Does Reduction of Hyperglycemia With Insulin Impact Restenosis and Improve Clinical Outcomes Following PCI?

Studies consistently show that diabetes (DM) is an independent predictor of angiographic restenosis as well as clinical outcomes after PCI. A common criticism of the early PCI trials is that stents were not routinely used. However, even when stents are used, the presence of DM is associated with a higher restenosis rate and lower event rate survival. In a series of 3,554 consecutive patients (715 DM patients) undergoing stenting procedures at a single centre the incidence of restenosis and total vessel occlusion by angiographic assessment was significantly higher in diabetes. Increased restenosis rates were consistently demonstrated across a broad range of lesion types.

The pathophysiology of restenosis is viewed as a complex temporal sequence of interactions involving several cellular and mechanical factors including elastic recoil, thrombosis, intimal hyperplasia, extra cellular matrix elaboration, apoptosis, oxidative stress and unfavorable arterial remodeling ("arterial shrinkage"). The exposure of subendothelial elements initiates platelet adhesion and activation. Activated platelets at the site of injury secrete growth factors that release smooth muscle cells from growth inhibition and induce their proliferation and subsequent migration from the media to the intima. Smooth muscle cell proliferation continues beyond the phase of platelet deposition. Extracellular matrix is produced and secreted by smooth muscle cells that have migrated into the injured intimal zone. This hypocellular matrix material forms the bulk of the intimal tissue. Although mechanical factors such as early vessel elastic recoil may play a major role following balloon angioplasty, this mechanism should not significantly affect the stented segments as the stent provides a rigid endovascular scaffold. Similarly, late arterial remodelling which has been postulated to be a significant factor for the development of restenosis after PCI should not have a major effect in the context of stents. Therefore, the major mechanism contributing to in-stent restenosis is aggressive intimal hyperplasia.

Recent studies demonstrate that DM is characterized by diffuse intimal hyperplasia within the stented segment. DM is an independent predictor of the volume of intimal hyperplasia within the stent. The pattern of stent restenosis in patients with DM tends to be more diffuse and proliferative and therefore more likely to lead to total vessel occlusion. This is significant because diffuse restenosis is difficult to manage with repeat percutaneous procedures.

Hyperglycemia has been postulated to promote the restenotic process in diabetes by the following mechanisms: i. endothelial cell dysfunction; ii. increased platelet aggregation and thrombus formation; iii. dysregulation of growth factor expression; iv. abnormal extracellular matrix deposition; v. advanced isolation and products.

Approaches to preventing stent restenosis have had limited effect. Pharmacologic trials have universally failed to show a reduction in restenosis rates in human subjects. Recent reports suggested radiation therapy (brachytherapy) especially applied locally either via catheters or through radioactive stents has a potential to reduce the proliferative response. Although this approach holds great promise there are unresolved logistic issues, safety issues, and cost issues limiting wide-spread application.