Vasoreactivity, Inflammation and vascular effects of Thiazolidinediones in Insulin resistance

Abstract

In the pathophysiology of atherosclerosis, based on the respons to injury mechanism, the pathophysiological phenomenons endothelial dysfunction and inflammation are playing a pivitol role.

Endothelial dysfunction is characterized by a shift towards reduced vasodilation, a pro-inflammatory state, and pro-thrombic properties. Endothelial dysfunction is associated with most forms of cardiovascular disease such as hypertension, coronary artery disease, chronic heart failure, peripheral artery disease, diabetes, and chronic renal failure. Furthermore the severity of endothelial dysfunction has been shown to have prognostic value for cardiovascular events.

Evidence that atherosclerosis is a chronic inflammatory disease emerged when pathologic studies showed that T-lymphocytes and macrophages are present in the shoulder regions of atherosclerotic plaques in individuals who died from acute myocardial events. Subsequent studies implicated a multitude of pro-inflammatory targets that appear to be involved in atherogenesis, atherosclerosis and plaque rupture.

In the current thesis we explored several aspects of the described model of vascular injury in the setting of type 2 diabetes. Type 2 diabetes is emerging as a worldwide epidemic and currently about 200 million people are affected worldwide. An important cause for this increased incidence is the associated increase in patients with insulin resistance (approximately 400 million worldwide right now). Insulin resistance is driven by central obesity and is secondary to free fatty acid fluxes towards muscle and liver. Several risk factors such as glucose intolerance, hyperinsulinemia, obesity, dyslipidemia, hypertension, but also endothelial dysfunction and inflammation, have been found to cluster and often precede type 2 diabetes mellitus. Seeing the importance for primary prevention of early identification, the National Cholesterol Education Program (NCEP) of the US created in 2001 a readily applicable definition for daily clinical practice for this cluster of metabolic abnormalities, often referred to as the metabolic syndrome. Although a pathophysiological construct seems plausible, future research must unrevel pathophysiology and clinical use before the metabolic syndrome can be designated as a ‘syndrome’. The individual components that make up the syndrome should be treated coherently. These are the end-sites of the vascular tree. However other risk factors act like trunk of this vascular tree. Awareness of the underlying disorders is important for understanding the pathophyiology and thus coherent treatment: be aware for insulin resistance and its associated (non-) traditional risk factors like endothelial dysfunction and inflammation.

The discovery of nuclear peroxisome proliferator-activated receptors (PPARs) and subsequent insight into their role in several metabolic pathways was a major breakthrough in the understanding of pathophysiological mechanisms underlying the insulin resistance syndrome. The Thiazolidinediones (TZDs) as a drug subclass are PPAR-γ agonists that have been exhaustively shown to improve peripheral (predominantly skeletal muscle) insulin sensitivity in both animals and humans. In addition to their effects on insulin sensitivity, TZDs have demonstrated both direct and indirect vascular effects, including improved endothelial function, decreased vascular inflammation, lowered plasma FFA levels, improved LDL phenotype, and inhibition of VSMC proliferation. The TZDs have been demonstrated to reduce elevations in blood pressure and microalbuminuria and to improve fibrinolysis with consequent reversal of the procoagulant state.

Recently in the first Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROACTIVE) pioglitazone treatment reduced the relative risk for the combined endpoint death, myocardial infarction, and stroke with 16%. Other trials, like RECORD, CHICAGO, and PERISCOPE, are planned to report in 2007.

Several issues concerning TZD treatment are yet to be resolved. The apparent paradox of adipocyte differentiation with weight gain concurring with the insulin-sensitising effects of TZDs is not completely understood. The TZD-induced decrease in blood pressure accompanied by an increase in the plasma volume has not been fully explained but make the TZDs contra-indicated for patients with heart failure. An important issue that needs to be resolved is the importance of raised cholesterol levels, in particular raised LDL levels, caused by rosiglitazone. Future research may provide answers to these questions, particularly with respect to the role of PPAR-γ, but also PPAR-α, in vascular pathophysiology. Although the concept of TZDs is promising, further research and additional long-term clinical trials concerning cardiovascular endpoints, are needed.