Data from the Centers for Disease Control and Prevention indicate that the prevalence of diabetes is increasing steadily and is coupled with a rise in obesity. Studies such as the Nurses' Health Study show that even slight glucose abnormalities, namely insulin resistance, increase the risk of myocardial infarctions, strokes, other cardiovascular disease, and mortality. Insulin resistance was found to accelerate atherosclerosis, inflammation, the onset of diabetes, cardiovascular disease, obesity, hypertension, chronic kidney disease, and dyslipidemia. Adiponectin was found to have potent antiinflammatory and antiatherosclerotic effects. Similarly, studies indicate that peroxisome proliferators-activated receptor agonists have the potential to treat obesity, diabetes, and atherosclerosis. From a preventive standpoint, it was shown that intensive glucose control reduces long-term cardiovascular risk. This intensive control approach included the use of thiazolidinediones (TZDs; troglitazone, pioglitazone, and rosiglitazone), which were demonstrated to have vascular and nonglycemic effects beyond glucose-lowering. A drawback of using TZDs is peripheral fluid retention. The DREAM study showed that participants with impaired fasting glucose or impaired glucose tolerance who are free from cardiovascular disease benefited significantly from taking 8 mg rosiglitazone per day. The ADOPT study provided evidence that rosiglitazone is more efficient at controlling glycemic loss and maintaining low glycosylated hemoglobin levels than metformin and glyburide. Data from the CHICAGO study indicate that the progression of carotid artery intima-media thickness, a marker of atherosclerosis and a surrogate end point for cardiovascular disease, was slowed more with pioglitazone than glimepiride in a racially diverse population of men and women with diabetes mellitus type 2. Overall, investigators have shifted from a focus on hyperglycemia to a multifactorial approach to risk management in diabetes. This multifactorial approach includes intensive glycemic control, lifestyle intervention, and intensive management of comorbid (dyslipidemia, hypertension, early renal disease) conditions. The implementation of a regular, rigorous exercise and diet program greatly decreased insulin resistance and allowed far more patients to reach their glycosylated hemoglobin goals. Studies with atrovastatin show significant improvement in cardiovascular risk factors in patients with diabetes and hypertension. Short-term studies provide support for the administration of a combination of TZD + sulfonylureas in patients with diabetes mellitus type 2. Likewise, studies have shown that a combination of TZDs + metformin reduced the risk of myocardial infarction. Finally, dipeptidyl peptidase-IV inhibitors and glycolipoprotein-1 analogs show potential for helping prevent the deterioration of glucose metabolism in early diabetes mellitus type 2.