Is There Evidence That Oral Hypoglycemic Agents Reduce Cardiovascular Morbidity or Mortality? No

D iabetes induces a high degree of morbidity and significant reduction of life expectancy in affected subjects. Microvascular complications include retinopathy, nephropathy, and neuropathy, which frequently are underlying factors of major morbidity and disability associated with diabetes. However, macrovascular complications, and mainly cardiovascular disease, are still the leading causes of death in diabetic subjects. Thus, improved cardiovascular outcome will have a clearly favorable effect on mortality in this group of patients. Since the introduction of the U.K. Prospective Diabetes Study (UKPDS) trials in 1998, it has become widely accepted that controlling hyperglycemia improves microvascular outcome in diabetic patients (1,2). However, to date, there is no compelling evidence that improving glycemic control has, in itself, beneficial effects on macrovascular complications and cardiovascular clinical end points. Although hyperglycemia is the hallmark of diabetes, it is still unclear whether there is a causative relationship between increased blood glucose levels and the evolution of arterial atherosclerosis. Moreover, other metabolic disorders that have been clearly linked to plaque formation seem to coexist with, rather than being caused by, hyperglycemia. These metabolic abnormalities include dyslipidemia, abdominal obesity, hypertension, low-grade inflammation, and coagulopathies. This hypothesis is supported by the findings of Haffner et al. (3) from a population-based study of diabetes and cardiovascular disease. In this study, it was demonstrated that normoglycemic subjects who subsequently developed diabetes had an atherogenic pattern of risk factors, including dyslipidemia, overweight, insulin resistance, and hypertension, years before frank diabetes was diagnosed (3). In another study, Haffner et al. (4) clearly demonstrated that diabetic patients without previous myocardial infarction (MI) have as high a risk of MI as nondiabetic patients with previous MI. Overall, these findings support the hypothesis that diabetes and other atherogenic risk factors are manifestations of one entity leading to arterial atherosclerosis. The constellation of insulin resistance and abnormal glucose metabolism with other atherogenic risk factors is commonly referred to as the metabolic syndrome.