The Effects of Dietary Erythritol on Platelet Reactivity and Vascular Inflammation (EASI)

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

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

Study Overview

• Status: Recruiting
• Conditions: Platelet Aggregation, Spontaneous; Vascular Thrombosis
• Intervention / Treatment: Other: Erythritol; Other: Aspartame

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Kimber L. Stanhope, Ph.D.; Phone Number: 5302190914; Email: klstanhope@ucdavis.edu
• Study Contact Backup: Name: Marinelle Nunez, B.S.; Phone Number: 530-752-2146; Email: mvnunez@ucdavis.edu

Study Locations

• United States
  • California
    • Davis, California, United States, 95616
      • Recruiting
      • Ragle Human Nutrition Research Center, University of California, Davis
      • Contact: Kimber Stanhope, Ph.D.; Phone Number: 530-752-3720; Email: klstanhope@ucdavis.edu
      • Contact: Marinelle Nunez, B.S.; Phone Number: 530-752-2146; Email: mvnunez@ucdavis.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Erythritol-sweetened beverage; 1-gram erythritol/kg body weight/day, divided into three beverage servings and fruit-flavored with Kool-Aid® unsweetened drink mix.	Other: Erythritol; Erythritol is a naturally occurring and non-nutritive sugar alcohol that is classified as generally recognized as safe (GRAS); Other Names: Noncaloric sugar alcohol
Placebo Comparator: Aspartame-sweetened beverage; 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; 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.; Other Names: Noncaloric sweetener

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma concentration of glucose	Change in plasma fasting glucose 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 triglyceride	Change in plasma fasting triglyceride 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 cholesterol	Change in plasma fasting cholesterol 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 low density lipoprotein cholesterol	Change in plasma fasting low density lipoprotein cholesterol 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 high density lipoprotein cholesterol	Change in plasma fasting high density lipoprotein cholesterol 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 apolipoprotein B	Change in plasma fasting apolipoprotein B 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 apolipoprotein CIII	Change in plasma fasting apolipoprotein CIII 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 uric acid	Change in plasma fasting uric acid 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

Collaborators and Investigators

• Sponsor: University of California, Davis

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2023
• Primary Completion (Estimated): May 31, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: June 6, 2023
• First Submitted That Met QC Criteria: July 21, 2023
• First Posted (Actual): August 1, 2023

Study Record Updates

• Last Update Posted (Actual): December 5, 2025
• Last Update Submitted That Met QC Criteria: December 3, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: vascular inflammation; platelet activation; dietary intervention; erythritol; aspartame
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Embolism and Thrombosis; Thrombosis; Platelet Aggregation, Spontaneous; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Organic Chemicals; Carbohydrates; Alcohols; Sugar Alcohols; Dipeptides; Erythritol; Ethanol; Aspartame
• Other Study ID Numbers: 2030510

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No