Study Of Drinks With Artificial Sweeteners in People With Type 2 Diabetes

Study Overview
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Brief Summary
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Diet beverages sweetened with artificial sweeteners occupy a unique category in the food environment as they are a source of intensely sweet taste with no calories. Diet beverages are the single largest contributor to artificial sweetener intake in the U.S. diet, and people with diabetes are the highest consumers of diet beverages, tending to consume them as a replacement for dietary sources of sugar, especially in place of sugar-sweetened beverages. This behavior has been endorsed by dietetic and scientific organizations, and diet beverages are marketed as being synonymous with better health, suitable for weight loss, and thus advantageous for diabetes control. The underlying public health concern is that there are few data to support or refute the benefit or harm of habitual diet beverage consumption by people with diabetes; therefore randomized trials with relevant outcomes must be conducted because they would address many limitations of previous research and have major implications for dietary recommendations on diet beverage intake and primary and secondary prevention of chronic disease. To begin addressing this important scientific gap the investigators are testing the effect of diet beverage intake on diabetes control parameters in free-living adults with type 2 diabetes in a randomized, two arm parallel trial with a run-in period of 2-weeks and an active intervention period of 24-weeks. This study will recruit 200 patients with type 2 diabetes who are usual consumers of commercial diet beverages and randomize them to receive and consume either: 1) A commercial diet beverage of choice (3 servings or 24 oz. daily); or 2) Unflavored bottled water of choice (sparkling or plain) (3 servings or 24 oz. daily). The primary outcome will be a central measure of clinical diabetes control in glycated hemoglobin (HbA1c). The study will also measure the nature and magnitude of glycemic excursions via continuous glucose monitors, as well as clinical markers of cardiometabolic risk and kidney function. Lastly, investigators will measure plausible mechanisms whereby diet beverage intake may alter risk by assessing the effect of diet beverage intake on the functional composition of the gut microbiome via stool samples and comprehensive metabolomics, satiety hormones, as well as usual dietary intake, and upstream behavioral pathways which may inform dietary intake patterns.

Official Title
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Effect of Artificially Sweetened Beverages on Diabetes Control in Adults With Type 2 Diabetes

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Behavioral: Diet Beverage
* Behavioral: Water


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: We will include men, women and non-binary participants with T2D, age 35 years and older, able to provide informed consent, otherwise healthy, who meet the following criteria: Physician diagnosed type 2 diabetes ≥ 6 months prior to screening HbA1c 6.5-8.5% at participant screening Current treatment with lifestyle changes or stable diabetes-related medication levels for the past 3 months Willingness to provide consent to contact treating physician and physician agreement to refrain from changing diabetes-related medications during the trial (change defined as > 2 fold change in dose of any 1 hyperglycemic agent or addition or subtraction of an agent) No physician-directed medication change for 3 months if prescribed medication for lipids or blood pressure Usual consumers of diet beverages (≥ 3 servings/ week (24 oz.) and the willingness to maintain fidelity of the intervention, and participate in all aspects of the intervention Not actively looking to make major lifestyle alterations during the study period with stable weight for 2 months (within 3%). Exclusion Criteria: Type 1 diabetes or suspected type 1 diabetes (lean with polyuria, polydipsia, and weight loss with little response to metformin) Secondary diabetes due to specific causes (e.g. monogenic syndromes, pancreatic surgery, and pancreatitis) Diabetic Ketoacidosis hospitalization within last 6 months Severe/major hypoglycemia in the last 3 months-severe/major hypoglycemia is defined as a hypoglycemic event in which patient requires assistance of another person to manage the episode Glucocorticoid use (prednisone 2.5 mg/d or more or its equivalent) History of intolerance or allergy to diet beverages or AS or phenylketonuria Any condition that is known to affect the validity of the glycemic measures (Hba1c) Major cardiovascular disease event or surgery within past 6 months Gastrointestinal disease Renal or liver disease Current treatment for cancer Those with major surgery planned or history of bariatric surgery Antibiotic treatment (> 6 days) within past 6 months Currently pregnant (via self-report) or planning to become pregnant during study period; <1 year postpartum and breast feeding Current participation in another interventional clinical trial Previous randomization in this study, Heavy alcohol consumption (on average >2 drinks/day for women and >3 drinks/day for men) Habitual consumer of SSB ≥ 1 serving / day (8 oz.) Does not drink diet beverages BMI < 20.0 kg/m2

Ages Eligible for Study
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Minimum Age: 35 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: This study is testing the effect of commercial diet beverage intake on diabetes control parameters in free-living adults with type 2 diabetes in a randomized, two arm parallel trial with a run-in period of 2-weeks and an active intervention period of 24-weeks. We will recruit 200 patients with type 2 diabetes who are usual consumers of commercial diet beverages and randomize them to receive and consume either: 1) A commercial diet beverage of choice (3 servings or 24 oz. daily); or 2) Unflavored bottled water of choice (sparkling or plain) (3 servings or 24 oz. daily).
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Diet Beverage<br>Participants will receive and consume three daily servings (24 ounces) of a non-caloric commercial diet beverage of their choice sweetened with FDA approved artificial sweeteners. | Behavioral: Diet Beverage<br>* Participants will receive and consume three daily servings (24 ounces) of a non-caloric commercial diet beverage of their choice sweetened with FDA approved artificial sweeteners.<br>|
| Experimental: Water<br>Participants will receive and consume three daily servings (24 ounces) of plain bottled/canned water in place of their usual commercial diet beverage. The water will be unflavored, unsweetened, non-caloric, and may be plain or sparkling. Participants randomized to consume water will be instructed to avoid intake of diet beverages. | Behavioral: Water<br>* Participants will receive and consume three daily servings (24 ounces) of plain bottled/canned water in place of their usual commercial diet beverage. The water will be unflavored, unsweetened, non-caloric, and may be plain or sparkling. Participants randomized to consume water will be instructed to avoid intake of diet beverages.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c | Glycated hemoglobin | 0, 12, 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time In Range | Time in range is collected by a masked Continuous Glucose Monitor (CGM), which measures individual glucose levels every 15 minutes for two weeks via a sensor placed on the participants upper arm (underside). Time in Range is defined as the % of time each day with a glucose measure between 70-180 mg/dl. The range of CGM data for inclusion in this study will be 5 to 14 days, consistent with manufacturer's recommendations. | All 14 day periods: Run-in (2-weeks, usual-baseline), weeks 11 and 12 (14 days), weeks 23 and 24 (14 days) | 
| Glycemic Variability | Glycemic variability is collected by a masked Continuous Glucose Monitor (CGM), which measures individual glucose levels every 15 minutes for two weeks via a sensor placed on the participants upper arm (underside). Glycemic variability is defined as the CV and SD. The range of CGM data for inclusion in this study will be 5 to 14 days, consistent with manufacturer's recommendations. | All 14 day periods: Run-in (2-weeks, usual-baseline), weeks 11 and 12 (14 days), weeks 23 and 24 (14 days) | 
| Other CGM metrics | Multiple metrics are able to be calculated by CGM. The primary secondary endpoint for CGM will be Time In Range. Reporting of any other CGM metrics will be prefaced with this statement and the residual CGM metrics will be analyzed and interpreted cautiously and conservatively. They include: Mean glucose, glycemic variability, and episodes of hypoglycemia/hyperglycemia. | All 14 day periods: Run-in (2-weeks, usual-baseline), weeks 11 and 12 (14 days), weeks 23 and 24 (14 days) | 
| Lipid panel (Total cholesterol, LDL cholesterol, HDL cholesterol, Fasting Triglycerides), all mg/dL | A lipid panel is a standard measurement for assessing clinical CVD risk | 0, 12, 24 weeks | 
| Kidney function | Serum creatinine is a standard clinical measurement for kidney function | 0, 6, 12, 18, 24 weeks | 
| Fasting glucose and Insulin | Standard clinical measures | 0, 6, 12, 18, 24 weeks | 
| Fructosamine/Glycated Albumin | Fructosamine and glycated albumin levels represent usual glycemia over the past 2-3 weeks, and are considered valid markers of short term clinical glycemic patterns by the American Diabetes Association | 0, 6, 12, 18, 24 weeks | 
| Blood pressure | Systolic and Diastolic blood pressure, standard clinical measurement | 0, 6, 12, 18, 24 weeks | 
| Weight (kg) | Weight measured on standardized scale in gown | 0, 6, 12, 18, 24 weeks | 
| Dietary Quality (Healthy Eating Index) | Assessed by multiple unannounced 24-hour dietary recalls that will occur during the run-in to assess usual habits (2 recalls over 2 weeks) and the active intervention (5 recalls over 24 weeks), to measure any changes in diet quality metric. Results will be used to calculate a metric of diet quality in the Healthy Eating Index that is based upon the USDA Dietary Guidelines. | Run-in period (2 weeks), Active intervention (Up to 24 weeks). | 
| DHP-18 | A diabetes-specific patient reported outcome measure developed to evaluate the health-related quality of life of people living with type 2 diabetes | 0, 6, 12, 18, 24 weeks | 
| Food Craving Inventory | Measures different domains of general and specific food cravings | 0, 6, 12, 18, 24 weeks | 
| Sleep Quality and Patterns | Pittsburgh Sleep Quality Index | 0, 6, 12, 18, 24 weeks | 
| Physical activity | Objectively measured via Activpal | All 14 day periods: Run-in (2-weeks, usual-baseline), weeks 11 and 12 (14 days), weeks 23 and 24 (14 days) | 
| Serotonin | Chemical and neurotransmitter measured in blood with myriad roles, including appetite and digestion | 0, 12, 24 weeks: Samples collected and stabilized at these time points and frozen for future analyses | 
| Leptin | Hormone measured in the blood with satiety related role | 0, 12, 24 weeks: Samples collected and stabilized at these time points and frozen for future analyses | 
| Thyroid Stimulating Hormone (TSH) | Hormone measured in the blood with energy balance related role | 0, 12, 24 weeks: Samples collected and stabilized at these time points and frozen for future analyses | 
| Neuropeptide Y | Peptide measured in the blood with satiety related role | 0, 12, 24 weeks: Samples collected and stabilized at these time points and frozen for future analyses | 
| cholecystokinin (CCK) | Peptide measured in the blood with satiety related role | 0, 12, 24 weeks: Samples collected and stabilized at these time points and frozen for future analyses | 
| Gut Microbiome | Measured with kit: Self-collection and stabilization of microbial DNA from feces for gut microbiome profiling | 0, 12, 24 weeks: Samples collected and stabilized at these time points and frozen for future analyses | 
| Comprehensive metabolomics | Serum collection for comprehensive metabolomics analysis for integrative analysis with gut microbiome | 0, 12, 24 weeks: Samples collected and stabilized at these time points and frozen for future analyses | 
| Dietary Practices | Short questionnaire assessing dietary behaviors related to meal frequency, timing, and eating away from home | 0, 6, 12, 18, 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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continuous glucose monitor, metabolomics, Diet beverages, diet, diabetes control, artificial sweeteners, gut microbiome