Effects of ROSIglitazone on Inflammatory Markers and Adipokines in Diabetic Patients Using an Angiotensin Receptor Blocker (TELmisartan) - The ROSITEL Study

Overview

The purpose of the ROSITEL study is to assess the effects of rosiglitazone, as compared to standard oral therapies for diabetes (metformin/sulfonylurea), on inflammatory markers and adipokine levels in diabetic patients using an angiotensin receptor blocker (ARB). We hypothesize that ARB-treated diabetic patients receiving rosiglitazone will experience greater reductions in vascular inflammation and levels of leptin and resistin, associated with increased adiponectin levels, compared to a metformin/sulfonylurea regimen, and that these benefits will result in part, from greater improvements in insulin sensitivity in the rosiglitazone group.

Type 2 diabetes is a chronic and progressive disease that is strongly associated with all-cause and cardiovascular mortality. The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that glycemic control alone only modestly reduces the risk of macrovascular disease among type 2 diabetic patients . Insulin resistance, which has been identified as an important underlying or associated factor in the pathogenesis of type 2 diabetes, is the main proposed mechanism responsible for the accelerated atherosclerosis noted in this population. Evidence continues to accumulate supporting the role of chronic subclinical vascular inflammation as a central component in the development of atherosclerosis, insulin resistance and type 2 diabetes. Markers of subclinical inflammation, in particular C-reactive protein (CRP) and interleukin-6 (IL-6), have been shown to be independent predictors of both diabetes and cardiovascular risk. More recently, the visceral adipocyte has been recognized to produce a number of metabolically and hormonally active substances, collectively called adipokines. The adipokine adiponectin may have antiatherogenic and anti-inflammatory properties. High levels of adiponectin seem to be associated with protection against type 2 diabetes and atherosclerosis via anti-inflammatory pathways. Unlike adiponectin, leptin and resistin are examples of adipokines that seem to be associated with the development of both atherosclerosis and insulin resistance. Rosiglitazone is a thiazolidinedione drug that is approved for the treatment of type 2 diabetes. As a nuclear peroxisome proliferator-activated receptor-γ agonist, rosiglitazone reduces insulin resistance, thereby sensitizing the liver, muscle, and adipose tissue to the actions of circulating insulin. Treatment with rosiglitazone has been demonstrated to favourably modify levels of inflammatory biomarkers and adipokines, to attenuate endothelial dysfunction, and to reduce coronary events following percutaneous coronary intervention. Diabetes and hypertension co-exist in approximately 75% of patients and this combination synergistically augments cardiovascular risk. In fact, blood pressure control seems to be of greater importance in the prevention of macrovascular disease than is glycemic control. Therefore, in patients with diabetes, dual targeting of insulin resistance and blood pressure is essential to reduce overall atherosclerotic risk. Recent evidence suggests that angiotensin receptor blockers (ARB) in addition to their antihypertensive efficacy may directly improve insulin sensitivity. These unique attributes of ARB's may prove particularly beneficial when combined with an insulin sensitizer, such as rosiglitazone, in the treatment of diabetic patients. The rationale therefore of the ROSITEL study is to compare the effects of rosiglitazone to usual therapy on adipokine levels, inflammatory markers, and insulin sensitivity in ARB-treated diabetic patients with suboptimal glycemic control.