Hypoglycemia, diabetes, and cardiovascular disease.

Cardiovascular disease (CVD) remains the leading cause of death in people with diabetes, and the risk of CVD for adults with diabetes is at least two to four times the risk in adults without diabetes. Complications of diabetes, including not only CVD but also microvascular diseases such as retinopathy and nephropathy, are a major health and financial burden. Diabetes is a disease of glucose intolerance, and so much of the research on complications has focused on the role of hyperglycemia. Clinical trials have clearly demonstrated the role of hyperglycemia in microvascular complications of diabetes, but there appears to be less evidence for as strong of a relationship between hyperglycemia and CVD in people with diabetes. Hypoglycemia has become a more pressing health concern as intensive glycemic control has become the standard of care in diabetes. Clinical trials of intensive glucose lowering in both type 1 and type 2 diabetes populations has resulted in significantly increased hypoglycemia, with no decrease in CVD during the trial period, although several studies have shown a reduction in CVD with extended follow-up. There is evidence that hypoglycemia may adversely affect cardiovascular risk in patients with diabetes, and this is one potential explanation for the lack of CVD prevention in trials of intensive glycemic control. Hypoglycemia causes a cascade of physiologic effects and may induce oxidative stress and cardiac arrhythmias, contribute to sudden cardiac death, and cause ischemic cerebral damage, presenting several potential mechanisms through which acute and chronic episodes of hypoglycemia may increase CVD risk. In this review, we examine the risk factors and prevalence of hypoglycemia in diabetes, review the evidence for an association of both acute and chronic hypoglycemia with CVD in adults with diabetes, and discuss potential mechanisms through which hypoglycemia may adversely affect cardiovascular risk.