EDITORIAL (SEE CHOI ET AL, P. 2654)

Decreasing Restenosis Following The potential of peroxisome proliferator–activated receptor ␥ agonists

atients with type 2 diabetes are dis- Thiazolidinediones are a class of perior effects to metformin in protecting proportionately affected by car- drugs that have been developed as insulin the vasculature. Furthermore, markers of P diovascular disease (CVD), and sensitizers and are effective in the treat- inflammation were decreased to a greater cardiovascular events are a major cause ment of hyperglycemia in diabetes. Their extent in the rosiglitazone-treated group, for morbidity and mortality in this popu- mechanism of action is related to their supporting the association between vas- lation. Despite significant improvements activity as agonists to peroxisome prolif- cular events and inflammation. These in the management of CVD, patients with erator–activated receptor ␥ (PPAR-␥), a findings confirm the benefits seen with diabetes continue to be seriously im- receptor that is present in several tissues other thiazolidinediones following angio- pacted by this problem (1). While treat- including the vasculature (14). Troglita- plasty (21), although one small study ments with lipid-lowering therapy and zone, the first drug in this class, was with- demonstrated no effect with rosiglitazone aggressive blood pressure lowering have drawn due to liver toxicity. Rosiglitazone (22). been particularly effective in reducing and pioglitazone are thiazolidinediones There appears to be a strong theoret- cardiovascular events, treatments to re- that are currently available for the treat- ical basis for these findings. Arterial reste- duce blood glucose have had a less im- ment of diabetes, and several agonists to nosis is associated with an intensive ␥ ␣ pressive impact on macrovascular PPAR- , as well as dual agonists to the cell (VSMC) pro- ␥ complications (2). In the UKPDS (U.K. and isoforms, are in development. Soon liferation and migration of the interior of Prospective Diabetes Study), only treat- after their approval for treatment of hy- the wall, ultimately leading ment with metformin led to a significant perglycemia, other effects of this class of to significant vascular occlusion (23). reduction in cardiovascular events in a drugs, which have the potential to allevi- PPAR-␥ agonists are known to inhibit the subgroup of obese subjects (3). Since its ate the problem of CVD in diabetes, were growth of VSMCs in vitro and in animal original description there has been much noted (15). Such effects are also recog- studies (24). Interestingly, in animal stud- experimental, clinical, and epidemiologi- nized, albeit to a lesser extent, with other ies, PPAR-␥ agonists seem to have this ef- cal data to support the association of the insulin-sensitizing agents such as met- fect independent of the presence of insulin resistance syndrome with CVD formin, but not with drugs that stimulate diabetes or insulin resistance. This may be (4). Additionally, other “nontraditional” insulin production and other agents used because vascular cells, including VSMCs cardiovascular risk factors associated with in the treatment of diabetes. The findings and endothelial cells, contain receptors insulin resistance have been frequently have led to much speculation because this ␥ implicated in the causation and progres- class of drugs may have significant poten- for PPAR- (14) and because drugs that sion of vascular disease in diabetes (5). tial in decreasing cardiovascular events bind to this receptor decrease growth and Following cardiovascular interven- associated with diabetes in general and migration of the VSMCs while improving tions such as balloon angioplasty, patients restenosis following angioplasty in partic- endothelial function, including produc- with diabetes appear to have a higher rate ular. Indeed, more recent studies have tion of the key vasodilator, nitric oxide ␥ (5). It is noteworthy that the influence ap- of restenosis (6). Although the develop- shown that PPAR- agonists improve key ␥ ment of has led to an improvement surrogate markers of the atherosclerotic pears to be specific to PPAR- agonists, ␣ in outcomes, people with diabetes con- process, including inflammation, abnor- whereas agonists to the isoform affect tinue to have a worse prognosis than mal fibrinolysis, vascular reactivity, and VSMC growth and intimal hyperplasia to those without this disorder (7–10). Our thickness of the intima of the carotid ar- a much lesser extent (25). The endothe- understanding of the pathophysiology of tery (5,16–19). lium also plays a very important role in restenosis has improved significantly, and In this issue of Diabetes Care, Choi et modulating neointimal formation. Pre- increased attention has been focused on al. (20) have demonstrated that patients vention of restenosis may be achieved by the role of insulin resistance in the devel- having a coronary implant who were improving endothelial function and pro- opment of this complication (11,12), randomized to receive rosiglitazone had a moting endothelial regeneration through leading to the investigation of the impact significant reduction in restenosis, as well the use of various strategies, including in- of insulin sensitizers in alleviating reste- as diameter reduction, compared creasing circulating progenitor endothe- nosis. There are considerable animal data with a control group who received equal lial cells (26). PPAR-␥ agonists improve supporting the hypothesis that the accel- glucose-lowering therapy with other endothelial function in subjects with the erated response to vascular seen in agents. Importantly, several patients in metabolic syndrome (27) and, in an ani- type 2 diabetes may be reduced by agents the control group received metformin, mal model, promote the differentiation of improving insulin sensitivity (13). suggesting that rosiglitazone may have su- angiogenic progenitor cells toward the

2764 DIABETES CARE, VOLUME 27, NUMBER 11, NOVEMBER 2004 Editorial endothelial lineage and attenuate resteno- MD, FRCP, Tulane University Medical Center, Divi- following implantation. sis after angioplasty (28). sion of Endocrinology, Department of Medicine, J Am CollCardiol 32:584–589, 1998 1430 Tulane Ave. (SL 53), New Orleans, LA 70112. 11. Piatti P, Di Mario C, Monti LD, Fragasso While these developments have kin- E-mail: [email protected]. dled much hope for the prevention of re- G, Sgura F, Caumo A, Setola E, Lucotti P, V.A.F. has received honoraria, consulting fees, Galluccio E, Ronchi C, Origgi A, Zavaroni and cardiovascular events, it is and grant/research support from GlaxoSmithKline, I, Margonato A, Colombo A: Association important to recognize some limitations Takeda, Eli Lilly, and Pfizer. © 2004 by the American Diabetes Association. of insulin resistance, hyperleptinemia, of this class of drugs. Although liver tox- and impaired nitric oxide release with in- icity is no longer a major concern, weight stent restenosis in patients undergoing gain and edema are annoying in a popu- ●●●●●●●●●●●●●●●●●●●●●●● coronary stenting. Circulation 108:2074– lation prone to these side effects. The References 2081, 2003 former may be attenuated by lifestyle 1. Gu K, Cowie CC, Harris MI: Diabetes and 12. Kubota T, Kubota N, Moroi M, Terauchi change (29). It is important to recognize decline in heart disease mortality in US Y, Kobayashi T, Kamata K, Suzuki R, Tobe that edema is not necessarily synonymous adults. JAMA 281:1291–1297, 1999 K, Namiki A, Aizawa S, Nagai R, Ka- with congestive heart failure (CHF) and 2. 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