DPP-4 Inhibition and Neuroprotection: Do Mechanisms Matter?

  1. Richard P. Shannon
  1. Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
  1. Corresponding author: Richard P. Shannon, richard.shannon{at}uphs.upenn.edu.

It has long been recognized that type 2 diabetes is a cardiovascular (CV) disease equivalent (1). The recognition has led to the aggressive pursuit of glycemic control as a mechanism to reduced CV mortality. As such, reducing macrovascular complications related to type 2 diabetes has been a major target of antiglycemic therapies. To date, this clinical objective has remained elusive in contrast to the improvements in microvascular complications. Recent insights from large-scale clinical trials (25) have suggested that glucocentric approaches to mitigating CV risk in type 2 diabetes are insufficient and that attention to other CV risk factors such as lipids and blood pressure are equally important in these patients. More recently, investigators have sought strategies that are not merely antiglycemic but also cardioprotective. In this regard, incretin-based therapies have emerged as an exciting approach that seems to address both objectives. Nearly 120,000 type 2 diabetic subjects are currently being studied with respect to whether incretin-based therapies will reduce adverse CV events.

It is also well recognized that type 2 diabetes is a major risk factor for the development of ischemic stroke. Patients with diabetes are 2.9 times more likely to develop ischemic stroke than are age-matched control subjects (6,7). Moreover, the therapeutic options for reducing ischemic brain injury secondary to stroke have lagged behind comparable interventions designed to reduce myocardial infarct size and subsequent mortality, despite the fact that stroke is the third leading cause of death in the U.S. The pathophysiology of stroke involves the loss of striatal and progressively cortical neurons through ischemic injury and apoptosis …

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