Effect of Diabetes Mellitus on Cholesterol Metabolism

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Type 1 Diabetes Mellitus; Type 2 Diabetes Mellitus; Hypercholesterolemia	Drug: simvastatin or ezetimibe	Not Applicable

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Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	57 participants
Allocation:	Non-Randomized
Intervention Model:	Crossover Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Effect of Diabetes Mellitus on Cholesterol Absorption, Synthesis and Statin Efficacy
Study Start Date :	August 2008
Actual Primary Completion Date :	July 2013
Actual Study Completion Date :	July 2013

Arms and Interventions

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Arm	Intervention/treatment
Subjects with type 1 diabetes mellitus,; 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; Ezetimibe 10 mg by month for 6 weeks 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	Drug: simvastatin or ezetimibe; 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.; Other Name: Zocor or Zetia
Subjects with type 2 diabetes mellitus; 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; Ezetimibe 10 mg by month for 6 weeks 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	Drug: simvastatin or ezetimibe; 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.; Other Name: Zocor or Zetia

Outcome Measures

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Primary Outcome Measures :

1. Changes in LDL Cholesterol [ Time Frame: 6 weeks after starting drug therapy ]

   Subjects with T1DM or T2DM were assigned to alternating therapy with simvastatin (40 mg) or ezetimibe (10 mg) for 6 weeks in a crossover design.

   The data are reported as follows.

   Subjects with type 1 diabetes mellitus:

   Simvastatin: Changes in LDL after 6-week therapy with simvastatin (irrespective of the treatment order) Ezetimibe: Changes in LDL after 6-week therapy with ezetimibe (irrespective of the treatment order)

   Subjects with type 2 diabetes mellitus:

   Simvastatin: Changes in LDL after 6-week therapy with simvastatin (irrespective of the treatment order) Ezetimibe: Changes in LDL after 6-week therapy with ezetimibe (irrespective of the treatment order)

Secondary Outcome Measures :

1. Changes in Cholesterol Absorption or Synthesis Rates From the Baseline [ Time Frame: 6 weeks after initiation of drug therapy ]
   We did not complete analyses of this outcome as we ran out of funds to measure these variables though samples have been collected.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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®

Contacts and Locations

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Locations

United States, Wisconsin
Medical College of Wisconsin /Froedtert Hospital
Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

Medical College of Wisconsin

Investigators

Principal Investigator:	Srividya Kidambi, MD	Medical College of Wisconsin
Principal Investigator:	Shailendra B Patel, MD, PhD	Medical College of Wisconsin

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications of Results:

Ciriacks K, Coly G, Krishnaswami S, Patel SB, Kidambi S. Effects of simvastatin and ezetimibe in lowering low-density lipoprotein cholesterol in subjects with type 1 and type 2 diabetes mellitus. Metab Syndr Relat Disord. 2015 Mar;13(2):84-90. doi: 10.1089/met.2014.0114. Epub 2014 Dec 9.

Responsible Party:	Srividya Kidambi, MD, Assistant Professor, Endocrinology, Medical College of Wisconsin
ClinicalTrials.gov Identifier:	NCT00879710 History of Changes
Other Study ID Numbers:	PRO00002485
First Posted:	April 10, 2009
Results First Posted:	April 18, 2016
Last Update Posted:	April 18, 2016
Last Verified:	March 2016

Keywords provided by Srividya Kidambi, MD, Medical College of Wisconsin:

Diabetes Mellitus; Hypercholesterolemia; Simvastatin; Ezetimibe.

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1; Hypercholesterolemia; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Hyperlipidemias; Dyslipidemias	Lipid Metabolism Disorders; Simvastatin; Ezetimibe; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors