Effects of Thiazolidinediones Beyond Glycaemic Control

Abstract

The incidence of type 2 diabetes continues to increase in the western world over the past decade. Consequently, complications of this disease have reached crisis proportions. In addition to the classical oral hypoglycaemic agents, i.e. sulfonylureas, newer classes have emerged that work by different mechanisms such as insulin sensitizers. One such class are the thiazolidinediones (rosiglitazone and pioglitazone). These agents act as ligands for the gamma peroxisome proliferator-activated receptors (PPARs) and result in a lower glucose. Data from animal and human studies supports the concept that thiazolidinediones exert several other beneficial metabolic and vascular effects, in addition to glycaemic control, including improvement in lipid profile, blood pressure lowering, redistribution of body fat away from the central compartment, anti-inflammatory effects such as reduction in hs-CRP and microalbuminuria as well as subclinical vascular inflammation, improvement in endothelial function. Conversely, thiazolidinediones have well-established side effects, most important of which are fluid retention leading to weight gain and development of heart failure as well as an increased incidence of bone fractures. Moreover, evidence from clinical trials suggests that these agents do not reduce cardiovascular risk. This article discusses the pleiotropic effects of thiazolidinediones focusing on clinical cardiovascular outcomes as well as other potential therapeutic uses in the context of their side-effect profile.

Twelve Weeks of Pioglitazone Therapy Significantly Attenuates Dysmetabolism and Reduces Inflammation in Continuous Ambulatory Peritoneal Dialysis Patients—A Randomized Crossover Trial

“…The main concern with the use of PPARγ agonists, especially rosiglitazone, in the treatment of T2DM patients is the risk for adverse effects on cardiovascular safety, including the risks of heart failure, myocardial infarction, and stroke (24). Fluid retention may play an important role in the side effects of TZDs on cardiovascular events.…”

Treatment with the PPARγ agonist rosiglitazone downregulates interleukin-1 receptor antagonist in individuals with metabolic syndrome

“…Also, there is evidence that TZDs exert a number of pleiotropic effects that may play an important role in the treatment of type 2 diabetes and potentially also in other cardiovascular disorders (12,21). These effects include favorable outcome on blood pressure and potentially anti-inflammatory net effects.…”

“…However, the effect of PPARg agonists on inflammation is still unclear, and few studies are available regarding the potential anti-inflammatory effects of PPARg agonists in MetSyn prior to the development of diabetes. On the other hand, recent studies have suggested that PPARg agonists have other effects that may exacerbate CAD (12).…”

Prevention and current onset delay approaches of type 2 diabetes mellitus (T2DM)

“…These drugs act by stimulation of peroxisome proliferator-activated receptor-γ (PPAR-γ), which increases hepatic and peripheral insulin sensitivity by stimulating conversion of pre-adipocytes to adipocytes [24]. Adipocytes increase adiponectin, increasing insulin sensitivity.…”

“…Accumulating evidence also indicates that TZDs are associated with β-cell preservation [25], and some studies supports that they provide several other beneficial metabolic and vascular effects, e.g. improvement in lipid profile and blood pressure, peripheral redistribution of body fat and anti-inflammatory [24]. Their side effects, such as fluid retention and increased incidence of bone fractures, might indicate an unacceptable risk-to-benefit ratio in T2DM prevention.…”