Effect of Ezetimibe or Simvastatin or Both on Low Densitiy Lipoprotein -Subfractions in Patients With Type 2 Diabetes - Full Text View

Purpose

It is of interest how ezetimibe alone or in combination with statin may influence atherogenic dense Low Density Lipoprotein (dLDL) in patients with type 2 diabetes mellitus. The primary objective of this study will be whether there is a change of the concentrations of Apolipoprotein B (ApoB) in dLDL from baseline in each of the 3 treatment groups.

Condition	Intervention	Phase
Diabetes Mellitus Type 2 Hypercholesterolemia	Drug: ezetimibe Drug: simvastatin Drug: Ezetimibe 10/Simvastatin 20	Phase 4

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	The Effect of Ezetimibe 10 mg, Simvastatin 20 mg and the Combination of Simvastatin 20 mg Plus 10 mg Ezetimibe on Low Density Lipoprotein (LDL)-Subfractions in Patients With Type 2 Diabetes

Resource links provided by NLM:

MedlinePlus related topics: Cholesterol Diabetes Diabetes Type 2

Drug Information available for: Simvastatin Ezetimibe

U.S. FDA Resources

Further study details as provided by University Hospital Freiburg:

Primary Outcome Measures:

Change of the concentration of apolipoprotein B (ApoB) in dense Low Densitiy Lipoprotein (dLDL) from baseline with ezetimibe, simvastatin or the combination of both drugs [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
multicentre, randomized, open-label study investigation in 6-week effect of ezetimibe (10mg/d), simvastatin (20mg/d) or combination of ezetimibe 10mg/simvastatin 20mg/d on concentrations of dLDL separated by preparative gradient ultracentrifugation in patients with type 2 diabetes.

Secondary Outcome Measures:

Change of the concentrations of Total Cholesterol [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
Change of the concentrations of Low Densitiy Lipoprotein (LDL) -Cholesterol [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
Change of the concentrations of High Density Lipoprotein (HDL) -Cholesterol [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
Change of the concentrations of triglycerides [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]

Enrollment:	41
Study Start Date:	November 2007
Study Completion Date:	June 2010
Primary Completion Date:	May 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Ezetimibe 10mg/d intake of ezetimibe 10mg per day for six weeks after wash-out	Drug: ezetimibe ezetimibe 10 mg per day for six weeks Other Name: Ezetrol 10 mg
Active Comparator: Simvastatin 20 mg per day intake of simvastatin 20 mg per day for six weeks after wash-out	Drug: simvastatin Simvastatin 20 mg per day for six weeks Other Name: Zocor MSD
Active Comparator: Ezetimibe 10 mg/d and Simvastatin 20mg/d intake of ezetimibe 10 mg and simvastatin 20 mg per day for six weeks after wash-out	Drug: Ezetimibe 10/Simvastatin 20 Ezetimibe 10mg/Simvastatin 20mg per day for six weeks Other Name: Inegy 10/20

Detailed Description:

The selective cholesterol resorption inhibitor ezetimibe belongs to a new class of cholesterol lowering drugs. It is of interest how ezetimibe alone or in combination with statin may influence atherogenic dense Low Density Lipoprotein (dLDL) in patients with type 2 diabetes mellitus.

The primary objective of this study will be whether there is a change of the concentrations of Apolipoprotein B (ApoB) in dLDL from baseline in each of the 3 treatment groups. The comparison between treatment groups is exploratory due to insufficient power to detect any change between treatments.

Eligibility

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

men > 18 and ≤ 75 years
post-menopausal women ≤ 75 years (follicle stimulating hormone (FSH) >30 mIU/ml, women > 60 years FSH > 20 mIU/ml )
well controlled diabetes mellitus type II (glycohaemoglobin ≤ 8,0 %)
LDL-cholesterol ≤ 160 mg/dl
LDL-subfractions: concentration of apoB-100 in dLDL (LDL-5 und LDL-6) > 25 mg/dl
written informed consent

Exclusion Criteria:

participation in a clinical trial within the last 30 d before screening- visit
patient is unable to give written informed consent
Body mass index <15 kg/m² and > 35 kg/m²
clinical atherosclerotic disease (coronary heart disease, peripheral artery disease, carotid artery disease)
malignoma
uncontrolled arterial hypertension (>160/>100 mmHg)
clinically relevant disease of liver and/or kidneys
clinically relevant endocrinally or hematologic problems
allergy to study medication (Ezetimibe and/or Simvastatin)
alcohol- or drug abuse
laboratory: alanine aminotransferase, aspartate aminotransferase, total bilirubin > 3 x ULN, creatine kinase > 5 x ULN
Concurrent treatment with potent CYP3A4-inhibitors (e.g. itraconazole, ketoconazole, HIV-protease-inhibitors, erythromycin, clarithromycin, telithromycin und nefazodone)
other relevant diseases

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01384058

Locations

Germany
Institut für Stoffwechselforschung
Frankfurt, Germany, 60322
Stephan Jacob, MD
Villingen-.Schwenningen, Germany, 78048

Sponsors and Collaborators

University Hospital Freiburg

Essex Pharma GmbH

Investigators

Principal Investigator:

Karl Winkler, MD

University Hospital Freiburg

More Information

Publications:

Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998 Jul 23;339(4):229-34.

Reaven GM, Chen YD, Jeppesen J, Maheux P, Krauss RM. Insulin resistance and hyperinsulinemia in individuals with small, dense low density lipoprotein particles. J Clin Invest. 1993 Jul;92(1):141-6.

Austin MA, Edwards KL. Small, dense low density lipoproteins, the insulin resistance syndrome and noninsulin-dependent diabetes. Curr Opin Lipidol. 1996 Jun;7(3):167-71. Review.

Winkler K, Abletshauser C, Hoffmann MM, Friedrich I, Baumstark MW, Wieland H, März W. Effect of fluvastatin slow-release on low density lipoprotein (LDL) subfractions in patients with type 2 diabetes mellitus: baseline LDL profile determines specific mode of action. J Clin Endocrinol Metab. 2002 Dec;87(12):5485-90.

Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation. 1990 Aug;82(2):495-506.

Nigon F, Lesnik P, Rouis M, Chapman MJ. Discrete subspecies of human low density lipoproteins are heterogeneous in their interaction with the cellular LDL receptor. J Lipid Res. 1991 Nov;32(11):1741-53.

Dejager S, Bruckert E, Chapman MJ. Dense low density lipoprotein subspecies with diminished oxidative resistance predominate in combined hyperlipidemia. J Lipid Res. 1993 Feb;34(2):295-308.

Anber V, Griffin BA, McConnell M, Packard CJ, Shepherd J. Influence of plasma lipid and LDL-subfraction profile on the interaction between low density lipoprotein with human arterial wall proteoglycans. Atherosclerosis. 1996 Aug 2;124(2):261-71.

Nordestgaard BG, Nielsen LB. Atherosclerosis and arterial influx of lipoproteins. Curr Opin Lipidol. 1994 Aug;5(4):252-7. Review.

Griffin BA, Freeman DJ, Tait GW, Thomson J, Caslake MJ, Packard CJ, Shepherd J. Role of plasma triglyceride in the regulation of plasma low density lipoprotein (LDL) subfractions: relative contribution of small, dense LDL to coronary heart disease risk. Atherosclerosis. 1994 Apr;106(2):241-53.

Gardner CD, Fortmann SP, Krauss RM. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA. 1996 Sep 18;276(11):875-81.

Stampfer MJ, Krauss RM, Ma J, Blanche PJ, Holl LG, Sacks FM, Hennekens CH. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA. 1996 Sep 18;276(11):882-8.

Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Després JP. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Québec Cardiovascular Study. Circulation. 1997 Jan 7;95(1):69-75.

Berneis KK, Krauss RM. Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res. 2002 Sep;43(9):1363-79. Review.

Blake GJ, Otvos JD, Rifai N, Ridker PM. Low-density lipoprotein particle concentration and size as determined by nuclear magnetic resonance spectroscopy as predictors of cardiovascular disease in women. Circulation. 2002 Oct 8;106(15):1930-7.

ALTSCHUL R, HOFFER A, STEPHEN JD. Influence of nicotinic acid on serum cholesterol in man. Arch Biochem Biophys. 1955 Feb;54(2):558-9. No abstract available.

DiPalma JR, Thayer WS. Use of niacin as a drug. Annu Rev Nutr. 1991;11:169-87. Review. No abstract available.

Winkler K, Weltzien P, Friedrich I, Schmitz H, Nickell HH, Hauck P, Hoffmann MM, Baumstark MW, Wieland H, März W. Qualitative effect of fenofibrate and quantitative effect of atorvastatin on LDL profile in combined hyperlipidemia with dense LDL. Exp Clin Endocrinol Diabetes. 2004 May;112(5):241-7.

Winkler K, Konrad T, Füllert S, Friedrich I, Destani R, Baumstark MW, Krebs K, Wieland H, März W. Pioglitazone reduces atherogenic dense LDL particles in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study. Diabetes Care. 2003 Sep;26(9):2588-94.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Winkler K, Jacob S, Müller-Schewe T, Hoffmann MM, Konrad T. Ezetimibe alone and in combination lowers the concentration of small, dense low-density lipoproteins in type 2 diabetes mellitus. Atherosclerosis. 2012 Jan;220(1):189-93. Epub 2011 Nov 9.

Responsible Party:	Karl Winkler, MD, Prof. Dr. med., Kommissarischer Ärztlicher Direktor, University Hospital Freiburg
ClinicalTrials.gov Identifier:	NCT01384058 History of Changes
Other Study ID Numbers:	442006, 2006-005906-30
Study First Received:	June 23, 2011
Last Updated:	June 18, 2012
Health Authority:	Germany: Ethics Commission Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by University Hospital Freiburg:

atherogenic lipoprotein
cardiovascular disease
coronary artery disease
type 2 diabetes
small, dense LDL

Additional relevant MeSH terms:

Diabetes Mellitus
Diabetes Mellitus, Type 2
Hypercholesterolemia
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Simvastatin

Ezetimibe
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Lipid Regulating Agents
Therapeutic Uses
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Enzyme Inhibitors

ClinicalTrials.gov processed this record on June 18, 2013

Effect of Ezetimibe or Simvastatin or Both on Low Densitiy Lipoprotein -Subfractions in Patients With Type 2 Diabetes (EZE)