Thiazolidinediones and Risk of Repeat Target Vessel Revascularization Following Percutaneous Coronary Intervention

Abstract

OBJECTIVE -Thiazolidinediones (TZDs) (rosiglitazone and pioglitazone) are a class of antidiabetes agents that have a high affinity for peroxisome proliferator-activated receptor-␥. TZDs initiate a multitude of physiologic processes that may elicit benefits as systemic agents for the prevention of restenosis requiring revascularization following percutaneous coronary intervention (PCI). Numerous trials have evaluated the impact of TZDs on repeat target vessel revascularization (TVR) in patients following PCI; however, several limitations (small sample size, inconclusive results, and risk factor stratification) complicate definitive conclusions. A meta-analysis was performed to evaluate the impact of TZDs on repeat TVR following PCI.RESEARCH DESIGN AND METHODS -Included trials met the following criteria: 1) prospective, randomized controlled trials evaluating available TZDs versus standards of care; 2) well-described protocol; 3) minimum of 6 months of follow-up; and 4) data provided on repeat TVR. Data are presented as relative risks (RRs) with 95% CIs. R estenosis requiring revascularization is a significant limitation of percutaneous coronary intervention (PCI). Despite the advent of improved mechanics and drug-eluting stents, the cumulative restenosis rate remains 20 -30% in the general PCI population and approaches 40% among patients with diabetes (1-5). It is possible that an inhibitory effect on restenosis may result from a synergistic combination of local and systemic strategies aiming at different mechanisms for reducing pathological neointimal formation (6). Several attempts have been made to reduce instent restenosis rates via systemic pharmacological agents, but, to date, these results have been disappointing (7,8). RESULTSPeroxisome proliferator-activated receptors (PPARs) are nuclear receptor isoforms (including PPAR-␣, PPAR-␥, and PPAR-␦) that play a critical role in many physiologic processes (9). Endogenous ligands are hypothesized to affect lipid regulation and metabolism, whereas more potent synthetic PPAR ligands, such as the fibrates and thiazolidinediones (TZDs), are effective in the treatment of dyslipidemia and diabetes (10).TZDs, commonly referred to as glitazones, are a class of antidiabetes agents that represent the first synthetic compounds identified as high-affinity selective PPAR-␥ agonists. Two glitazones, rosiglitazone (Avandia; GlaxoSmithKline) and pioglitazone (Actos; Takeda/ Lilly), are commercially available for the treatment of type 2 diabetes. The first approved TZD, troglitazone (Rezulin; Warner-Lambert), was withdrawn from the market in 2000 due to idiosyncratic hepatitis.TZDs activate PPAR-␥ receptors providing improved insulin sensitivity and glucose control. TZDs also demonstrate favorable effects in artherogenic dyslipidemia without dramatic changes in LDL concentrations (11). In addition to the benefit on glycemia and lipids, TZDs inhibit inflammatory cell responses, as well as inhibit proliferation of vascular smooth muscle cells (VSMCs), development of artherosclerot...

The Avandia Debate

“…TZDs decrease vascular smooth muscle cell and neointimal proliferation. A meta-analysis of seven clinical trials including 608 individuals has shown a reduction in the rate of restenosis with TZD treatment (7). Furthermore, recent evidence suggests reduction in carotid intima-medial thickness (IMT) with TZDs (8 -11).…”

PPAR-γ as a therapeutic target in cardiovascular disease: evidence and uncertainty

“…Several small, randomized trials have been performed in diabetic and nondiabetic patients after bare metal stent implantation, with clinical and angiographic endpoints. Metaanalyses of these trials suggest that TZDs may reduce late lumen loss and need for further target vessel revascularization, with more convincing effects in diabetics and with pioglitazone than in nondiabetics or with rosiglitazone (119)(120)(121). It has also been hypothesized that salutary endothelial effects of PPAR-␥ activation might reduce the risk of stent thrombosis after drugeluting stent implantation ( 122 ), but to date there are no data to either corroborate or refute this.…”

Glycemic control and the heart: it matters how you get there

“…Pioglitazone administration to insulin‐resistant non‐diabetic patients after stroke was just reported to be associated with a reduction in stroke and in myocardial infarction in the Insulin Resistance Intervention after Stroke (IRIS) trial, as further discussed in the accompanying Commentary by Professor Inzucchi, recalling the findings of the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROACTIVE) study among diabetic patients . Looking at another important manifestation of coronary atherosclerosis, a meta‐analysis of seven randomized controlled trials involving 608 people following percutaneous coronary intervention showed that the use of either rosiglitazone or pioglitazone was associated with a more than 50 % reduction in the need for repeat target vessel revascularization; presaging the IRIS findings, this risk was similarly reduced among individuals with and without diabetes . Can it be that the use of treatment strategies associated with improvement in glycemia, but not intrinsically increasing the likelihood of hypoglycemia, are indeed the right approaches?…”