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

• Diet Beverage (Behavioral): 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.
• Water (Behavioral): 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.

Primary outcomes

• HbA1c [Time 0 (directly after 2-week run-in), 12, 24 weeks]: Glycated hemoglobin

Secondary outcomes

• Time In Range [All 14 day periods: Run-in (2-weeks, usual-baseline), weeks 11 and 12 (14 days), weeks 23 and 24 (14 days)]: 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.
• Glycemic Variability [All 14 day periods: Run-in (2-weeks, usual-baseline), weeks 11 and 12 (14 days), weeks 23 and 24 (14 days)]: 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 Standard Deviation (SD) of the mean glucose during the wear period. The range of CGM data for inclusion in this study will be 5 to 14 days, consistent with manufacturer's recommendations.
• Mean Glucose (mg/dl) [All 14 day periods: Run-in (2-weeks, usual-baseline), weeks 11 and 12 (14 days), weeks 23 and 24 (14 days)]: A measure of the mean, 24 hour glucose concentration calculated across all recorded glucose readings during the wear period
• Fasting Glucose [Time 0 (directly after 2-week run-in), 12, 24 weeks]: Standard (mg/dl) measure taken fasting (morning) during baseline, 12 weeks, 24 weeks
• Fasting Insulin (Pmol/L) [Time 0 (directly after 2-week run-in), week 12, week 24]: Standard lab measurement for fasting insulin assessment
• Fructosamine [Time 0 (directly after 2-week run-in),12, 24 weeks]: Fructosamine (umol/L) represents usual glycemia over the past 2-3 weeks, and is considered a valid marker of short term clinical glycemic patterns by the American Diabetes Association
• Weight (kg) [Time 0 (directly after 2-week run-in), 12, 24 weeks]: Weight measured on standardized scale in gown
• Total Cholesterol (mg/dL) [Time 0 (directly after 2-week run-in), 12, 24 weeks]: Total cholesterol was measured as part of a lipid panel, a standard measurement for assessing clinical CVD risk
• Kidney Function [Time 0 (directly after 2-week run-in),12, 24 weeks]: eGFR-Cystatin-C (estimated glomerular filtration rate) = mL/min/1.73 m\^2
• Systolic Blood Pressure [Time 0 (directly after 2-week run-in),12, 24 weeks]: Systolic blood pressure (mmHg)
• Diastolic Blood Pressure [Time 0 (directly after 2-week run-in), 12, 24 weeks]: Standard part of blood pressure measurement (mmHG)
• Apolipoprotein-AI [Time 0 (directly after 2-week run-in), 12, 24 weeks]: Apo-AI the major protein component of high density lipoprotein (HDL)
• Apolipoprotein B [Time 0 (directly after 2-week run-in), 12, 24 weeks]: ApoB levels indicate the atherogenic particle concentration independent of the particle cholesterol content
• Fibrinogen (mg/dL) [Time 0 (directly after 2-week run-in), 12, 24 weeks]: A protein involved in forming blood clots in the body
• C-reactive Protein [Time 0 (directly after 2-week run-in), 12, 24 weeks]: biomarker of inflammation
• Aspartate Aminotransferase (AST) (U/L) [Time 0 (directly after 2-week run-in), 12, 24 weeks]: AST (aspartate aminotransferase) is an enzyme that reflects liver function
• Aminotransferase (ALT) (U/L) [Time 0 (directly after 2-week run-in), 12, 24 weeks]: ALT (alanine transaminase) is an enzyme, a protein that reflects liver function
• Alkaline Phosphatase (ALKPhos ) (U/L) [Time 0 (directly after 2-week run-in), 12, 24 weeks]: ALP is an enzyme, a protein, that reflects liver function
• Thyroid Stimulating Hormone (TSH) [Time 0 (directly after 2-week run-in), 12, 24 weeks]: Hormone measured in the blood with energy balance related role
• Dietary Quality (Healthy Eating Index -HEI) [Run-in period (2 weeks) - baseline, Week 1-12 (period 1), Week 13-24 (period 2).]: The Healthy Eating Index (HEI) is a measure of diet quality used to assess how well a set of foods aligns with key recommendations and dietary patterns published in the Dietary Guidelines for Americans (Dietary Guidelines). The overall HEI scores are made up of 13 components that reflect the different food groups and key recommendations in the Dietary Guidelines for Americans. The HEI is scored 0-100 (low to high), with higher scores representing greater reported intake of an overall dietary pattern aligning with USDA Dietary Guidelines. In the SODAS study, dietary intake was assessed by multiple unannounced 24-hour dietary recalls that occurred during the 2-week run-in period to assess usual habits (2 recalls over 2 weeks) and the active intervention (5 recalls over 24 weeks: 2 to 3 recalls during weeks 1-12 (period 1), and 2 to 3 recalls during weeks 13-24 (period 2). to measure any changes in diet quality. Scores during each period represent the average score of recalls.
• The Diabetes Health Profile (DHP-18) [Time 0 (directly after 2-week run-in), 12, 24 weeks]: The Diabetes Health Profile (DHP-18) is used to assess health related quality of life in diabetes across three domains (psychological distress, barriers to activity and disinhibited eating). Each item is scored on a 4-point scale, and the subscale scores are then rescaled to a 0-100 range, with higher scores indicating poorer well-being.
• Food Craving Inventory (FCI) [Time 0 (directly after 2-week run-in), 12, 24 weeks]: The FCI is a valid and reliable self-report measure of specific food cravings. The inventory consists of 4 factors or subscales measuring cravings for high fats (8 items), carbohydrates/starches (8 items), sweets (8 items), and fast food fats (4 items), and a total score is calculated by summing the subscales. Participants rate each food on a 5-point Likert scale ranging from 0 (never) to 4 (always/almost every day). We calculated the total score by summing the individual item responses in each subscale. Higher scores indicate more frequent cravings of the 28 items.
• The Pittsburgh Sleep Quality Index (PSQI) [Time 0 (directly after 2-week run-in), 12, 24 weeks]: The Pittsburgh Sleep Quality Index (PSQI) is a self-report questionnaire that assesses sleep quality over a one-month time interval. Each component score of the PSQI ranges from 0 to 3, with 3 indicating the greatest dysfunction or disturbance. The seven component scores are then summed to obtain a global PSQI score, which ranges from 0 to 21. Higher scores indicate poorer sleep quality, with a score greater than 5 suggesting significant sleep difficulties
• Medication Effect Score (MES) [Time 0 (directly after 2-week run-in), 6, 12, 18, 24 weeks]: The medication effect score (MES) is a measure of overall diabetes regimen intensity, and is based on the dosages of medications used and their potencies. The MES is calculated for each diabetes medication in a regimen using the following equation: (actual drug dose/maximum drug dose) × drug-specific adjustment factor. The adjustment factor equates to the expected decrease in HbA1c achieved by the drug as monotherapy. The MES presumes a linear relationship between medication dosage and HbA1c, and the sum of MES values attributed to individual medications represents the maximum A1c reduction that may be expected by the regimen. It is a continuous variable with range 0 (no medications), and the maximum achievable MES is patient specific and dependent on the total number of and dose of medications reported.
• Therapeutic Intensity Score (TIS) [Time 0 (directly after 2-week run-in), 6, 12, 18, 24 weeks]: The therapeutic intensity score (TIS) is a summary measure that accounts for the number of medications and the relative doses a patient received to lower blood pressure. It is a continuous variable with range 0 (no medications), and the maximum achievable TIS is patient specific and dependent on the total number of antihypertensive medications reported.

Sex: All, ages: 35 Years to any

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

Participant flow

Outcome results

• HbA1c (Primary), Mean, Hba1c(%): Diet Beverage 7.19 +/- 1.10; Water 7.20 +/- 0.69
• Time In Range (Secondary), Mean, % Time in Range: Diet Beverage 76.0 +/- 19.2; Water 72.3 +/- 20.9
• Glycemic Variability (Secondary), Mean, SD of mean glucose (mg/dl): Diet Beverage 39.6 +/- 14.7; Water 42.0 +/- 13.1
• Mean Glucose (mg/dl) (Secondary), Mean, mg/dl: Diet Beverage 147.3 +/- 42.1; Water 151.4 +/- 33.1
• Fasting Glucose (Secondary), Mean, mg/dl: Diet Beverage 147.5 +/- 40.0; Water 147.6 +/- 36.2
• Fasting Insulin (Pmol/L) (Secondary), Mean, pmol/L: Diet Beverage 128.0 +/- 97.1; Water 138.5 +/- 134.1
• Fructosamine (Secondary), Mean, umol/L: Diet Beverage 273.2 +/- 44.8; Water 285.5 +/- 42.4
• Weight (kg) (Secondary), Mean, kg: Diet Beverage 102.1 +/- 21.1; Water 96.1 +/- 21.5
• Total Cholesterol (mg/dL) (Secondary), Mean, mg/dl: Diet Beverage 165.9 +/- 41.3; Water 163.6 +/- 40.9
• Kidney Function (Secondary), Mean, eGFR-Cystatin-C (mL/min/1.73 m^2): Diet Beverage 83.2 +/- 21.1; Water 81.5 +/- 20.0
• Systolic Blood Pressure (Secondary), Mean, mmHG: Diet Beverage 136.3 +/- 15.0; Water 131.9 +/- 15.0
• Diastolic Blood Pressure (Secondary), Mean, mmHG: Diet Beverage 78.5 +/- 7.7; Water 76.6 +/- 7.4
• Apolipoprotein-AI (Secondary), Mean, mg/dL: Diet Beverage 146.6 +/- 24.3; Water 150.3 +/- 23.3
• Apolipoprotein B (Secondary), Mean, mg/dL: Diet Beverage 88.0 +/- 21.1; Water 85.0 +/- 24.0
• Fibrinogen (mg/dL) (Secondary), Mean, mg/dL: Diet Beverage 265.0 +/- 51.9; Water 269.3 +/- 55.1
• C-reactive Protein (Secondary), Mean, mg/L: Diet Beverage 3.93 +/- 3.73; Water 3.54 +/- 3.27
• Aspartate Aminotransferase (AST) (U/L) (Secondary), Mean, U/L: Diet Beverage 21.9 +/- 9.5; Water 24.9 +/- 15.2
• Aminotransferase (ALT) (U/L) (Secondary), Mean, U/L: Diet Beverage 26.6 +/- 14.5; Water 28.2 +/- 21.6
• Alkaline Phosphatase (ALKPhos ) (U/L) (Secondary), Mean, U/L: Diet Beverage 88.0 +/- 41.8; Water 83.3 +/- 24.7
• Thyroid Stimulating Hormone (TSH) (Secondary), Mean, µU/mL: Diet Beverage 2.45 +/- 1.58; Water 2.17 +/- 1.34
• 6 more outcome measures not shown.

Adverse events

Time frame: 26 weeks (2 week run-in period and 24-week randomized intervention period)

• Study Protocol (PDF, 2019-05-30)
• Statistical Analysis Plan (PDF, 2024-04-30)

NIH grants: R01DK117028