Effects of Sweetener Consumption on Risk Factors for Heart Disease in Prediabetic Subjects

NCT07377097 | Not Yet Recruiting

• 1 other identifier: Sweetheart-Study
• Study Type: interventional
• Target: 80
• Locations: 0 countries
• Sites: N/A

Brief Summary

The aim of this prospective interventional study is to investigate the metabolic effects of consuming artificial and natural sweeteners in persons with prediabetes. Prediabetes is a condition characterized by blood sugar levels that are elevated above normal but not yet meeting the criteria for type 2 diabetes. This condition markedly increases the risk of progressing to type 2 diabetes, which in turn can lead to complications including cardiovascular diseases. Artificial sweeteners such as saccharin and sucralose, as well as natural sugar substitutes like erythritol, are increasingly used as alternatives to sugar and are recommended for individuals at cardiometabolic risk - including overweight individuals, patients with prediabetes, or diabetics - to help reduce caloric intake. Recent literature has reported possible negative associations between artificial sweeteners and blood sugar regulation in healthy subjects (1). Additionally, effects on various blood cells have been observed. For example, erythritol has been shown to alter platelet function leading to increased reactivity in healthy study participants following consumption (2). However, the impact of alternative sweeteners on metabolic processes and their effects on blood coagulation in patients with prediabetes-a population at increased risk-has not been systematically studied. In this planned interventional study, 80 patients meeting laboratory criteria for prediabetes will be randomly assigned to one of four groups, each receiving a different intervention for two weeks: saccharin, sucralose, erythritol, or a control group receiving water. The doses reflect the acceptable daily intake or known doses that are considered safe. After enrollment, participants will visit the study center 2 times: before starting the intervention and after completing the intervention. During these visits, biological samples such as blood, urine, and stool will be collected to study metabolism, gut bacteria, immune and blood cell function. Tests will include an oral glucose tolerance test, coagulation tests, and additional blood analyses. Additionally, participants will wear a glucose monitor to track blood sugar fluctuations during the intervention. The investigators hypothesize that consumption of alternative sweeteners negatively affects blood sugar regulation and insulin sensitivity in patients with prediabetes. Furthermore, this study will explore how the candidate sweeteners influence the gut microbiome, blood cells and other metabolic factors in this population.

Conditions

Metabolic Syndrome; Insulin Resistance; Thrombosis; Hypercoagulable State; Cardiovascular (CV) Risk; Cardiovascular Diseases (CVD); Prediabetes; Prediabetes / Type 2 Diabetes; Sweeteners; Prediabetic State; Cardiovascular Risk Factors

Outcome Measures

Primary Outcomes (1)

• Change of glucose tolerance

  Measured by AUC of oral glucose tolerance test

  Baseline vs. within 1 week after intervention

Secondary Outcomes (9)

• Change of microbiome

  Baseline vs. within 1 week after intervention

• Flow cytometry analysis of changes in frequency of circulating monocyte subsets (%)

  Baseline vs. within 1 week after intervention

• Flow cytometry analysis of changes in platelet activation marker expression (% positive platelets)

  Baseline vs. within 1 week after intervention

• Flow cytometry analysis of changes in platelet activation marker expression (MFI)

  Baseline vs. within 1 week after intervention

• Changes in lipid profile

  Baseline vs. within 1 week after intervention

Study Arms (4)

Saccharin Group

ACTIVE COMPARATOR

Intervention: Saccharin

Dietary Supplement: Saccharin

Sucralose Group

ACTIVE COMPARATOR

Intervention: Sucralose

Dietary Supplement: Sucralose

Erythritol Group

ACTIVE COMPARATOR

Intervention: Erythritol

Dietary Supplement: Erythritol

Control Group

PLACEBO COMPARATOR

Intervention: Vehicle

Dietary Supplement: Vehicle

Interventions

Saccharin DIETARY_SUPPLEMENT

Participants in the saccharin group will consume 5 mg/kg body weight of saccharin daily, dissolved in 500 mL of water. This corresponds to the maximum recommended daily intake as determined by EFSA and JECFA (the joint FAO/WHO Expert Committee on Food Additives).

Saccharin Group

Sucralose DIETARY_SUPPLEMENT

Participants in the sucralose group will consume 15 mg/kg body weight of sucralose daily in 500 mL of water, representing the maximum recommended daily intake.

Sucralose Group

Erythritol DIETARY_SUPPLEMENT

Those in the erythritol group will consume 0.5 g/kg body weight of erythritol daily in 500 mL of water, a dose considered safe and below levels that cause digestive discomfort (European Food Safety Authority \[EFSA\], 2023).

Erythritol Group

Vehicle DIETARY_SUPPLEMENT

Participants in the control group (vehicle) will receive a vehicle consisting of 500 mL unsweetened lemon soda

Control Group

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Presence of prediabetes (HbA1c 5.7-6.4% or glucose after oral glucose tolerance test 140 to 199 mg/dL)
• Written informed consent available

You may not qualify if:

• Inability to communicate sufficiently in the required language
• Dementia or other significantly cognitively impairing condition
• Current pregnancy or breastfeeding
• Other severe internal, neurological, or psychiatric condition
• History of gout
• History of gallstones / diagnosis of cholelithiasis

Sponsors & Collaborators

• Charite University, Berlin, Germany: lead

Related Publications (2)

• 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.

  PMID: 39114916 BACKGROUND

• Suez J, Cohen Y, Valdes-Mas R, Mor U, Dori-Bachash M, Federici S, Zmora N, Leshem A, Heinemann M, Linevsky R, Zur M, Ben-Zeev Brik R, Bukimer A, Eliyahu-Miller S, Metz A, Fischbein R, Sharov O, Malitsky S, Itkin M, Stettner N, Harmelin A, Shapiro H, Stein-Thoeringer CK, Segal E, Elinav E. Personalized microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance. Cell. 2022 Sep 1;185(18):3307-3328.e19. doi: 10.1016/j.cell.2022.07.016. Epub 2022 Aug 19.

  PMID: 35987213 BACKGROUND

MeSH Terms

Conditions

Prediabetic State; Metabolic Syndrome; Insulin Resistance; Thrombosis; Thrombophilia; Cardiovascular Diseases; Diabetes Mellitus, Type 2

Interventions

Saccharin; trichlorosucrose; Erythritol

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism; Embolism and Thrombosis; Vascular Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Benzothiazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Sugar Alcohols; Alcohols; Carbohydrates

Central Study Contacts

Marco Witkowski, MD, PhD

CONTACT

+49 (0)30 450543775; fs-cpc@charite.de

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Marco Witkowski, MD, PhD

Study Record Dates

• First Submitted: December 11, 2025
• First Posted: January 29, 2026
• Study Start: January 5, 2026
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 1, 2026
• Last Updated: January 29, 2026

Record last verified: 2025-12