Rosiglitazone Decreases Plasma Levels of Osteoprotegerin in a Randomized Clinical Trial with Type 2 Diabetes Patients

Abstract

Cardiovascular disease is the leading cause of death in patients with type 2 diabetes mellitus (T2DM). We suggested that plasma osteoprotegerin (OPG), a strong, independent predictor of cardiovascular disease, could discriminate between anti-diabetic treatments depending on their benefits regarding cardiovascular disease. The South Danish Diabetes Study, an investigator-driven, randomized, controlled clinical trial lasting 2 years, was used to test this hypothesis in patient groups with different medication strategies (insulin aspart or NPH insulin, added either metformin ⁄ placebo or rosiglitazone ⁄ placebo). A total of 371 individuals were eligible for the study. Basic variables were analysed along with measurement of plasma OPG and HbA 1c at the beginning and end of the study. Only rosiglitazone treatment caused a significant decrease in plasma OPG concentrations (p = 0.003), while no significant change was seen in the other treatment groups. The effect of rosiglitazone on plasma OPG remained significant in a univariate analysis adjusted for change in HbA 1c (p = 0.013). Of note, the change in plasma OPG significantly correlated with HbA 1c improvement in rosiglitazone-treated patients (R = 0.29, p = 0.0002), while this correlation was poor in those not receiving rosiglitazone (R = 0.06, p = 0.48). Treatment with rosiglitazone among patients with T2DM reduces the concentration of plasma OPG. This is not seen with metformin despite similar reductions in HbA 1c . Alteration in the OPG ⁄ RANKL pathway by glitazones may have implications for the understanding of both cardiovascular effects and bone side effects of the drug.Cardiovascular disease (CVD) is the leading cause of death in patients with type 2 diabetes mellitus (T2DM) [1,2]. Thus, a high number of diabetic patients suffer from heart disease, cerebrovascular disease or peripheral arterial disease [3][4][5]. Measures of glycaemic status correlate with and predict large vessel disease, and a meta-analysis has indicated that there may be beneficial effects of intensive glucose-lowering treatment on CVD events in diabetes, although this is debated [4,[6][7][8]. Reports have shown that peroxisome proliferatoractivated receptor (PPAR) c agonists (e.g. glitazones) in addition to their effects on insulin sensitivity improve some cardiovascular risk factors, e.g. blood pressure, coagulation factors and inflammation [9][10][11]. Moreover, experimental studies seem to indicate that activity of PPAR-c agonists is beneficial in relation to the atherogenic process. However, a recent meta-analysis has indicated that glitazones might be associated with an increased risk of myocardial infarction [12]. Recently, the final evaluation of the RECORD study revealed an increased risk of heart failure with the drug, but no increase in death from cardiac causes or all-cause mortality. Moreover, an increased risk of some fractures, mainly in women, was found when rosiglitazone was added to other glucose-lowering therapy in patients with T2DM compatible with other studi...

Comparative effects of metformin and pioglitazone on fetuin-A and osteoprotegerin concentrations in patients with newly diagnosed diabetes: A randomized clinical trial

“…In line with our findings, recently a pilot study in PCOS found comparable levels of OPG in PCOS women and their age-and BMI-matched controls to remain unaffected during insulin sensitizing treatment with pioglitazone [39]. To the best of our knowledge, only two studies have assessed the efficacy of metformin and pioglitazone/rosiglitazone treatment on the levels of OPG in T2DM subject, with both of these reports demonstrating a significant reduction in OPG only with pioglitazone/rosiglitazone treatment [40,41]. In this regard, more studies on the comparative effect of pioglitazone and metformin with lengthier follow-ups are needed.…”

“…Previous reports in T2DM-induced atherosclerosis demonstrated plasma OPG levels are positively correlated with FPG and HbA1c [41,46], however, in our series of newly diagnosed T2DM subjects; we found no significant relationship between theses indices and OPG serum levels. Similarly, Nybo et al found that the OPG reducing effect of rosiglitazone in T2DM subjects is not seen with metformin despite similar reductions in HbA1c [40]. In line with our findings, Secchiero et al suggested that the inflammation-driven hyperglycemia, rather than the high glucose levels per se, is involved in the increase of OPG observed in both diabetic patients and diabetic mice [10].…”

Metformin, but Not Rosiglitazone, Attenuates the Increasing Plasma Levels of a New Cardiovascular Marker, Fibulin-1, in Patients With Type 2 Diabetes

“…Our findings fit well with the notion that metformin may exert direct beneficial effects in the arterial wall and expand this idea by pointing toward metformininduced alterations in the metabolism of the ECM molecule fibulin-1. Somewhat surprising, we did not find that rosiglitazone changed plasma fibulin-1, despite the fact that previous publications have shown that glitazones may influence arterial functions and change vascular biomarkers (41,42). Nevertheless, it seems that even though rosiglitazone may reverse endothelial dysfunction, it did not change arterial remodeling in a study of Zucker diabetic fatty rats (43).…”

Protective Effect of Metformin on Periapical Lesions in Rats by Decreasing the Ratio of Receptor Activator of Nuclear Factor Kappa B Ligand/Osteoprotegerin

“…Furthermore, Lrp5 can regulate the osteoblast-osteoclast coupling by affecting the RANK-RANKL and OPG pathways (30). Compared with rosiglitazone, which is also a diabetes drug, metformin maintains the plasma levels of OPG and rosiglitazone decreases the plasma levels of OPG in patients with type 2 diabetes (31). Metformin was recently shown to reduce osteoclast differentiation and activity by stimulating OPG and inhibiting RANKL mRNA and protein expression in osteoblasts (11).…”