Diabetes
Conditions
Keywords
Metformin, Type 2 Diabetes, Youth, Microbiome, Gastrointestinal Side Effects
Brief summary
Background: Metformin is a pill youth with type 2 diabetes take. It can cause side effects like diarrhea and upset stomach. Researchers want to see if a fiber supplement can help decrease these side effects. Objective: To see if a prebiotic fiber supplement helps improve the gastrointestinal side effects of people taking metformin and helps with their blood sugars. Eligibility: People ages 10-25 with type 2 diabetes who are taking or will take metformin Design: Participants will be screened with: Physical exam Medical history Blood and urine tests Meeting with a nutritionist Participants will stop taking all diabetes medication for 1 week. They will then take metformin by mouth for 1 week. They will be randomly assigned to take either a fiber supplement or a placebo by mouth during the same week. They will then stop all study treatments for 2-3 weeks. Then they will restart metformin for 1 week. The groups that received the fiber versus the placebo will be reversed. All participants will then continue taking metformin and take the fiber for 1 month. Participants will have 6 visits over about 2 months. These will include: Blood and urine tests Meal tests: A plastic tube will be inserted in the participant s arm vein for blood draws. They will drink a special meal. Dual-energy x-ray absorptiometry (DXA) scan: Participants will lie on their back while the scan measures their body fat and muscle. While they are home, participants will: Fill out daily surveys online Wear daily activity and blood sugar monitors Collect their stool Eat only certain foods for two 1-week periods...
Detailed description
Metformin is the most widely prescribed anti-diabetes medication in the world and the first-line therapy for treating type 2 diabetes (T2D) in youth and adults. However, metformin s glucose-lowering ability is variable in clinical practice, and efficacy is further limited by poor medication adherence because of metformin-associated adverse effects. Gastrointestinal (GI) symptoms such as bloating, abdominal discomfort, cramping, and diarrhea are the most common side effects associated with metformin use occurring in up to 80% of individuals at drug initiation and up to 30% in individuals on chronic treatment. In youth with type 2 diabetes, the burden of metformin-associated side effects is high because metformin is the only oral FDA-approved for treatment and there are no other oral alternatives. Therefore, identifying ways to mitigate these GI side effects, especially in youth with type 2 diabetes, is of high clinical significance. New data suggest that metformin-induced changes in the gut and/ or the microbiome may be related to both its beneficial (glucose-lowering) and adverse effects. To address this clinical challenge, prebiotic fibers that are non-digestible food ingredients, may help to improve metformin tolerability by increasing beneficial bacteria and stool metabolites, such as short chain fatty acid (SCFA) stool concentrations. This pilot study will test the hypothesis that a prebiotic microbiome modulator (MM) - containing prebiotic fibers and polyphenols - will reduce GI side effects of metformin at time of initiation and change the stool metabolite profile in youth and young adults with T2D treated with metformin, age 10-25 years who are not on insulin therapy. The 9-week study will have 2 phases and 6 outpatient visits at the NIH Clinical Center. Phase 1 is a 5-week randomized double blind cross-over trial with two 1-week intervention periods (metformin + prebiotic and metformin + placebo) during which subjects will eat a standardized diet. Phase 2 will occur immediately following phase 1 in which participants will start an open-label 4-week intervention with metformin and the prebiotic MM.
Interventions
DIETARY_SUPPLEMENTBiomebliss
BiomeBliss is a commercially available powder containing prebiotic fiber (inulin and beta glucan), along with blueberry extract providing polyphenols.
DRUGMetformin
Metformin is a commonly used antidiabetic medication, and the only oral medication approved for children and adolescents under 18 years old. Though reasonably effective, gastro-intestinal side effects are common (80% at initiation, and 10-30% after long term use). Metformin dosing at clinically recommended doses will be titrated per protocol during the study.
DIETARY_SUPPLEMENTPlacebo
Placebo Comparator
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
10 Years to 25 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: 1. Age 10-25 years 2. Pubertal or post-pubertal: Girls - Tanner stage IV-V breast; Boys - Testicular volume \>10cc 3. Diagnosis of type 2 diabetes by American Diabetes Association (ADA) guidelines \[36\] or with established diagnosis previously treated with metformin. 4. Negative test for diabetes-related autoantibodies (glutamic acid decarboxylase 65 and tyrosine phosphatase-related islet antigen 2 (IA-2)) documented in NIH CRIS chart or via outside laboratory assessment within the last 10 years. 5. Hemoglobin A1C \<8% at study initiation
Exclusion criteria
1. Pregnancy or breastfeeding 2. Allergy to study medications 3. Allergy or self-reported intolerance to blueberry, pomegranate, or oats, soy, gluten or dairy products. 4. Chronic insulin therapy or insulin use within the last 3 months 5. Treatment with other medications which are known to affect the parameters under study, including antibiotics within the last month, immunosuppressants, proton-pump inhibitors, supraphysiologic systemic steroids, probiotic or prebiotic supplements 6. Heavy yogurt consumption (2 or more servings of \>=6 oz per day) 7. Chronic GI disease, gastric bypass surgery, cancer diagnosis or autoimmune disease 8. Metabolic derangement such as metabolic acidosis, severe hyperglycemia (fasting blood glucose \>= 200mg/dL), and/or liver enzymes \> three times the upper limit of normal. 9. Any other condition that, in the opinion of the investigators, will increase risk to the subject, or impede the accurate collection of study-related data. 10. Body weight \>= 450lbs 11. Body weight \<=58kg 12. Hemoglobin concentration \<10g/dL
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Gastrointestinal (GI) Tolerability Score | 1 week (assessed daily for 7 days) | A composite tolerability score based on 4 GI side effect profile categories (stool consistency, urgency to evacuate, bloating sensation, and flatulence), assessed by daily survey, will be calculated using a principal components analysis. A scale range of GI tolerability score is (1.14, 3.3). A higher tolerability score indicates a lower side effect profile |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stool Short Chain Fatty Acids (SCFA) | 1 week and 4 weeks | Stool SCFA, including propionate and butyrate, will be measured in stool samples. SCFAs are microbial metabolites that are gut mediators of metabolism. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Then Prebiotic Participant will take Placebo during Period 1 and Prebiotic during Period 2
Biomebliss: BiomeBliss is a commercially available powder containing prebiotic fiber (inulin and beta glucan), along with blueberry extract providing polyphenols.
Metformin: Metformin is a commonly used antidiabetic medication, and the only oral medication approved for children and adolescents under 18 years old. Though reasonably effective, gastro-intestinal side effects are common (80% at initiation, and 10-30% after long term use). Metformin dosing at clinically recommended doses will be titrated per protocol during the study.
Placebo: Placebo Comparator | 4 |
| Prebiotic Then Placebo Participant will take Prebiotic during Period 1 and Placebo during Period 2
Biomebliss: BiomeBliss is a commercially available powder containing prebiotic fiber (inulin and beta glucan), along with blueberry extract providing polyphenols.
Metformin: Metformin is a commonly used antidiabetic medication, and the only oral medication approved for children and adolescents under 18 years old. Though reasonably effective, gastro-intestinal side effects are common (80% at initiation, and 10-30% after long term use). Metformin dosing at clinically recommended doses will be titrated per protocol during the study.
Placebo: Placebo Comparator | 2 |
| Total | 6 |
Baseline characteristics
| Characteristic | Prebiotic Then Placebo | Total | Placebo Then Prebiotic |
|---|---|---|---|
| Age, Continuous | 16.5 years STANDARD_DEVIATION 3.54 | 17.2 years STANDARD_DEVIATION 1.72 | 17.5 years STANDARD_DEVIATION 0.58 |
| Body Mass Index | 39.41 kg/m^2 STANDARD_DEVIATION 2.4 | 41.33 kg/m^2 STANDARD_DEVIATION 8.6 | 42.29 kg/m^2 STANDARD_DEVIATION 10.9 |
| Diastolic Blood Pressure | 64.5 mmHg STANDARD_DEVIATION 3.5 | 69.8 mmHg STANDARD_DEVIATION 5 | 72.5 mmHg STANDARD_DEVIATION 3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 6 Participants | 4 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 | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 2 Participants |
| Systolic Blood Pressure | 116.5 mmHg STANDARD_DEVIATION 17.7 | 125.8 mmHg STANDARD_DEVIATION 12.5 | 130.5 mmHg STANDARD_DEVIATION 8.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 2 | 0 / 4 | 0 / 2 |
| other Total, other adverse events | 1 / 4 | 0 / 2 | 4 / 4 | 1 / 2 |
| serious Total, serious adverse events | 0 / 4 | 0 / 2 | 0 / 4 | 0 / 2 |
Outcome results
Primary
Gastrointestinal (GI) Tolerability Score
A composite tolerability score based on 4 GI side effect profile categories (stool consistency, urgency to evacuate, bloating sensation, and flatulence), assessed by daily survey, will be calculated using a principal components analysis. A scale range of GI tolerability score is (1.14, 3.3). A higher tolerability score indicates a lower side effect profile
Time frame: 1 week (assessed daily for 7 days)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Then Prebiotic | Gastrointestinal (GI) Tolerability Score | Period 1 | 2.31 score on a scale | Standard Deviation 0.62 |
| Placebo Then Prebiotic | Gastrointestinal (GI) Tolerability Score | Period 2 | 2.70 score on a scale | Standard Deviation 0.27 |
| Prebiotic Then Placebo | Gastrointestinal (GI) Tolerability Score | Period 1 | 2.63 score on a scale | Standard Deviation 0.33 |
| Prebiotic Then Placebo | Gastrointestinal (GI) Tolerability Score | Period 2 | 2.71 score on a scale | Standard Deviation 0.22 |
Secondary
Stool Short Chain Fatty Acids (SCFA)
Stool SCFA, including propionate and butyrate, will be measured in stool samples. SCFAs are microbial metabolites that are gut mediators of metabolism.
Time frame: 1 week and 4 weeks
Population: SCFA analysis of stool samples was not and never will be conducted, data was not collected for this Outcome Measure.