Diabetes Mellitus, Insulin-Dependent, Hypercholesterolemia
Conditions
Keywords
Type 1 diabetes, Children, Statins, Hypercholesterolemia, Lipoproteins, C reactive protein, Continuous glucose monitors, Adolescence, Abdominal magnetic resonance imaging, Toll like receptors, Receptors of advanced glycation end products, Nutrition
Brief summary
Children with type1 diabetes (T1DM) have increased risk for cardiovascular disease (CVD) due to chronic increase in the blood sugars and inflammation. If there is also increased in cholesterol, it creates a highly abnormal environment not fully corrected by improved control of the blood sugars. CVD remains the principal risk of mortality in T1DM, and its prevention and treatment, compelling in children. This grant proposal encompasses 3 separate, yet interrelated projects addressing different aspects of CVD risk in children with T1DM. Project #1: a randomized controlled trial on the safety and efficacy of a class of drugs called statins, which lower bad cholesterol in the body, in children with diabetes and elevated bad cholesterol. We will measure changes in concentration of blood inflammatory markers and for the 1st time, correlate levels of these markers with changes in blood sugar as measured by continuous glucose sensors, instruments that measure the blood sugar continuously through a small needle under the skin. Project #2: is a laboratory study to investigate the genetics and concentration of key molecules that participate in the inflammatory cascade and atheromatous plaque formation that causes CVD. Expression levels in children with T1DM will be compared with those in healthy controls for the 1st time. Project #3: examines the use of abdominal aortic MRI to measure damage to the arteries in children with T1DM and healthy age-matched controls. The results of these studies will likely provide important new data on the use of statins in children with diabetes.
Interventions
DRUGAtorvastatin
10 or 20 mg daily
10 or 20 mg daily
Sponsors
Pfizer
Medtronic
Quest Diagnostics-Nichols Insitute
Nemours Children's Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
10 Years to 20 Years
Healthy volunteers
Yes
Inclusion criteria
Project 1 * T1DM diagnosed clinically for \> 1 year * any HbA1C * on stable insulin therapy * Ages: 10 - 20 years * both genders * BMI \< 85th percentile * Fasting LDL-C\>100mg/dl * Normal thyroid function Inclusion Criteria:Projects 2 and 3 * T1DM diagnosed clinically for \> 3 year * HbA1C \> 8% * on stable insulin therapy * Ages: 12- 20 years * both genders * BMI \< 85th percentile * Fasting LDL-C\>100mg/dl * Normal thyroid function
Exclusion criteria
Projects 1,2 and 3 * Severe dyslipidemia (LDL-C \>160, TG \> 400 mg/dl) * Smoking * Pregnancy * Current use of anti-inflammatory or immunomodulatory drugs, lipid lowering, antidiabetic drugs * Patients with hypertension and/or microalbuminuria will be allowed using balanced randomization and standardized treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| LDL-C Levels Assessed at Randomization and 6 Months | Randomization and 6 months | To assess if the use of statins in children with type 1 DM is safe, improves measures of LDL-C. Subjects will have a physical exam, laboratories, nutritional counseling and moderate aerobic exercise recommended. Diabetes management will be intensified. At 3 months fasting lipoprotein fractions (ion mobility)re-drawn and if LDL-C \>100mg/dl patients will be randomized to treatment with statins or placebo for 6 months, randomization stratified by BP and microalbuminuria, duration of diabetes and HgA1C. At 1 month safety labs will be repeated and blood withdrawn again at 3 and 6 months from baseline. |
| Hs-CRP Levels Assessed at Randomization and 6 Months | Randomization and 6 months | To assess if the use of statins in children with type 1 DM decreases the concentration of inflammatory markers. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MAGE | Randomization and 6 months | Mean amplitude of glycemic excursion (MAGE) with continuous glucose monitoring (CGM - IPro®, Medtronic Minimed) worn blindly for 6d to assess glucose variability |
| RAGE | Randomization and 6 months | Receptor for Advanced Glycation End Products |
| Descending Aortic Strain | Randomization | Subclinical atherosclerosis and arterial stiffness of abdominal aortic MRI |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Atorvastatin Atorvastatin: 10 or 20 mg daily | 21 |
| Placebo Atorvastatin Placebo: 10 or 20 mg daily | 21 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Dropped at Randomization due to high LFT | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Moved Out of State | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Atorvastatin |
|---|---|---|---|
| Age, Continuous | 15.4 years STANDARD_DEVIATION 2.7 | 15.1 years STANDARD_DEVIATION 2.4 | 14.9 years STANDARD_DEVIATION 2.2 |
| Race/Ethnicity, Customized non-Hispanic white | 14 participants | 31 participants | 17 participants |
| Race/Ethnicity, Customized Other | 7 participants | 11 participants | 4 participants |
| Region of Enrollment United States | 21 participants | 42 participants | 21 participants |
| Sex: Female, Male Female | 9 Participants | 20 Participants | 11 Participants |
| Sex: Female, Male Male | 12 Participants | 22 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 21 | 7 / 21 |
| serious Total, serious adverse events | 1 / 21 | 0 / 21 |
Outcome results
Primary
Hs-CRP Levels Assessed at Randomization and 6 Months
To assess if the use of statins in children with type 1 DM decreases the concentration of inflammatory markers.
Time frame: Randomization and 6 months
Population: Project #1
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atorvastatin LDL-C at Randomization | Hs-CRP Levels Assessed at Randomization and 6 Months | 0.363 mg/dL |
| Atorvastatin LDL-C at 6 Months | Hs-CRP Levels Assessed at Randomization and 6 Months | 0.419 mg/dL |
| Placebo LDL-C at Randomization | Hs-CRP Levels Assessed at Randomization and 6 Months | 0.248 mg/dL |
| Placebo LDL-C at 6 Months | Hs-CRP Levels Assessed at Randomization and 6 Months | 0.446 mg/dL |
p-value: 0.913Wilcoxon (Mann-Whitney)
Primary
LDL-C Levels Assessed at Randomization and 6 Months
To assess if the use of statins in children with type 1 DM is safe, improves measures of LDL-C. Subjects will have a physical exam, laboratories, nutritional counseling and moderate aerobic exercise recommended. Diabetes management will be intensified. At 3 months fasting lipoprotein fractions (ion mobility)re-drawn and if LDL-C \>100mg/dl patients will be randomized to treatment with statins or placebo for 6 months, randomization stratified by BP and microalbuminuria, duration of diabetes and HgA1C. At 1 month safety labs will be repeated and blood withdrawn again at 3 and 6 months from baseline.
Time frame: Randomization and 6 months
Population: Project #1. Adjusted for age, gender and ISS (Insulin sensitivity score)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atorvastatin LDL-C at Randomization | LDL-C Levels Assessed at Randomization and 6 Months | 128 mg/dL | Standard Error 4 |
| Atorvastatin LDL-C at 6 Months | LDL-C Levels Assessed at Randomization and 6 Months | 87 mg/dL | Standard Error 5 |
| Placebo LDL-C at Randomization | LDL-C Levels Assessed at Randomization and 6 Months | 126 mg/dL | Standard Error 5 |
| Placebo LDL-C at 6 Months | LDL-C Levels Assessed at Randomization and 6 Months | 133 mg/dL | Standard Error 8 |
p-value: <0.0001Mixed Models Analysis
Secondary
Descending Aortic Strain
Subclinical atherosclerosis and arterial stiffness of abdominal aortic MRI
Time frame: Randomization
Population: Project #3. Study Subjects were given the option to participate in the Project #3 MRI substudy; 11 Atorvastatin and 8 Placebo Subjects participated in Project #3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atorvastatin LDL-C at Randomization | Descending Aortic Strain | 27.2 percent area change | Standard Deviation 6.4 |
| Atorvastatin LDL-C at 6 Months | Descending Aortic Strain | 29 percent area change | Standard Deviation 8.5 |
p-value: 0.09t-test, 2 sided
Secondary
MAGE
Mean amplitude of glycemic excursion (MAGE) with continuous glucose monitoring (CGM - IPro®, Medtronic Minimed) worn blindly for 6d to assess glucose variability
Time frame: Randomization and 6 months
Population: Project #1. 4 Atorvastatin and 8 Placebo Subjects did not complete their CGM at 6months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atorvastatin LDL-C at Randomization | MAGE | 150 mg/dL | Standard Error 9 |
| Atorvastatin LDL-C at 6 Months | MAGE | 156 mg/dL | Standard Error 13 |
| Placebo LDL-C at Randomization | MAGE | 156 mg/dL | Standard Error 6 |
| Placebo LDL-C at 6 Months | MAGE | 152 mg/dL | Standard Error 8 |
Secondary
RAGE
Receptor for Advanced Glycation End Products
Time frame: Randomization and 6 months
Population: Project #2. Study Subjects were given the option to participate in the Project #2 genetic substudy; 9 Atorvastatin and 12 Placebo Subjects participated in Project #2. 1 Atorvastatin and 1 Placebo Subject did not complete the 6 month genetic test.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atorvastatin LDL-C at Randomization | RAGE | 49 pg/mL | Standard Error 11 |
| Atorvastatin LDL-C at 6 Months | RAGE | 35 pg/mL | Standard Error 5 |
| Placebo LDL-C at Randomization | RAGE | 50 pg/mL | Standard Error 7 |
| Placebo LDL-C at 6 Months | RAGE | 58 pg/mL | Standard Error 17 |