Context: Recent prospective clinical trials have failed to confirm a unique benefit from normalization of glycemia on cardiovascular disease outcomes, despite evidence from basic vascular biology, epidemiological, and cohort studies.
Evidence acquisition: The literature was searched using the http://www.ncbi.nlm.nih.gov search engine including over 20 million citations on MEDLINE (1970 to present). Keyword searches included: atherosclerosis, cardiovascular, and glucose. Epidemiological, cohort, and interventional data on cardiovascular disease outcomes and glycemic control were reviewed along with analysis of recent reviews on this topic.
Evidence synthesis: High glucose activates a proatherogenic phenotype in all cell types in the vessel wall including endothelial cells, vascular smooth muscle cells, inflammatory cells, fibroblasts, and platelets, leading to a feedforward atherogenic response. EPIDEMIOLOGICAL AND COHORT STUDIES: Epidemiological and cohort evidence indicates a clear and consistent correlation of glycemia with cardiovascular disease. A recent report of over 25,000 subjects with diabetes in the Swedish National Diabetes Registry verifies this relationship in contemporary practice. Interventional Studies: Prospective randomized interventions targeting a hemoglobin A1c of 6-6.5% for cardiovascular disease prevention failed to consistently decrease cardiovascular events or all-cause mortality.
Conclusions: Basic vascular biology data plus epidemiological and cohort evidence would predict that glucose control should impact cardiovascular events. Prospective clinical trials demonstrate that current strategies that improve blood glucose do not achieve this goal but suggest that a period of optimal control may confer long-term cardiovascular disease benefit. Clinicians should target a hemoglobin A1c of 7% for the prevention of microvascular complications, individualized to avoid hypoglycemia.