasma Polyol Levels at 30 Minutes Post Polyol Ingestion | Measuring changes in levels of plasma polyols before versus after xylitol or erythritol ingestion, using established techniques by mass spectrometry. Xylitol concentrations are reported in the two xylitol intervention arms. Erythritol concentrations are reported in the erythritol and glucose intervention arms. | Posted | Median | Inter-Quartile Range | umol/L (uM) | Baseline and 30 minutes post ingestion of polyol intervention |
|
|
|
| Primary | Urinary Polyol Levels After Polyol Ingestion | Measuring the urinary levels of polyols (xylitol or erythritol) 30 minutes after xylitol or erythritol ingestion, using established techniques by mass spectrometry. Xylitol was measured, and is reported below, in the two xylitol intervention arms and erythritol was measured, and is reported below, in the erythritol and glucose intervention arms. | Posted | Median | Inter-Quartile Range | uM | 30 minutes |
|
|
|
| Primary | Change From Baseline in Urinary Polyol Levels at 30 Minutes Post Polyol Ingestion | Measuring changes in levels of urinary polyols before versus after xylitol or erythritol ingestion, using established techniques by mass spectrometry. Xylitol was measured, and is reported below, in the two xylitol intervention arms and erythritol was measured, and is reported below, in the erythritol and glucose intervention arms. | Posted | Median | Inter-Quartile Range | uM | Baseline and 30 minutes post ingestion of polyol intervention |
|
|
|
| Secondary | Change From Baseline in Plasma Lipid Profile at 1 Day Post Polyol Ingestion | Measuring changes in lipid levels as markers of changes in metabolism before versus after xylitol or erythritol ingestion. | Not all subjects had blood drawn at 1 day post-sweetener ingestion. Blood samples at 1 day post ingestion were only obtained from 13 subjects who consumed 30g erythritol and 4 subjects who consumed 30g of xylitol. No subjects taking glucose or 5mg of xylitol had blood drawn at 1 day post-ingestion. | Posted | Median | Inter-Quartile Range | mg/dL | Baseline and 1 day post ingestion of polyol intervention |
|
|
|
| 0 |
| 10 |
| 0 |
| 10 |
| 0 |
| 10 |
| EG001 | Erythritol, 30g | oral erythritol, a potent artificial sweetener erythritol, 30g: Intervention is a drink consisting of 300mL of water containing 30g of erythritol as a single oral dose. | 0 | 25 | 0 | 25 | 0 | 25 |
| EG002 | Xylitol, 5g | oral xylitol, a potent artificial sweetener xylitol, 5g: Intervention is a drink consisting of 300mL of water containing 5g of xylitol as a single oral dose. | 0 | 5 | 0 | 5 | 0 | 5 |
| EG003 | Glucose, 30g | oral glucose, delivered as dextrose glucose, 30g: Intervention is a drink consisting of 300mL of water containing 30g of glucose (dextrose) as a single oral dose. | 0 | 10 | 0 | 10 | 0 | 10 |
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| D006601 |
| Hexoses |
| D009005 | Monosaccharides |
| D000073893 | Sugars |
| 1uM ADP at 30 minutes post polyol ingestion |
|
| 2 uM ADP at Baseline |
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| 2 uM ADP at 30 minutes post polyol ingestion |
|
| 3uM ADP at Baseline |
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| 3uM ADP at 30 minutes post polyol ingestion |
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| 4uM ADP at Baseline |
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| 4uM ADP at 30 minutes post polyol ingestion |
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| 2.5 uM TRAP6 at Baseline |
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| 2.5 uM TRAP6 at 30 minutes post polyol ingestion |
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| 5.0 uM TRAP6 at Baseline |
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| 5.0 uM TRAP6 at 30 minutes post polyol ingestion |
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| 7.5 uM TRAP6 at Baseline |
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| 7.5 uM TRAP6 at 30 minutes post polyol ingestion |
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| 10.0 uM TRAP6 at Baseline |
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| 10.0 uM TRAP6 at 30 minutes post polyol ingestion |
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| 30 minutes post-ingestion of polyol |
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| 30-minutes Post Polyol Ingestion |
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| HDL at Baseline |
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| HDL at 1 day Post Polyol Ingestion |
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| Triglycerides at Baseline |
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| Triglycerides at 1 day Post Polyol Ingestion |
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| Calculated LDL at Baseline |
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| Calculated LDL at 1 day Post Polyol Ingestion |
|