Effect of diabetes drugs tested on atherosclerosis

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CHICAGO, Nov. 13 — In an 18-month study comparing the effects of two diabetes drugs in patients with type 2 diabetes, one drug appeared to stop progression of artery narrowing, researchers reported today at the American Heart Association’s Scientific Sessions 2006.

Researchers presented results of the Carotid Intima-Media THICkness in Atherosclerosis Using PioGlitazOne (CHICAGO) study in a late-breaking clinical trials session. The study will be simultaneously published in the Journal of the American Medical Association.

Carotid intima-media thickness (CIMT) is the thickness of the inner lining of neck arteries that carry blood to the brain and is a marker of the extent of artery-clogging plaque (atherosclerosis) throughout the body.

CHICAGO is a phase IIIb, multicenter, double-blind, randomized, two-arm study comparing pioglitazone to glimepiride. Pioglitazone, a drug in a class of drugs called thiazolidinediones, makes muscle and fat tissue more sensitive to insulin, the substance that helps break down sugar in the blood. The other drug, glimepiride, is a sulfonylurea drug – a class of drug that stimulates insulin secretion. CHICAGO is the largest and longest CIMT study.

“From baseline to the final visit, there was a significant difference in CIMT in favor of the pioglitazone group,” said Theodore Mazzone, M.D., chair of the trial and chief of Endocrinology, Diabetes and Metabolism in the Department of Medicine at the University of Illinois at Chicago.

“Over the 18-month treatment period, the glimepiride group’s CIMT continued to progress whereas progression was virtually arrested in the pioglitazone group.”

The CHICAGO study included 462 patients with type 2 diabetes (ages 45–85) recruited from the multi-racial/ethnic population of the Chicago area. In type 2 diabetes, the body produces insulin but fails to use it efficiently to metabolize blood sugar. Doctors in this study could add insulin or metformin in addition to the investigational drugs, if necessary, to keep blood sugar in check, Mazzone said.

Researchers randomly assigned patients to receive one of three doses of pioglitazone or one of three doses of glimepiride. After 18 months, the researchers measured the absolute change in CIMT.

“If supported by additional research, these findings would indicate that pioglitazone can delay the progression of atherosclerosis in patients with diabetes,” Mazzone said.

The findings are particularly significant because the benefits were found in patients whose blood sugar, blood pressure and cholesterol levels were at or near American Diabetes Association/American Heart Association targets, he said. This suggests a potentially novel mechanism for managing cardiovascular risk in patients with diabetes.

“Diabetes is a huge public health problem,” Mazzone said. “It is estimated that one out of every three babies born in the United States this year will develop diabetes at some time in his or her life. Diabetes is a major risk factor for heart attack, and diabetic subjects have a poorer prognosis after a heart attack than non-diabetic subjects.”

Pioglitazone is structurally similar to another drug, troglitazone, which was associated with liver toxicity and removed from the market. Although no data indicates the same risk from pioglitazone, patients should have their liver enzymes evaluated before starting this therapy, he said. The thiazolidones also carry a risk of fluid retention that can lead to or worsen heart failure.

In this study, one pioglitazone patient was hospitalized for heart failure, which was reversed when doctors discontinued the drug. While the study was not large enough to measure a significant difference in cardiovascular (CVD) events, researchers reported 10 CVD events in the glimepiride group and four in the pioglitazone group.

The benefits of pioglitazone over glimepiride applied across the board: to the less obese and more obese patients, to those whose blood sugar was in good control and those for whom it was poorly controlled, and to younger and older subjects.

“People with diabetes do much worse after a heart attack or stroke than those without diabetes, and they die more frequently,” Mazzone said. “We have learned a lot about managing cardiovascular risk in people with diabetes using blood pressure and lipid medications but still more needs to be done. So we need to evaluate novel approaches like this one.”

Co-authors are: Peter M. Meyer, Ph.D.; Steven B. Feinstein, M.D.; Michael H. Davidson, M.D.; George T. Kondos, M.D.; Ralph B. D’Agostino Sr., Ph.D.; Alfonso Perez, M.D.; Jean-Claude Provost, M.D.; and Steven M. Haffner, M.D.

Takeda Pharmaceuticals North America, Inc. funded the study.

Disclosures: Dr. Mazzone is a consultant for and has received speaking honoraria from Takeda Pharmaceuticals North America, Inc., Merck & Co., Inc., Amlyn Corp., Novartis Pharmaceuticals and Pfizer, Inc.

Statements and conclusions of abstract authors that are presented at American Heart Association scientific meetings are solely those of the abstract authors and do not necessarily reflect association policy or position. The American Heart Association makes no representation or warranty as to their accuracy or reliability..

NR06-1118 (SS06/Mazzone/CHICAGO)
11/13/2006
2008 American Heart Association, Inc.
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