Cardiovascular disease in diabetes: where does glucose fit in?

Abstract

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.

Figures

Fig. 1.

Pathogenesis of atherosclerosis in the context of diabetes. [Adapted with permission from J. A. Colwell et al.: Am J Med 75:67–80, 1983 (4). © Elsevier.]

Fig. 2.

Observational data from the Swedish National Registry. A significant correlation of glycemic control with cardiovascular events was demonstrated in 18,334 patients (age, 30–79 yr) followed for a mean of 5.6 yr (1997–2003). The endpoints of coronary heart disease (A), stroke (B), CVD (C), and total mortality (D) were assessed by quartile mean hemoglobin A1c (baseline or updated), and all demonstrated a significant correlation with hemoglobin A1c. E–J, A significant increase in events with increasing hemoglobin A1c was observed with or without previous CVD and regardless of duration of diabetes. HbA1c, Hemoglobin A1c. [Reprinted with permission from K. Eeg-Olofsson et al.: J Intern Med 268:471–482, 2010 (47). © Wiley.]