Diabetes Drug May Have Plaque Benefit

According to Nobuhiro Tahara, MD, PhD, of Kurume University in Japan, in patients with impaired glucose tolerance or type 2 diabetes accompanied by carotid atherosclerosis, pioglitazone and glimepiride reduced fasting plasma glucose to a similar extent after four months of treatment but only pioglitazone reduced atherosclerotic plaque inflammation (P<0.01).

The sole independent predictor of a reduction in inflammation was an increase in high-density lipid (HDL) cholesterol level, which occurred with pioglitazone, but not glimepiride.

"These findings suggest that HDL-cholesterol-increasing effects of pioglitazone could mainly be involved in the suppression of atherosclerotic plaque inflammation in our patients," Tahara and colleagues wrote, adding that they could not exclude the possibility of some other mechanism.

They noted that previous studies, including AIM-HIGH, have failed to show any benefit from raising HDL cholesterol levels on hard cardiovascular events.

In an accompanying editorial, Ahmed Tawakol, MD, of Massachusetts General Hospital in Boston, and Aloke Finn, MD, of Emory University in Atlanta, added that, "It is important to note that it remains unclear whether lowering plaque inflammation is the mechanism by which statins and pioglitazone therapy decrease cardiovascular events or even whether, in general, reductions in inflammation would translate into clinical benefit."

Pioglitazone has been shown to be better than glimepiride for preventing the progression of atherosclerosis in patients with diabetes, and the PROactive trial suggested that the drug might have a plaque-stabilizing effect. But there are no data on whether any specific oral hypoglycemic agent is preferred for preventing atherosclerotic plaque inflammation.

To compare pioglitazone and glimepiride (Amaryl), Tahara and colleagues recruited 52 patients with impaired glucose tolerance or type 2 diabetes. All also had evidence of carotid atherosclerosis.

The patients were randomized to 15 mg to 30 mg of pioglitazone or 0.5 mg to 4 mg of glimepiride for four months, with titration of the doses to maintain a fasting plasma glucose of 110 mg/dL or lower.

Plaque inflammation was measured at baseline and at the completion of the study. Scans were done on the carotid arteries and the ascending aorta of the aortic arch because those areas are associated with atherothrombotic stroke, according to the researchers.

At baseline, there was no between-group difference in the target-to-background ratio, which is a measure of plaque inflammation. After four months, both pioglitazone and glimepiride reduced fasting plasma glucose and hemoglobin A1c similarly.

Pioglitazone increased weight and waist circumference and decreased high-sensitivity C-reactive protein (hs-CRP). Glimepiride increased hs-CRP. There were no significant changes in blood pressure, fasting plasma insulin, low-density lipid cholesterol, or triglycerides in either group.

Pioglitazone significantly decreased atherosclerotic plaque inflammation according to FDG-PET, whereas glimepiride treatment resulted in a nonsignificant increase in inflammation.

Thus, the researchers wrote, "Pioglitazone may be a promising strategy for the treatment of atherosclerotic plaque inflammation in impaired glucose tolerant or type 2 diabetic patients."

They acknowledged some limitations of the study, including the small sample size; the possibility of confounding by the use of nonstudy medications; the short duration; and the lack of statistical power to detect differences in cardiovascular endpoints.

Practice Pearls:

• Explain that pioglitazone (Actos) may reduce atherosclerotic plaque inflammation, independent of its glucose-lowering effects.

• Note that the sole independent predictor of a reduction in inflammation was an increase in HDL cholesterol level, which occurred with pioglitazone, but not glimepiride.

Tawakol A, Finn A "Imaging inflammatory changes in atherosclerosis: multimodal imaging hitting stride" JACC Cardiovasc Imaging 2011; 4: 1119-1122.