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New Data Show ACTOS® (pioglitazone HCl) Halted Progression of Atherosclerosis as Indicated by CIMT in Patients With Type 2 Diabetes

November 13, 2006

Results demonstrated significant improvements on cardiovascular markers beyond glycemic control

Chicago, IL, November 13, 2006 – Researchers today presented data showing that ACTOS® (pioglitazone HCl) halted the progression of atherosclerosis as measured by carotid intima-media thickness (CIMT) in patients with type 2 diabetes. Results from the clinical trial, CHICAGO (Carotid intima-media tHICkness in Atherosclerosis using pioGlitazOne), are part of a late-breaker presentation at the American Heart Association’s Scientific Sessions 2006, coincidentally being held in Chicago, and coincide with an early online issue of the Journal of the American Medical Association. Trial results will also be published in the December 6 print issue of JAMA.

“The CHICAGO study is another interesting piece of the puzzle, adding to the understanding of how pioglitazone may confer benefits beyond glycemic control,” said Theodore Mazzone, M.D., F.A.C.P., professor of medicine and director of the Section of Endocrinology, Diabetes and Metabolism at the University of Illinois at Chicago. “Although physicians have aggressively treated cardiovascular risk, people living with diabetes are still at a higher risk for heart disease. And while additional studies are needed to determine how reductions in CIMT with pioglitazone might prevent cardiovascular events, we do know that new approaches to addressing CV risk factors in diabetes are critical.”

CHICAGO is the largest and longest study to examine the effects of ACTOS on measures of the atherosclerotic disease process in patients with type 2 diabetes, most of whom had no clinical evidence of heart disease. Atherosclerosis, a condition that leads to reduced or blocked blood flow, is accelerated in patients with type 2 diabetes. Carotid intima-media thickness, or CIMT, is defined as the thickness of the inner lining of a patient’s carotid, or neck artery. A thickened carotid intima-media layer is a surrogate marker for heart attack and stroke. Measuring CIMT using ultrasonography is a well-accepted, noninvasive way to assess atherosclerosis. The study also looked at cardiovascular endpoints, glycemic control, lipid profiles, blood pressure and other atherosclerotic markers.

“Our focus has been on helping patients to effectively manage their diabetes and to reduce their risk of complications. CHICAGO is a unique study showing that the improved cardiovascular outcomes, exhibited by patients at highest risk for CVD on ACTOS in the PROactive Trial, may extend to patients earlier in the disease progression,” said John Yates, M.D., president, Takeda Pharmaceuticals Global Research & Development. “Heart disease is the leading cause of death for people living with diabetes and, while significant progress has been made in understanding the link between diabetes and heart disease, we still have a long way to go.”

CHICAGO Trial Design & Results
The CHICAGO trial was an 18-month, multicenter, randomized study that enrolled 462 patients with type 2 diabetes, all from the Chicago area. The primary goal was to compare the effects of ACTOS versus glimepiride, a sulfonylurea (SU), on carotid intima-media thickness (CIMT), defined as the thickness of the inner lining of a patient’s neck arteries. The trial also assessed the occurrence of cardiovascular events (i.e., death, heart attack and stroke) and cardiovascular disease risk factors in patients with type 2 diabetes.

The analysis demonstrated a statistically significant relative reduction in the progression of CIMT with ACTOS. According to the results, patients in the ACTOS arm showed a -0.001 mm change in arterial thickness from baseline versus an increase of 0.012 mm in the glimepiride arm, a total difference of 0.013 mm between the two arms (P=0.017). The results also showed a highly significant relative change in the maximum CIMT values, commonly considered a more indicative measure of overall treatment impact. The glimepiride-treated group showed a 0.026 increase, compared to a 0.002 increase in the ACTOS-treated group, resulting in a treatment difference of 0.024 (P=0.008). Studies show that, for people living with diabetes, CIMT progresses at an increased rate.

Typical of SUs, initial glycemic control was better with glimepiride compared to ACTOS. However, by study end, ACTOS provided significantly better glycemic control based on reductions in A1C levels, which in the ACTOS-treated group decreased by 0.33 percent versus the glimepiride group that saw a decrease of 0.01 percent, resulting in a -0.32 percent (P=0.002) difference between the two arms.

Adjudicated cardiac events, composite endpoints of non-fatal myocardial infarction (MI), non-fatal stroke and death, showed no events in the ACTOS arm (n=230) and 2 events in the glimepiride arm (n=228).

ACTOS decreased triglyceride levels by 13.5 percent versus an increase of 2.1 percent with glimepiride (P=0.001), and increased HDL-C levels by 12.8 percent versus a decrease of 1.1 percent with glimepiride (P=0.001). Both treatment arms had increases in LDL-C levels: 5.8 percent with ACTOS compared to 1 percent with glimepiride (P=0.12).

“I believe that CHICAGO will be viewed in the context of other large cardiovascular studies with ACTOS: the PROactive study, which found that ACTOS may reduce the combined risk of heart attack, stroke and death in high-risk patients with type 2 diabetes; and the PERISCOPE trial, which is studying the effects of ACTOS on progression or regression of atherosclerosis in the coronary arteries using intravascular ultrasound,” said Dr. Yates.

ACTOS works by directly targeting insulin resistance, a condition in which the body does not efficiently use the insulin it produces to control blood glucose levels. ACTOS is taken once daily as an adjunct to diet and exercise, and is approved for use for type 2 diabetes as monotherapy to lower blood glucose and in combination therapy with insulin, sulfonylureas or metformin.

Additional Information
ACTOS is not for everyone. ACTOS can cause fluid retention that may lead to or worsen heart failure, so tell your doctor if you have a history of these conditions. Talk to your doctor immediately if you experience rapid weight gain, fluid retention, or shortness of breath while taking ACTOS. If you have moderate to severe heart failure, ACTOS is not recommended. Your doctor should perform a blood test to check for liver problems before you start ACTOS and periodically thereafter.

Do not take ACTOS if you have active liver disease. Talk to your doctor immediately if you experience nausea, vomiting, stomach pain, tiredness, loss of appetite, dark urine, or yellowing of the skin. If you are of childbearing age, talk to your doctor before taking ACTOS as it could increase your chance of becoming pregnant. Some people taking ACTOS may experience flu-like symptoms, mild to moderate swelling of legs and ankles, and anemia. When taking ACTOS with insulin or sulfonylureas, you may be at risk for low blood glucose.

Please visit the ACTOS website at www.actos.com for complete Prescribing Information.

Takeda Pharmaceuticals North America, Inc.
Based in Deerfield, Ill., Takeda Pharmaceuticals North America, Inc. is a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, the largest pharmaceutical company in Japan. In the United States, Takeda currently markets oral diabetes, insomnia, cholesterol-lowering and gastroenterology treatments, and through Takeda Global Research & Development, Takeda has a robust pipeline with compounds in development for diabetes, cardiovascular disease and other conditions. Takeda is committed to striving toward better health for individuals and progress in medicine by developing superior pharmaceutical products. To learn more about the company and its products, visit www.tpna.com .

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