Effect of Diabetes Mellitus on Cholesterol Metabolism
Effect of Diabetes Mellitus on Cholesterol Metabolism
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.
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.
Inclusion Criteria:

 -  Type 1 DM:

 -  Age > 18 years

 -  Subjects diagnosed with type 1 DM (diagnosed based upon history of ketoacidosis,
 proven insulin dependence, absent C-peptide and or positive autoantibody profile (such
 as anti-GAD etc.)

 -  Stable A1C < 8.5%

 -  BMI < 31

 -  Type 2 DM:

 -  Age > 18 years

 -  Subjects diagnosed with type II DM (diagnosed as adult onset, not-insulin dependent
 and not on insulin)

 -  Stable A1C < 8.5%

 -  BMI < 31

 Exclusion Criteria:

 -  History of active, unstable cardiovascular disease (including MI, CHF, Stroke, Angina,
 CABG, stenting/PTCA, peripheral vascular disease, intermittent claudication)

 -  Pregnancy, nursing or likely to get pregnant during the course of the study (not on
 oral contraceptives and premenopausal)

 -  Chronic Kidney Disease (creatinine > 2.0)

 -  Liver function test abnormalities, not previously worked up (AST or ALT >4x upper
 limit of normal)

 -  Active substance abuse including alcohol

 -  History of severe Hypertriglyceridemia (untreated TG > 500) and on therapy

 -  Use of agents that interfere with cholesterol absorption (such as fiber, resins etc.)
 which can not be discontinued for the duration of the study

 -  Actively enrolled in a weight loss program or following a special diet ( e.g.: Atkins
 diet)

 -  History of malignancy <5y

 -  History of Rhabdomyolysis and Myopathy

 -  Use of on-going oral corticosteroids

 -  History of HIV infection

 -  Use of following drugs/compounds: cyclosporine, itraconazole, ketoconazole,
 erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, gemfibrozil,
 niacin, amiodarone, verapamil or large quantities of grape fruit juice (> 1 quart per
 day)

 -  Proteinuria: more than or equal to 300mg/24 hours calculated from random urine
 specimen.

 -  BMI >31

 -  Anyone with hypersensitivity to either one of the study medications

 -  Allergy to Soy bean products

 -  Unable to consume milk products with or without Lactaid®