Insulin resistance drug with anti-inflammatory effects reduces risk factors

A drug, which reduces insulin resistance and also may have anti-inflammatory and other effects on blood vessels, lowered cardiovascular risk factors in patients with diabetes more than another diabetes medicine, even though both drugs improved blood sugar control equally, according to a new study (PDF) in the June 21, 2005, issue of the Journal of the American College of Cardiology.

“Improvement of glucose control alone is not enough to reduce the cardiovascular risk of type 2 diabetic patients. Insulin resistance is a major contributor to increased cardiovascular risk and effective treatment of insulin resistance reduces all cardiovascular risk indicators,” said Andreas Pfützner, M.D., Ph.D. at the IKFE - Institute for Clinical Research and Development in Mainz, Germany, and the University of Applied Sciences in Rheinbach, Germany.

A total of 192 patients were enrolled in a six-month, prospective, open-label, controlled clinical study. They were randomized to receive either pioglitazone (45 mg) or glimepiride (1 to 6 mg, with the intent to optimize therapy). Both drugs improve blood sugar control, but there are indications that pioglitazone and other drugs known as thiazolidinediones also have anti-inflammatory effects on the walls of blood vessels.

The researchers tracked HbA1c, which indicates how well blood sugar is being controlled, as well as several cardiovascular risk factors. While blood sugar control was comparable in both groups; the patients taking pioglitazone had improved scores on measures of cholesterol, carotid artery wall thickness and other cardiovascular risk factors.

“In this study, we achieved, for the first time, a comparable decrease in HbA1c in both treatment groups. The differences between the groups can not thus be attributed to differences in glycemic control, as has been done in previous studies,” Dr. Pfützner said.

Takeda Pharma, the maker of pioglitazone (brand name Actos), supported this study. Glimepiride (brand name Amaryl) is made by Aventis Pharmaceuticals.

People with diabetes have a much higher than normal risk of cardiovascular disease. Dr. Pfützner said these results shed light on how the diseases are linked.

“Yes, insulin resistance on the vascular cells is a major driver of increased cardiovascular risk but can be treated effectively,” he said.

Dr. Pfützner explained that insulin is active in the linings of blood vessels. He said it is related to the production of nitric oxide, which, in turn, plays a role in anti-inflammatory responses. While both pioglitazone and glimepiride improve blood glucose control, pioglitazone also reduces insulin resistance within blood vessels, while glimepiride does not.

Dr. Pfützner said researchers are awaiting the results of clinical trials that will measure actual health outcomes of people with diabetes taking pioglitazone, but he noted that the variables tracked in this study are strong indicators of cardiovascular risk.

Kenneth R. Feingold, M.D., at the University of California – San Francisco and the VA Medical Center in San Francisco, Calif., who was not connected with this study, said the results showing greater benefits from pioglitazone - even though blood sugar control was equivalent in both groups - have many implications for clinicians and researchers in the field.

“It’s a very interesting paper in that you lower the glucose by two different means and you get different effects on these intermediate markers of atherosclerosis risk,” Dr. Feingold said.

Although this study was not designed to measure actual health outcomes, Dr. Feingold said the results are suggestive of long term health benefits because the markers used are closely linked to heart disease risk, including a measure of blood vessel wall thickness and inflammation.

“The intima-media thickness is a pretty good marker of atherosclerosis, and the reduction with pioglitazone treatment was impressive,” he said.

The American College of Cardiology, a 31,000-member nonprofit professional medical society and teaching institution, is dedicated to fostering optimal cardiovascular care and disease prevention through professional education, promotion of research, leadership in the development of standards and guidelines, and the formulation of health care policy.