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Simvastatin Reduces Circulating Osteoprotegerin Levels in Patients With Type 2 Diabetes

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ClinicalTrials.gov Identifier: NCT00471549
Recruitment Status : Completed
First Posted : May 10, 2007
Last Update Posted : May 10, 2007
Sponsor:
Information provided by:

Study Description
Brief Summary:

Diabetes is associated with dyslipidaemia leading to generalized atherosclerosis, cardiovascular disease (CVD) and nephropathy. Osteoprotegerin (OPG), a glycoprotein involved in bone homeostasis, has been implicated in the pathogenesis leading up vessel calcification. Furthermore, CVD in diabetics is associated with increased levels of OPG.

Aim: To investigate whether low dose simvastatin treatment (10-20 mg/day) reduces circulating levels of OPG as well as adhesion molecules (VCAM-1; vascular cell adhesion molecule-1, ICAM; intercellular cell adhesion molecule).


Condition or disease Intervention/treatment Phase
Type 2 Diabetes Drug: Statin (simvastatin) Phase 4

Detailed Description:

Type 2 diabetes is associated with an increased risk of macro- and microvascular complications, resulting from a generalized injury to the vascular endothelium. The pathophysiological mechanisms leading to cardio vascular disease (CVD) in diabetics are not well defined. However, there is accumulating evidence, that damage to vascular smooth muscle cells and endothelial cells partly occur through vessel shear stress, changes in nitric oxide, and increased cytokine levels (i.e. TNF-α: tumour necrosis factor-α and IL-1: interleukin-1). This ultimately results in sclerosis of the basal membrane caused by endothelial cell proliferation and increased vascular permeability, allowing protein to leak into the extra cellular matrix. Atherosclerotic lesions may also arise as a result of accumulation of monocytes and macrophages containing oxidised LDL (foam cells) in the arterial wall. This process is initiated by the expression of adhesion molecules (e.g. VCAM-1; vascular cell adhesion molecule-1, ICAM; intercellular cell adhesion molecule) on the luminal surface of vascular endothelial cells, allowing cellular attachment and migration into the vascular wall.

Osteoprotegerin (OPG), a secreted basic glycoprotein and member of the TNF receptor superfamily, is a soluble receptor activator of nuclear factor-κB (RANK) ligand (RANKL), and TNF-related apoptosis inducing ligand (TRAIL), though with much lower affinity to TRAIL compared to RANKL. OPG works as a decoy-receptor preventing the RANK-RANKL interaction, thereby reducing the biological effect. The RANK-RANKL system induces osteoclast differentiation and activation whereby bone absorption is promoted. Due to its properties as a decoy receptor, OPG antagonizes this effect and inhibits bone loss. In addition to the effects on osteoclasts, the RANK-RANKL system has been proposed to have cardiovascular effects. Thus, activation of the RANK-RANKL system induces VCAM-1 synthesis, prolongs endothelial cell survival, promotes angiogenesis, and reduces TNF-α levels. In contrast, elevated levels of OPG are associated with the severity of CVD, although it is presently unclear whether this association reflects a cause-effect relationship or is purely coincidental.

Cholesterol-lowering therapy with statins reduces cardiovascular mortality and morbidity risk in diabetics and non-diabetic subjects. According to recent studies, statins may have additional, pleiotropic effects and may in fact stabilize atherosclerotic plaques. Experimental data obtained in animal models indicate dose-dependent angiogenetic effects and promotion of vascular structure formation. It is therefore of interest that recent, in vitro studies by Ben-Tahl et al. and Rasmussen et al. suggest that statins may suppress OPG and adhesion molecule production in humans. Thus, umbilical vein endothelial cells and smooth vascular muscle cells incubated with simvastatin and stimulated with TNF-α and IL-1 secreted less OPG than control cells. Under normal circumstances, exposure to cytokines (TNF-α and IL-1) is a powerful stimulus to OPG production in vascular cells and these results therefore seem to support the concept, that simvastatin may ameliorate some of the deleterious effects of inflammation.

This study was conducted to examine the effect of simvastatin treatment on circulating OPG and adhesion molecule levels in a group of type 2 diabetic patients at increased risk for cardiovascular disease (CVD) due to persistent microalbuminuria. Since both OPG and adhesion molecules are associated with CVD and potentially modifiable by statin treatment this could help improve our understanding of potentially pleiotropic effects of statins in reducing CVD.


Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double
Primary Purpose: Treatment
Official Title: Simvastatin Reduces Plasma Osteoprotegerin in Type 2 Diabetic Patients With Microalbuminuria
Study Start Date : June 1991
Study Completion Date : December 1993

Resource links provided by the National Library of Medicine

Drug Information available for: Simvastatin
U.S. FDA Resources

Arms and Interventions


Outcome Measures

Primary Outcome Measures :
  1. Relative reduction in circulating osteoprotegerin levels [ Time Frame: 18 weeks ]

Secondary Outcome Measures :
  1. Relative reduction in adhesion molecules (ICAM and VCAM) [ Time Frame: 18 weeks ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 2 diabetes
  • Persistent microalbuminuria
  • Fasting plasma cholesterol > 5.5 mmol/liter
  • Fasting plasma triglycerides < 4.5 mmol/liter
  • Fasting HbA1c < 10 %
  • Fasting serum C-peptide > 0.49 nmol/liter
  • Blood pressure < 155/95

Exclusion Criteria:

  • Signs of primary kidney disease
  • Signs of primary hepatic disease
  • Signs of insufficiently treated cardiac disease
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00471549


Sponsors and Collaborators
University of Aarhus
Investigators
Principal Investigator: Carl E Mogensen, MD Aarhus University Hospital, Department M
Principal Investigator: Soren Nielsen, MD, PhD Aarhus University Hospital, Department M
More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
ClinicalTrials.gov Identifier: NCT00471549     History of Changes
Other Study ID Numbers: 1991/2128
First Posted: May 10, 2007    Key Record Dates
Last Update Posted: May 10, 2007
Last Verified: May 2007

Keywords provided by University of Aarhus:
Diabetes
Dyslipidaemia
Atherosclerosis
Osteoprotegerin
Adhesion molecules
Simvastatin

Additional relevant MeSH terms:
Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Simvastatin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors