Statins in Children With Type 1 Diabetes and Hypercholesterolemia

Study Overview
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Brief Summary
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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.

Official Title
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Statins in Children With Type 1 Diabetes: Effects on Metabolism, Inflammation and Endothelial Function

Conditions
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Diabetes Mellitus, Insulin-Dependent, Hypercholesterolemia

Intervention / Treatment
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* Drug: Atorvastatin
* Drug: Atorvastatin Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atorvastatin<br> | Drug: Atorvastatin<br>* 10 or 20 mg daily<br>* Other names: Lipitor;|
| Placebo Comparator: Placebo<br> | Drug: Atorvastatin Placebo<br>* 10 or 20 mg daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Randomization and 6 months | 
| 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. | Randomization and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MAGE | Mean amplitude of glycemic excursion (MAGE) with continuous glucose monitoring (CGM - IPro®, Medtronic Minimed) worn blindly for 6d to assess glucose variability | Randomization and 6 months | 
| RAGE | Receptor for Advanced Glycation End Products | Randomization and 6 months | 
| Descending Aortic Strain | Subclinical atherosclerosis and arterial stiffness of abdominal aortic MRI | Randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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