Diabetic atherosclerotic disease evolves in stages

Atherosclerosis and its complications develop in stages. Each of each of these stages is affected by different metabolic abnormalities, said Scott Grundy, MD, PhD, during the annual Edwin Bierman lecture.

In 1992, Dr. Bierman proposed the "black box," which is the idea that features unique to diabetes contribute to the excess risk of coronary heart disease (CHD) in patients with diabetes. The black box included features such as a procoagulant state, insulin resistance and hyperinsulinemia, glycation and advanced glycation of proteins in plasma and the arterial wall, abnormalities of apoprotein and lipoprotein particles, and others.

Dr. Grundy labeled the stages of atherosclerosis as initiation, progression, and disruption of atherosclerotic plaque, followed by thrombosis and eventually acute cardiovascular syndromes and cardiovascular death.

Elevation of apo B-containing lipoproteins contributes to the early stages of atherosclerosis (initiation, progression, and disruption). Lowering of low-density lipoprotein (LDL) cholesterol has been proven to prevent acute CHD events, probably by interfering with the disruption of atherosclerotic plaque (plaque stabilization), said Dr. Grundy.

Don't underestimate importance of HTN
"Hypertension cannot be underestimated in its importance," said Dr. Grundy, director of the Center for Human Nutrition, chair of department of clinical nutrition, and professor of internal medicine at the University of Texas Southwestern Medical Center, Dallas. Most of the effect of an elevated blood pressure is on the progression of atherosclerosis.

Inflammatory cytokines (ie, interleukin-6, tumor necrosis factor-alpha, plasminogen activator inhibitor-1, C-reactive protein, matrix metalloproteinase-12, and so on) produced by obesity and smoking work to accelerate the disruption and thrombosis phases.

Diabetes is a prothrombotic condition characterized by increases in clotting factors and clot resistance to fibrinolysis along with alterations in platelet reactivity. Antiplatelet therapy has been shown to reduce cardiovascular risk by about 25%.

The precise role of hyperglycemia in atherosclerosis is unclear. Hyperglycemia is associated with glycation of proteins, glycoxidation (oxidative stress), and activation of protein kinase C, which might argue for a role in early stages. But it's also involved in events leading to cardiovascular mortality, as evidenced by data showing that diabetic patients have worse survival following myocardial infarction compared with nondiabetics and the poor prognosis of men and women with diabetes after the onset of CHD.

Practical implications
This model of diabetes and atherosclerosis has several practical implications. LDL cholesterol-lowering therapy should begin long before the onset of type 2 diabetes, especially in patients with metabolic syndrome. LDL-lowering therapy should then beintensified after the onset of type 2 diabetes.

Blood pressure lowering should also begin long before the onset of type 2 diabetes, and intensified after its onset.

Lifestyle intervention (ie, weight reduction) before the development of type 2 diabetes may prevent progression to diabetes and reduce arterial inflammation. Smoking cessation will prevent arterial inflammation.

Low-dose aspirin should be prescribed when the 10-year risk for CHD reaches 10% or higher using the Framingham risk equation. Aspirin therapy should be continued after the onset of diabetes. Some patients with diabetes may have aspirin resistance, he said. Clinical trials to test the efficacy of aspirin and other antiplatelet drugs are needed.

Clinical trials should no longer be conducted to assess whether glucose lowering will reduce acute cardiovascular events. The focus of clinical trials should be changed to assess the effects of hyperglycemia on cardiovascular complications after the onset of cardiovascular disease, Dr. Grundy said.