Cardiovascular Risk Factor
Conditions
Keywords
insulin sensitivity, vascular function, blood pressure, continuous glucose monitoring, trimethylamine N-oxide (TMAO)
Brief summary
Trimethylamine-N-oxide (TMAO), a metabolite produced by gut microbial metabolism of dietary choline, has recently been causally linked to atherosclerosis in animal models and has been shown to be predictive of cardiovascular disease (CVD) risk in some but not all cohort studies. The relevance of observations in animals to humans is unclear and little information is available on the mechanisms linking TMAO to increased CVD risk. Vascular dysfunction plays a critical role in the initiation and progression of atherothrombotic disease. Whether TMAO impairs vascular function in humans is not known. The purpose of this study is to determine if short term supplementation of dietary choline, which increases TMAO, affects CVD risk factors, such as glucose homeostasis and vascular function.
Interventions
DIETARY_SUPPLEMENTCholine
1000 mg (2 x 500 mg) choline bitartrate capsules (over-the-counter supplement)
DIETARY_SUPPLEMENTPlacebo
Choline-matched 1000 mg (2 x 500 mg) placebo (maltodextrin) capsules
Sponsors
National Institute on Aging (NIA)
Virginia Polytechnic Institute and State University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Outcomes Assessor)
Intervention model description
Double-blind, placebo-controlled, crossover design
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
Yes
Inclusion criteria
* Age 18-79 years * Weight stable for previous 6 months (+2.0kg) * Sedentary to recreationally active (\<30 min aerobic exercise \<2x/wk) * No plans to gain/lose weight or change physical activity level * Verbal and written informed consent * Willing to be randomized to treatment order * Fully vaccinated against COVID-19
Exclusion criteria
* BMI \> 35 kg/m2 * Smoking * Pregnant or plans of becoming pregnant * Vegetarian or Vegan * Changed dietary patterns within the last month * Diabetes (or use of diabetes medications) or unstable heart disease * Untreated high blood pressure or high cholesterol * Health problems that mide it unsafe to participate * Taking medications, vitamins or supplements that could affect study outcomes (including but not limited to aspirin, antibiotics, prebiotics, and probiotics) * Known allergy, hypersensitivity, intolerance to choline supplement or its ingredients * Trimethylaminuria or fish odor syndrome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Insulin Sensitivity at 4 Weeks | Calculated difference between the baseline and 4-week testing session for each intervention | Participants will complete a 2-hour glucose tolerance test at baseline, immediately following the first intervention, after a 2-week washout, and immediately following the second intervention. A catheter will be placed in one of the participant's arms. After a baseline blood draw to measure fasting levels of glucose, insulin, cholesterol and other factors, participants will drink a glucose beverage (75 g). Blood will be collected in small amounts (less than one half teaspoon) at eight timepoints over a 2-hour period. Insulin sensitivity will be calculated using Matsuda's index (a ratio with no units). This test will be conducted two times separated by about 4 weeks for each intervention (choline, placebo). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in 24-hour Area Under the Curve for Glucose Levels After Supplementation | Difference in 24-hour glucose levels during free living at baseline and 4 weeks | Glucose will be monitored by a Continuous Glucose Monitor (CGM) sensor (Enlite Sensor; Medtronic, Inc. or FreeStyle Libre Pro; Abbott) and this will be placed on the participant's abdomen or back of the upper arm in order to measure glucose continuously. The measured glucose levels will be assessed by an iPro2 Professional CGM; Medtronic, Inc. or FreeStyle Libre Pro reader; Abbott; and the CGM will be worn for 4 consecutive days. This test will be conducted two times separated by about 4 weeks for each intervention (choline, placebo). |
Countries
United States
Participant flow
Recruitment details
14 individuals were screened and 10 were randomized. Those not randomized voluntarily withdrew from the study.
Pre-assignment details
4 enrolled participants voluntarily withdrew from the study and did not complete any pre-testing sessions before their first assigned intervention.
Participants by arm
| Arm | Count |
|---|---|
| Choline, Then Placebo Participants will consume 1000 mg (2 x 500 mg) of choline supplement per day for 4 weeks, including post-testing sessions. A 2-week washout period will follow the first intervention. Then the participants will consume 1000 mg (2 x 500 mg) of placebo per day for 4 weeks, including post-testing sessions | 3 |
| Placebo, Then Choline Participants will consume 1000 mg (2 x 500 mg) of placebo per day for 4 weeks, including post-testing sessions. A 2-week washout period will follow the first intervention. Then the participants will consume 1000 mg (2 x 500 mg) of choline supplement per day for 4 weeks, including post-testing sessions. | 7 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did not complete oral glucose tolerance tests due to low BP. Did complete other study measures. | 0 | 1 |
Baseline characteristics
| Characteristic | Choline, Then Placebo | Total | Placebo, Then Choline |
|---|---|---|---|
| Age, Continuous | 44 years STANDARD_DEVIATION 16 | 48 years STANDARD_DEVIATION 16 | 50 years STANDARD_DEVIATION 17 |
| Body Mass Index | 28.3 kg/m2 STANDARD_DEVIATION 3.4 | 25.5 kg/m2 STANDARD_DEVIATION 3.5 | 24.2 kg/m2 STANDARD_DEVIATION 2.96 |
| Diastolic blood pressure | 75 mmHg STANDARD_DEVIATION 9 | 73 mmHg STANDARD_DEVIATION 7 | 72 mmHg STANDARD_DEVIATION 6 |
| Glucose | 95 mg/dL STANDARD_DEVIATION 2 | 92 mg/dL STANDARD_DEVIATION 5 | 90 mg/dL STANDARD_DEVIATION 5 |
| HDL cholesterol | 42 mg/dL STANDARD_DEVIATION 3 | 51 mg/dL STANDARD_DEVIATION 17 | 55 mg/dL STANDARD_DEVIATION 20 |
| LDL cholesterol | 120 mg/dL STANDARD_DEVIATION 22 | 121 mg/dL STANDARD_DEVIATION 21 | 122 mg/dL STANDARD_DEVIATION 22 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 9 Participants | 6 Participants |
| Region of Enrollment United States | 3 participants | 10 participants | 7 participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 3 Participants |
| Systolic blood pressure | 121 mmHg STANDARD_DEVIATION 9 | 120 mmHg STANDARD_DEVIATION 13 | 119 mmHg STANDARD_DEVIATION 14 |
| Total cholesterol | 183 mg/dL STANDARD_DEVIATION 36 | 195 mg/dL STANDARD_DEVIATION 34 | 200 mg/dL STANDARD_DEVIATION 35 |
| Triglycerides | 113 mg/dL STANDARD_DEVIATION 63 | 116 mg/dL STANDARD_DEVIATION 62 | 117 mg/dL STANDARD_DEVIATION 66 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
Change From Baseline in Insulin Sensitivity at 4 Weeks
Participants will complete a 2-hour glucose tolerance test at baseline, immediately following the first intervention, after a 2-week washout, and immediately following the second intervention. A catheter will be placed in one of the participant's arms. After a baseline blood draw to measure fasting levels of glucose, insulin, cholesterol and other factors, participants will drink a glucose beverage (75 g). Blood will be collected in small amounts (less than one half teaspoon) at eight timepoints over a 2-hour period. Insulin sensitivity will be calculated using Matsuda's index (a ratio with no units). This test will be conducted two times separated by about 4 weeks for each intervention (choline, placebo).
Time frame: Calculated difference between the baseline and 4-week testing session for each intervention
Population: All participants received each supplementation intervention during their respective cross-over randomization assignment. Therefore, Outcome Measures are reported per intervention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Choline | Change From Baseline in Insulin Sensitivity at 4 Weeks | 0.28 Calculated Ratio - No units | Standard Deviation 0.8 |
| Placebo | Change From Baseline in Insulin Sensitivity at 4 Weeks | -0.29 Calculated Ratio - No units | Standard Deviation 0.45 |
Secondary
Change in 24-hour Area Under the Curve for Glucose Levels After Supplementation
Glucose will be monitored by a Continuous Glucose Monitor (CGM) sensor (Enlite Sensor; Medtronic, Inc. or FreeStyle Libre Pro; Abbott) and this will be placed on the participant's abdomen or back of the upper arm in order to measure glucose continuously. The measured glucose levels will be assessed by an iPro2 Professional CGM; Medtronic, Inc. or FreeStyle Libre Pro reader; Abbott; and the CGM will be worn for 4 consecutive days. This test will be conducted two times separated by about 4 weeks for each intervention (choline, placebo).
Time frame: Difference in 24-hour glucose levels during free living at baseline and 4 weeks
Population: All participants received each supplementation intervention during their respective cross-over randomization assignment. Therefore, Outcome Measures are reported per intervention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Choline | Change in 24-hour Area Under the Curve for Glucose Levels After Supplementation | 7032.5 mg/dL per day | Standard Deviation 10709.5 |
| Placebo | Change in 24-hour Area Under the Curve for Glucose Levels After Supplementation | -2685 mg/dL per day | Standard Deviation 17213.2 |