Lovastatin raises serum osteoprotegerin level in people with type 2 diabetic nephropathy
Introduction
Osteoprotegerin (OPG), a glycoprotein, is a member of the tumor necrotizing factor alpha (TNF-α) receptor super-family. This glycoprotein, in association with receptor activator of nuclear factor-κB ligand (RANKL) and its receptor RANK constitute the molecular triad which regulate bone metabolism through controlling osteoclasts [1]. RANKL by binding to its receptor RANK promotes osteoclastogenesis and bone resorption. The OPG binds to the RANKL, neutralizes it, and thereby inhibits the bone resorption [1].
Recently, evidence from in vitro and experimental studies showed that the OPG not only has a critical role in bone turnover, but also acts as an important regulatory molecule in the vasculature [2], [3], [4], [5]. Parallel clinical studies demonstrated that serum OPG levels are associated with cardiovascular events including coronary artery disease (CAD), cardiovascular mortality, and poor prognosis following acute myocardial infarction, vascular calcification, and stroke [6], [7], [8], [9], [10], [11], [12].
In large epidemiological studies, it was shown that people with diabetes have higher levels of OPG. It means that diabetic people are characterized by elevated OPG which is associated with sub-clinical atherosclerosis in both types of diabetes [13], [14], [15]. Also, in more recent studies on diabetic people, a strong association was observed between circulation OPG and microvascular complications [16], urinary albumin excretion [17], neuropathy [18] and carotid intima-media thickness [19]. Serum OPG was also associated with carotid intima-media thickness in women with previous gestational diabetes [20].
3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to lower serum cholesterol levels markedly and reduce cardiovascular morbidity and mortality [21]. Statins have many favorable pleiotropic effects including normalizing atherogenic lipid profile, reduction of inflammation, improvement of endothelial function and decrease of cardiovascular endpoints [22], [23], [24].
Considering the complementary therapy with statins in people with T2DN, anti-atherosclerotic and pleiotropic effects of statins and also recently reported association of OPG with cardiovascular events, no data are available on the effect of statins on the serum OPG in people with T2DN. The present study was designed to investigate the effects of lovastatin therapy and withdrawal on serum levels of OPG and soluble receptor activator of nuclear factor-κB ligand (sRANKL) in people with type 2 diabetic nephropathy (T2DN).
Section snippets
Study population
The present study was conducted in Sheikholraees Sub-Specialized Clinic of Tabriz University of Medical Sciences (Iran) from February 2006 to March 2008. After initial clinical and laboratory evaluations, 38 men with clinically documented T2DN were enrolled. Since female sexual hormones can affect biochemical and acute-phase markers of inflammation, we did not enroll women [25]. To eliminate potential confounding factors, people with type 2 diabetes (T2D) who had proteinuria lower than the
Results
Finally the data of 30 patients who successfully completed the study period was analyzed. The demographic characteristics of the studied people and renal function tests results are shown in Table 1.
Table 2 shows the results for FPG and lipid profile. FPG levels were not significantly changed following the intervention and withdrawal periods (p > 0.05). The Chol and LDL-C levels were significantly reduced following three months of lovastatin therapy. Additionally, lovastatin therapy resulted in
Discussion
The results of the present study showed that lovastatin therapy increased (6.5%) the OPG level and reduced the sRANKL level in people with T2DN, independent of the lipid profile, but dependent to inflammatory status changes. Lovastatin cessation also decreased serum levels of the OPG and increased sRANKL.
The serum OPG levels are elevated in people with diabetes [13], [16], [18], [28], [29], [30]. The origin of the increased serum OPG levels in subjects with diabetes without vascular disease is
Acknowledgments
The authors would like to thank Seth Marra and Professor Jafar Sadegh Tabrizi for his help in editing the paper.
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2020, AtherosclerosisCitation Excerpt :A small intervention study of 18 weeks treatment with low-dose simvastatin reported reduced OPG levels in eighteen T2D patients with microalbuminuria [13]. In contrast, an increase in OPG concentration after 90 days of lovastatin therapy (20 mg/day) has been reported in thirty patients with T2D, and OPG concentration returned to baseline 30 days after lovastatin withdrawal [31]. Additionally, an increase in circulating OPG levels in thirty patients with T2D and hypercholesterolemia was found after both 3 and 6 months of low-dose pravastatin [14].
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