Clinical trial NCT00879710
Conditions: Type 1 Diabetes Mellitus Type 2 Diabetes Mellitus Hypercholesterolemia
Keywords: Diabetes Mellitus Hypercholesterolemia Simvastatin Ezetimibe.
Sponsor: Medical College of Wisconsin
Start date: 2008-08-01; Completion date: 2013-07-01
Enrollment: 57 participants; Allocation: NON_RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
HMG CoA reductase inhibitors (statins) are commonly used to treat high cholesterol (HC) in both type 1 and type 2 diabetes mellitus (DM). Several studies have shown benefits of statin among patients of type 2 DM, however, no such data is available for patients with type 1 DM.

It is known from studies on cholesterol metabolism using surrogate markers that patients with type 1 DM have higher cholesterol absorption compared to normals and those with type 2 DM have higher cholesterol synthesis. Since statins inhibit synthesis, patients with type 1 DM may not have a good response and may respond better to cholesterol absorption inhibitors. The purpose of this study is to determine the cholesterol lowering effects of cholesterol absorption inhibitors and cholesterol synthesis inhibitors in subjects with type 1 and type 2 diabetes mellitus.

Detailed description:
Hypothesis:

1. Cholesterol absorption inhibitors like ezetimibe are more effective in lowering cholesterol in subjects with type 1 diabetes mellitus . The primary outcome measures are LDL cholesterol and cholesterol tracer absorption.
2. Cholesterol synthesis inhibitors like statins are more effective in lowering cholesterol in subjects with type 2 diabetes mellitus. The primary outcomes are LDL cholesterol and 24 Hour urinary mevalonic acid levels.
3. Response to statin is related to basal cholesterol synthesis rates. The primary outcomes are LDL cholesterol and 24 Hour urinary mevalonic acid levels.
4. Response to ezetimibe is related to basal absorption rates. The primary outcome measures are LDL cholesterol, phytosterol levels and cholesterol tracer absorption.

Specific Aims:

1. Measure baseline sterol absorption using plant sterol levels and and synthesis by using 24 h excretion of urinary mevalonic acid levels in type 1 and type 2 subjects
2. Measure changes in lipid parameters, cholesterol synthesis and absorption markers in type 1 and type 2 subjects before and after 6 week therapy with simvastatin and 6 week therapy with ezetimibe after a 4 week washout period
3. Start collecting blood for future genetic analysis for polymorphisms in cholesterol absorption genes

Specific Methods:

VISIT 1: Evaluation of all the subjects that are willing to participate in the study would be carried out at the GCRC until required sample size is recruited and will include the following:

1. Sign informed consent
2. Complete a health questionnaire that has a standardized format to collect basic information regarding past and current medical history
3. Physical exam that includes measurement of blood pressure, height, weight, waist and hip circumference will be performed.
4. Blood (30ml) would be drawn for baseline chemistry including creatinine, ALT, CPK, fasting lipid panel, Apo-B, Apo A1, glycated hemoglobin (HbA1c) and serum pregnancy test in women of child bearing age. Urine will be collected for urine analysis and presence of protein in the urine
5. Evaluation of inclusion/exclusion criteria Subjects fulfilling the inclusion and exclusion criteria would be recruited into the study

Following specific procedures will be followed:

At the start of the study, subjects who are already on any lipid lowering medication will be asked to stop the medications 4 weeks prior to obtaining the baseline labs. No changes will be made to their diet, exercise pattern or in treatment for the DM. This will be done by a telephone conversation.

VISIT 2 (Day 1): Subjects will report fasting to GCRC at 8 AM. Subjects will briefly meet with bionutritionist for 24 hour dietary recall and instructions to keep a food diary on day 2 and 3. Blood sample (50ml) will be collected for fasting glucose, insulin, lipid panel, Apo B, Apo A-1, CPK, Hb A1c, plasma and serum frozen for sterol analyses (by GC) and WBC separated for DNA extraction.

The subject will be asked to consume with a cholesterol tracer (Cholesterol D5). Subjects will be asked to consume the 8 ounces in entirety. They will be asked not to eat/drink anything (except water) until the lunch time. If 8 Ounces are inadequate for breakfast, subjects will be offered another 8 Oz serving of Carnation® Instant Breakfast in the same or different flavor. If the subject is lactose intolerant, Lactaid tablets will be offered to offset the effects of milk. If subjects are unable to consume milk (with or without Lactaid®) or allergic to soy bean oil, they will be ineligible to participate in the study. Subjects will be sent home with a urine jug to collect 24-hour urine on day 3.

VISIT 3 (Day 4): Subject will bring the urine jug and food diary back for analysis and that same day will have blood (20ml) collected for evaluation of tracers. Food diary will be reviewed by the bionutritionist. Urine pregnancy test will be performed in women of child bearing age. Subjects will be started on either simvastatin or ezetimibe (we will alternate the subjects so that half the sample will initially be treated with simvastatin and half will be started on ezetimibe). The dose of Simvastatin (Merck) is 40 mg orally at nighttime for 6 weeks and the dose of ezetimibe (Schering-Plough) is 10 mg taken orally once a day. Subjects will be instructed on low-fat diet (therapeutic life style changes diet) recommended by American Heart Association by the bionutritionist.

VISIT 4 (Day 46 ± 7 days): Subjects will report fasting to GCRC at 8 AM. The subject will consume Carnation® Instant Breakfast with a cholesterol tracer (Cholesterol D5). Subjects will be asked to maintain same dietary restriction as visit 2. Subjects will be sent home with a urine jug to collect 24-hour urine on day 3. Subjects will start food diary on day 47 and 48.

VISIT 5 (Day 49 ± 7 days): Subject will bring the urine jug and food diary back for analysis and that same day will have blood (40ml) collected for evaluation of tracers, lipid panel, Apo A1, Apo B 100, ALT, CPK, plasma and serum stored for sterol analyses (by GC). Same day, weight, waist and hip circumference will be measured again. Food diary will be reviewed by bionutritionist. Subjects will be asked to bring back pill bottles also for pill count. Simvastatin or ezetimibe will be stopped for 4 weeks.

VISIT 6 (Day 77 ± 7 days): Subjects will be asked to come fasting to GCRC at 8 AM. 15ml of blood will be collected to measure lipid panel, apo B100 and Apo A1, Hb A1C, and ALT levels. Urine pregnancy test will be performed in women of child bearing age. Subjects will be started on 10 mg of ezetimibe or 40 mg of simvastatin as mentioned above for next 6 weeks.

VISIT 7 (Day 119 ± 7 days): Subjects will report fasting to GCRC at 8 AM. The subject will consume a Carnation® Instant Breakfast with cholesterol tracer (Cholesterol D5). Subjects will be asked to maintain same dietary restriction as visit 2. Subjects will be sent home with a urine jug to collect 24-hour urine on day 3.

Subjects will start food diary on day 120 and 121

VISIT 8 (Day 122 ± 7 days): Subject will bring the urine jug and food diary back for analysis and that same day will have blood (40 ml) collected for evaluation of tracers, lipid panel, Apo B100, Apo A1, Hb A1c, ALT, CPK, plasma and serum stored for sterol analyses (by GC). Weight, waist and hip circumference will be measured again. Food diary will be reviewed by bionutritionist. Ezetimibe or simvastatin therapy will be stopped. Subjects will be asked to resume their usual cholesterol lowering medications.

Ending the Study:

Study will be ended when all the required participants are enrolled. We will also consider stopping the study when accumulated data suggests that risks exceed benefits of the study or if preliminary data suggests there is a clear advantage of treating a particular group with a certain agent.

Arms: arm 1: Half the subjects will start with arm (i.e. every other subject in order)

* Simvastatin 40 mg tablet by month daily for 6 weeks,
* 4 weeks washout period

Half the subjects will start with arm (i.e. every other subject in order)

* Ezetimibe 10 mg by month for 6 weeks
* 4 weeks washout period
* Simvastatin 40 mg tablet by month daily for 6 weeks arm 2: Half the subjects will start with arm (i.e. every other subject in order)

* Simvastatin 40 mg tablet by month daily for 6 weeks,
* 4 weeks washout period

Half the subjects will start with arm (i.e. every other subject in order)

* Ezetimibe 10 mg by month for 6 weeks
* 4 weeks washout period
* Simvastatin 40 mg tablet by month daily for 6 weeks arm 3: Half the subjects will start with arm (i.e. every other subject in order)

* Ezetimibe 10 mg by month for 6 weeks,
* 4 weeks washout period arm 4: Half the subjects will start with arm (i.e. every other subject in order) Ezetimibe 10 mg by month for 6 weeks,

•4 weeks washout period
Interventions: intervention 1: simvastatin or ezetimibe
Intervention descriptions: intervention 1: Subjects will be started on either simvastatin or ezetimibe (we will alternate the subjects so that half the sample will initially be treated with simvastatin and half will be started on ezetimibe). The dose of Simvastatin (Merck) is 40 mg orally at nighttime for 6 weeks and the dose of ezetimibe (Schering-Plough) is 10 mg taken orally once a day. Subjects will be instructed on low-fat diet (therapeutic life style changes diet) recommended by American Heart Association by the bionutritionist.

Protocol documents: