Simvastatin Reduces Plasma Osteoprotegerin in Type 2 Diabetic Patients With Microalbuminuria
- Birgitte Nellemann, RF1,
- Lars C. Gormsen, MD1,
- Jens Dollerup, MSC2,
- Ole Schmitz, MD3,
- Carl E. Mogensen, MD1,
- Lars M. Rasmussen, MD45 and
- Søren Nielsen, MD1
- 1Medical Department M, Aarhus University Hospital, Aarhus, Denmark
- 2Merck Research Laboratories, Copenhagen, Denmark
- 3Pharmacology, Aarhus University Hospital, Aarhus, Denmark
- 4Laboratory for Biochemical Pathology, Aarhus University Hospital, Aarhus, Denmark
- 5Department of Clinical Biochemistry, Odense University Hospital, Odense, Denmark
- Address correspondence and reprint requests to Søren Nielsen, MD, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Denmark. E-mail: nielsen.soren{at}dadlnet.dk
- CVD, cardiovascular disease
- ICAM, intercellular adhesion molecule
- OPG, osteoprotegerin
- RANK, receptor activator of nuclear factor-κB
- RANKL, RANK ligand
- TNF, tumor necrosis factor
- VCAM, vascular cell adhesion molecule
Osteoprotegerin (OPG), a secreted glycoprotein and member of the tumor necrosis factor (TNF) receptor superfamily, is a soluble receptor activator of nuclear factor-κB (RANK) ligand (RANKL) and TNF-related apoptosis-inducing ligand (1). OPG works as a decoy receptor preventing RANK/RANKL-induced osteoclast differentiation and activation (2). Moreover, the RANK/RANKL system has potential cardiovascular effects; the system induces vascular cell adhesion molecule (VCAM)-1 synthesis, prolongs endothelial cell survival, and promotes angiogenesis (3,4). Furthermore, OPG may be involved in cardiovascular disease (CVD). An epidemiological study identified OPG as an independent risk factor for CVD (5) and OPG is present in high concentrations in the arterial wall (6,7). Of note, diabetic patients are characterized by elevated OPG (3), which is associated with subclinical atherosclerosis in both type 1 (8) and type 2 (9) diabetes. Conversely, OPG may inhibit calcification in mice (10). Hence, it is possible that vascular calcification increases OPG, which then, in turn, is involved in calcification inhibition (4).
Development of atherosclerosis involves expression of adhesion molecules (e.g., VCAM-1 and intercellular adhesion molecule [ICAM]), allowing cellular attachment and migration of monocytes and macrophages into the vascular wall (11). Recent in vitro studies suggest that statins may suppress both OPG (12) and adhesion molecule (13) production.
Statin treatment reduces cardiovascular disease in type 2 diabetes (14). Moreover, additional so-called pleiotropic effects have also been proposed (15). Since both OPG and adhesion molecules are associated with CVD and potentially modifiable by statins, we examined the effect of simvastatin on OPG and adhesion molecules in type 2 diabetic patients at increased risk …
