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Review | Clinician's Corner

Diabetes and Atherosclerosis Epidemiology, Pathophysiology, and Management

Joshua A. Beckman, MD, MS; Mark A. Creager, MD; Peter Libby, MD
JAMA. 2002;287(19):2570-2581. doi:10.1001/jama.287.19.2570.
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Published online

Context Complications of atherosclerosis cause most morbidity and mortality in patients with diabetes mellitus. Despite the frequency and severity of disease, proven medical therapy remains incompletely understood and underused.

Objective To review the epidemiology, pathophysiology, and medical and invasive treatment of atherosclerosis in patients with diabetes mellitus.

Data Sources Using the index terms diabetes mellitus, myocardial infarction, peripheral vascular diseases, cerebrovascular accident, endothelium, vascular smooth muscle, platelets, thrombosis, cholesterol, hypertension, hyperglycemia, insulin, angioplasty, and coronary artery bypass, we searched the MEDLINE and EMBASE databases from 1976 to 2001. Additional data sources included bibliographies of identified articles and preliminary data presented at recent cardiology conferences.

Study Selection We selected original investigations and reviews of the epidemiology, pathophysiology, and therapy of atherosclerosis in diabetes. We selected randomized, double-blind, controlled studies, when available, to support therapeutic recommendations. Criteria for data inclusion (168 of 396) included publication in a peer-reviewed journal or presentation at a national cardiovascular society–sponsored meeting.

Data Extraction Data quality was determined by publication in peer-reviewed literature. Data extraction was performed by one of the authors.

Data Synthesis Diabetes mellitus markedly increases the risk of myocardial infarction, stroke, amputation, and death. The metabolic abnormalities caused by diabetes induce vascular dysfunction that predisposes this patient population to atherosclerosis. Blood pressure control, lipid-lowering therapy, angiotensin-converting enzyme inhibition, and antiplatelet drugs significantly reduce the risk of cardiovascular events. Although diabetic patients undergo revascularization procedures because of acute coronary syndromes or critical limb ischemia, the outcomes are less favorable than in nondiabetic cohorts.

Conclusions Since most patients with diabetes die from complications of atherosclerosis, they should receive intensive preventive interventions proven to reduce their cardiovascular risk.

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Figure 1. Endothelial Dysfunction in Diabetes
Graphic Jump Location
In diabetes, hyperglycemia, excess free fatty acid release, and insulin resistance engender adverse metabolic events within the endothelial cell. Activation of these systems impairs endothelial function, augments vasoconstriction, increases inflammation, and promotes thrombosis. Decreasing nitric oxide and increasing endothelin-1 and angiotensin II concentrations increase vascular tone and vascular smooth muscle cell growth and migration. Activation of the transcription factors nuclear factor κB (NF-κB) and activator protein 1 induces inflammatory gene expression, with liberation of leukocyte-attracting chemokines, increased production of inflammatory cytokines, and augmented expression of cellular adhesion molecules. Increased production of tissue factor and plasmin activator inhibitor 1 creates a prothrombotic milieu, while decreased endothelium-derived nitric oxide and prostacyclin favors platelet activation.
Figure 2. Antiatherosclerosis Therapy in Diabetes
Graphic Jump Location
Diabetic patients require therapy of each metabolic abnormality to attenuate atherogenesis. Excess liberation of free fatty acids results in the typical diabetic dyslipidemic phenotype consisting of increased triglycerides, decreased high-density lipoprotein, and increased oxidized, low-density lipoprotein. Statins and fibric acid derivatives improve the lipid profile and decrease its atherogenic tendency. Treatment of hypertension significantly decreases the rate of myocardial infarction and stroke in diabetes. Initial therapy should include agents that modify the renin-angiotensin system because of their proven additional microvascular and atherosclerosis benefits. β-Blocker therapy in diabetic patients with cardiovascular disease decreases morbidity and mortality. The heightened thrombotic potential of the diabetic state supports consideration of antiplatelet therapy to decrease the incidence of myocardial infarction and death in persons with diabetes. Although strict treatment of hyperglycemia does not significantly reduce the incidence of myocardial infarction or death, the preponderance of epidemiologic and pathophysiologic evidence suggests that hyperglycemia increases cardiovascular event rates and worsens outcome. The improvement in microvascular outcomes itself warrants vigorous pursuit of rigorous glycemic control in diabetes. ACE indicates angiotensin-converting enzyme.



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