ADA 2010: Cardiac disease in diabetes still a black box

In 1992, researcher Edwin Bierman, MD, described the development of cardiovascular disease in diabetes as a black box. Nearly 20 years later, it is still a black box.

"Atherosclerosis is the major cause of morbidity and mortality in all of our patients with diabetes, whether it is type 1 or type 2,” said Ira Goldberg, MD, professor of medicine, Columbia University Medical Center, speaking to a group at the 70th Scientific Sessions of the American Diabetes Association in Orlando, Fla. "Why does diabetes cause atherosclerosis? I don’t know."

Goldberg examined the state of diabetic cardiovascular disease research during the annual Edwin Bierman Lecture. There is growing evidence that hyperglycemia and hyperlipidemia play key roles in the development of coronary artery disease. There is just as much evidence supporting key roles for hypertension and lipid abnormalities.

One of the basic conundrums is the effect of lowering hemoglobin (Hb) A_1c. Reducing HbA_1c. has a dramatic and linear effect on microvascular disease, but reduction in macrovascular disease is far less dramatic.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial raised more questions. Intensive treatment to lower glucose produced an increase in fatal cardiac events but an ever-larger decline in nonfatal events.

At the same time, altering risk factors by lowering blood pressure and low-density lipoproteins has protective effects on both coronary artery disease and glucose control.

Plaque stability and regression are open questions. In the presence of diabetes, arterial plaque becomes less stable. Diabetes also inhibits the regression of plaque that normally occurs when cholesterol levels fall.

Glucose and insulin play roles in atherosclerosis. Insulin alters lipoproteins, mediates inflammation, decreases the size of necrotic cores, and more. Glucose encourages inflammation, among other effects, possibly by altering the balance between Ly-6C hi monocytes, which are proinflammatory, and Ly-6C lo monocytes, which are less inflammatory. Injecting hyperglycemic mice with phlorizin, an antiglucose agent, normalizes glucose levels and restores the normal monocyte balance.

"Glucose itself is toxic," Goldberg said. “We are still sorting out the role of diabetes versus risk factors and still studying alterations in plaque. But atherosclerosis is still a black box. I don’t know why diabetes increases atherosclerosis."