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Diabetes Care 27:2764-2766, 2004
© 2004 by the American Diabetes Association, Inc.

Editorials

Decreasing Restenosis Following Angioplasty

The potential of peroxisome proliferator-activated receptor {gamma} agonists

Vivian A. Fonseca, MD, FRCP, Jose Diez, MD and Dennis B. McNamara, PHD

1 Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana
2 Department of Pharmacology, Tulane University Health Sciences Center, New Orleans, Louisiana

Address correspondence to Vivian A. Fonseca, MD, FRCP, Tulane Unive rsity Medical Center, Division of Endocrinology, Department of Medicine, 1430 Tulane Ave. (SL 53), New Orleans, LA 70112. E-mail: vfonseca{at}tulane.edu

Patients with type 2 diabetes are disproportionately affected by cardiovascular disease (CVD), and cardiovascular events are a major cause for morbidity and mortality in this population. Despite significant improvements in the management of CVD, patients with diabetes continue to be seriously impacted by this problem (1). While treatments with lipid-lowering therapy and aggressive blood pressure lowering have been particularly effective in reducing cardiovascular events, treatments to reduce blood glucose have had a less impressive impact on macrovascular complications (2). In the UKPDS (U.K. Prospective Diabetes Study), only treatment with metformin led to a significant reduction in cardiovascular events in a subgroup of obese subjects (3). Since its original description there has been much experimental, clinical, and epidemiological data to support the association of the insulin resistance syndrome with CVD (4). Additionally, other "nontraditional" cardiovascular risk factors associated with insulin resistance have been frequently implicated in the causation and progression of vascular disease in diabetes (5).

Following cardiovascular interventions such as balloon angioplasty, patients with diabetes appear to have a higher rate of restenosis (6). Although the development of stents has led to an improvement in outcomes, people with diabetes continue to have a worse prognosis than those without this disorder (7–10). Our understanding of the pathophysiology of restenosis has improved significantly, and increased attention has been focused on the role of insulin resistance in the development of this complication (11,12), leading to the investigation of the impact of insulin sensitizers in alleviating restenosis. There are considerable animal data supporting the hypothesis that the accelerated response to vascular injury seen in type 2 diabetes may be reduced by agents improving insulin sensitivity (13).

Thiazolidinediones are a class of drugs that have been developed as insulin sensitizers and are effective in the treatment of hyperglycemia in diabetes. Their mechanism of action is related to their activity as agonists to peroxisome proliferator-activated receptor {gamma} (PPAR-{gamma}), a receptor that is present in several tissues including the vasculature (14). Troglitazone, the first drug in this class, was withdrawn due to liver toxicity. Rosiglitazone and pioglitazone are thiazolidinediones that are currently available for the treatment of diabetes, and several agonists to PPAR-{gamma}, as well as dual agonists to the {alpha} and {gamma} isoforms, are in development. Soon after their approval for treatment of hyperglycemia, other effects of this class of drugs, which have the potential to alleviate the problem of CVD in diabetes, were noted (15). Such effects are also recognized, albeit to a lesser extent, with other insulin-sensitizing agents such as metformin, but not with drugs that stimulate insulin production and other agents used in the treatment of diabetes. The findings have led to much speculation because this class of drugs may have significant potential in decreasing cardiovascular events associated with diabetes in general and restenosis following angioplasty in particular. Indeed, more recent studies have shown that PPAR-{gamma} agonists improve key surrogate markers of the atherosclerotic process, including inflammation, abnormal fibrinolysis, vascular reactivity, and thickness of the intima of the carotid artery (5,16–19).

In this issue of Diabetes Care, Choi et al. (20) have demonstrated that patients having a coronary stent implant who were randomized to receive rosiglitazone had a significant reduction in restenosis, as well as artery diameter reduction, compared with a control group who received equal glucose-lowering therapy with other agents. Importantly, several patients in the control group received metformin, suggesting that rosiglitazone may have superior effects to metformin in protecting the vasculature. Furthermore, markers of inflammation were decreased to a greater extent in the rosiglitazone-treated group, supporting the association between vascular events and inflammation. These findings confirm the benefits seen with other thiazolidinediones following angioplasty (21), although one small study demonstrated no effect with rosiglitazone (22).

There appears to be a strong theoretical basis for these findings. Arterial restenosis is associated with an intensive vascular smooth muscle cell (VSMC) proliferation and migration of the interior of the blood vessel wall, ultimately leading to significant vascular occlusion (23). PPAR-{gamma} agonists are known to inhibit the growth of VSMCs in vitro and in animal studies (24). Interestingly, in animal studies, PPAR-{gamma} agonists seem to have this effect independent of the presence of diabetes or insulin resistance. This may be because vascular cells, including VSMCs and endothelial cells, contain receptors for PPAR-{gamma} (14) and because drugs that bind to this receptor decrease growth and migration of the VSMCs while improving endothelial function, including production of the key vasodilator, nitric oxide (5). It is noteworthy that the influence appears to be specific to PPAR-{gamma} agonists, whereas agonists to the {alpha} isoform affect VSMC growth and intimal hyperplasia to a much lesser extent (25). The endothelium also plays a very important role in modulating neointimal formation. Prevention of restenosis may be achieved by improving endothelial function and promoting endothelial regeneration through the use of various strategies, including increasing circulating progenitor endothelial cells (26). PPAR-{gamma} agonists improve endothelial function in subjects with the metabolic syndrome (27) and, in an animal model, promote the differentiation of angiogenic progenitor cells toward the endothelial lineage and attenuate restenosis after angioplasty (28).

While these developments have kindled much hope for the prevention of restenosis and cardiovascular events, it is important to recognize some limitations of this class of drugs. Although liver toxicity is no longer a major concern, weight gain and edema are annoying in a population prone to these side effects. The former may be attenuated by lifestyle change (29). It is important to recognize that edema is not necessarily synonymous with congestive heart failure (CHF) and that these drugs should not be used in patients with advanced CHF (which is not uncommon in this population), and the joint recommendation of the American Diabetes Association and American Heart Association in this matter are worth considering (30).

Although the in vitro animal studies and small clinical studies discussed above are interesting, large multicenter studies are needed to confirm these findings before they can be translated into clinical practice. The BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) is currently being carried out in patients with type 2 diabetes who have documented coronary disease (www.bari2D.org). The aim of this study is to compare treatment efficacy between initial elective revascularization, either surgical or catheter based, combined with aggressive medical therapy and aggressive medical therapy alone. Also, this trial compares 5-year mortality in a strategy of hyperglycemia management with insulin sensitizers versus insulin secretagogues. The effects of the insulin-sensitizing strategy on the revascularized group may shed some light on the clinical benefits of thiazolidinediones on repeat revascularization and, in the whole cohort, on overall cardiovascular risk reduction. The study by Choi et al. supports this study design and is a significant step forward in realizing the potential of PPAR-{gamma} agonists as cardiovascular drugs.

Footnotes

V.A.F. has received honoraria, consulting fees, and grant/research support from GlaxoSmithKline, Takeda, Eli Lilly, and Pfizer.

References

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