Vasculotoxic effects of insulin and its role in atherosclerosis: what is the evidence?

As a result of ambiguous results from several recent trials in diabetes, scrutiny has focused on the potential effects of insulin and its role in atherosclerosis. This article reviews the premise that anti-diabetes therapy (type 2 diabetes) with insulin causes vascular impairment that leads to atherothrombosis and compromises vascular integrity, which may further potentiates cardiovascular morbidity and mortality. Underlying mechanisms are discussed, including metabolic derangements (blood pressure, lipids, body weight, and glucose) and how these factors trigger insulin-like growth factor (IGF) receptors, leading to cancer. Cellular and molecular mechanisms are discussed, as well as whether the negative results seen in recent glucose trials support this premise. As with most drug therapy, aggressive therapies designed to reach glucose control targets trigger multiple and inter-related mechanisms that, in many cases, go far beyond the pre-determined physiologic targets. From a clinical perspective, physicians should always stress lifestyle modifications, including physical exercise and diet, to their patients who show the first signs of metabolic impairment. Yet even within this context, diet and exercise should be the cornerstone of good therapy when pharmacotherapy is necessary. Given the amount of evidence seen to date with existing agents and the amount of information we do not yet know, patient-centered approaches to modifying behavior before intensive drug therapy are needed should be stressed.

A cardiologist's view of hypoglycemia.

Recent studies have failed to show an improvement in cardiovascular mortality with intensive glycemic control and aggressive glycated hemoglobin (A(1c)) targets less than 7.0%. Excessive hypoglycemic episodes with intensive glucose-lowering therapy are thought to be a major factor in the failure to show cardiovascular benefit in these trials. In this article, we review the physiology of glucose metabolism, the cardiovascular pathophysiology of hypoglycemia, and the trials with an intensive glucose-lowering strategy that have studied microvascular and macrovascular complications. We also review the current non-insulin drugs available for the treatment of diabetes and their potential hypoglycemic and cardiovascular impacts.

Cardiovascular comorbidities of type 2 diabetes mellitus: defining the potential of glucagonlike peptide-1-based therapies.

The global epidemic of diabetes mellitus (~95% type 2 diabetes) has been fueled by a parallel increase in obesity and overweight. Together, these metabolic disease epidemics have contributed to the increasing incidence and prevalence of cardiovascular disease. The accumulation of metabolic and cardiovascular risk factors in patients with type 2 diabetes--risk factors that may exacerbate one another--complicates treatment. Inadequate treatment, treatment that fails to achieve goals, increases the risk for cardiovascular morbidity and mortality. From a clinical perspective, type 2 diabetes is a cardiovascular disease, an observation that is supported by a range of epidemiologic, postmortem, and cardiovascular imaging studies. Vascular wall dysfunction, and particularly endothelial dysfunction, has been posited as a "common soil" linking dysglycemic and cardiovascular diseases. Vascular wall dysfunction promoted by environmental triggers (e.g., sedentary lifestyle) and metabolic triggers (chronic hyperglycemia, obesity) has been associated with the upregulation of reactive oxygen species and chronic inflammatory and hypercoagulable states, and as such with the pathogenesis of type 2 diabetes, atherosclerosis, and cardiovascular disease. Glucagon-like peptide-1 (GLP)-1, an incretin hormone, and synthetic GLP-1 receptor agonists represent promising new areas of research and therapeutics in the struggle not only against type 2 diabetes but also against the cardiovascular morbidity and mortality associated with type 2 diabetes. In a number of small trials in humans, as well as in preclinical and in vitro studies, both native GLP-1 and GLP-1 receptor agonists have demonstrated positive effects on a range of cardiovascular disease pathologies and clinical targets, including such markers of vascular inflammation as high-sensitivity C-reactive protein, plasminogen activator inhibitor-1, and brain natriuretic peptide. Reductions in markers of dyslipidemia such as elevated levels of triglycerides and free fatty acids have also been observed, as have cardioprotective functions. Larger trials of longer duration will be required to confirm preliminary findings. In large human trials, GLP-1 receptor agonists have been associated with significant reductions in both blood pressure and weight.

Implementing cardiovascular risk reduction in patients with cardiovascular disease and diabetes mellitus.

The role of cardiovascular risk reduction in patients with diabetes mellitus is significant as several factors have been found to promote accelerated atherosclerosis in persons with diabetes including hyperglycemia-induced endothelial dysfunction, impaired fibrinolysis, increased platelet aggregation, plaque instability, dysfunctional arterial remodeling, and fibrotic and calcified coronary arteries. Recent attention has focused on identifying a cardiovascular biomarker that would propose a better noninvasive way to detect or visualize subclinical cardiovascular disease and prevent cardiovascular events. This article reviews the use of commonly used cardiovascular risk assessment tools and emerging biomarkers including coronary artery calcium scanning, metabolomics, genomics, and the role of optimal revascularization and risk reduction strategies and their impact on reducing risk in patients with cardiovascular disease and diabetes.

Effect of glitazones on the progression of coronary artery disease in type 2 diabetes patients.

The effect of thiazolidinediones (TZDs) on the progression of atherosclerosis in diabetes patients remains unclear. There has been heightened interest in recent years in this class of diabetes medications due to the non-glycemic lowering effects, such as altering lipids, inflammation and hematologic profiles. There have been several exciting studies over the past few years focused on the mechanism of action of the TZDs with respect to alteration in the cardio-metabolic profile in diabetes patients. New tools such as intravascular ultrasound have been used to follow plaques characteristics over time on a much more sensitive scale than has ever been possible in the past by coronary angiograms. These advances have enabled researchers to follow closely the macrovascular effects of different anti-atherosclerotic medications such as statins and TZDs. This article reviews the pathophysiology of atherosclerosis in diabetes, the role that TZDs play in this process and the imaging trials looking at the progression or regression of atherosclerosis in patients treated with TZDs.