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Landmark PROactive Trial Investigates Effect of ACTOS® (pioglitazone HCl) on Cardiovascular Disease Progression

June 28, 2004

More than 5,000 patients with type 2 diabetes studied

Lincolnshire, IL, June 28, 2004 – In the July 2004 issue of Diabetes Care, researchers published the study design and baseline characteristics of patients enrolled in the landmark PROspective PioglitAzone Clinical Trial In MacroVascular Events Study (PROactive). PROactive is a European clinical trial assessing the effects of ACTOS® (pioglitazone HCl) on mortality and morbidity associated with cardiovascular disease progression in patients with type 2 diabetes. The study has enrolled 5,238 patients in 19 countries who have experienced one or more cardiovascular events such as a heart attack, coronary artery bypass surgery or stroke.

“Major studies have shown that sustained improvements in glycemic control significantly reduce the risk of some microvascular complications, but data remain inconclusive that intervention with conventional glucose-lowering agents is successful in modifying macrovascular disease,” said John Dormandy, M.D., professor of Vascular Sciences at St. George’s Hospital, London, and chairman of the PROactive study steering committee. “Recent studies have shown ACTOS has a beneficial effect on markers of cardiovascular risk, such as atherogenic lipids and c-reactive protein (CRP). Through PROactive, we will determine if the beneficial effects of ACTOS on cardiovascular risk factors translate into a reduction in cardiovascular mortality and morbidity in a high-risk population of patients with type 2 diabetes.”

Type 2 diabetes is associated with a two- to four-fold increase in cardiovascular disease as well as other cardiovascular risk factors such as high blood pressure and cholesterol disorders. Additionally, heart disease is the leading cause of mortality and morbidity for patients with type 2 diabetes.

“Previous studies have suggested ACTOS can provide benefits extending beyond improvements in glucose levels,” said John Yates, M.D., M.R.C.P., president, Takeda Global Research & Development. “Physicians who treat patients with type 2 diabetes face increasing challenges helping their patients manage cardiovascular risk factors. PROactive should generate important insights into whether the drug can play a larger role in the management of this devastating disease.”

In several large-scale trials, ACTOS consistently improved components of diabetic dyslipidemia, another cardiovascular disease risk factor, which is characterized by low HDL (“good”) cholesterol levels and high triglycerides. Smaller, mechanistic studies have shown statistically significant changes in small, dense LDL cholesterol and in CRP, an important marker of inflammation and a key factor in the development of coronary artery disease.

Study Design
PROactive is an ongoing randomized, double-blind, placebo-controlled outcome study assessing the incidence of cardiovascular complications of diabetes, e.g., heart attack, coronary artery bypass surgery or stroke, as well as overall mortality. The primary endpoint variable is the time from randomization to the first occurrence of any of the events in the composite endpoint, including death and major macrovascular events.

Pioglitazone or placebo is given as add-on therapy to existing diabetes management (including diet and exercise and other diabetes medications). Study medication was assigned using a central interactive voice response system. Investigators are encouraged to maintain glycemia within the limits outlined in the International Diabetes Federation (IDF) Europe Guidelines (A1C<6.5%).

Patients in the study are given pioglitazone at the highest tolerated dose (up to 45 mg) or placebo, with other diabetes medications (non-TZD oral glucose-lowering agents with or without insulin) administered concomitantly. Investigators optimize all therapy according to IDF Europe Guidelines by providing lipid-lowering and antihypertensive therapy, as needed. Patients who discontinue the study medication are being followed until the end of the study, with the study completion expected in 2005.

ACTOS, an insulin sensitizer belonging to the thiazolidinedione (TZD) class of oral antidiabetic medications, directly targets insulin resistance, a condition in which the body does not effectively 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 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 or edema (swelling), which 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, edema (swelling), or shortness of breath while taking ACTOS. If you have moderate to severe heart failure, ACTOS is not recommended.

Also, your doctor should perform a blood test to check for serious liver problems or active liver disease before you start ACTOS and regularly thereafter. Do not take ACTOS if you have active liver disease. Talk to your doctor immediately if you experience nausea, vomiting, stomach pain, tiredness, anorexia, dark urine, or yellowing of the skin. If you are of childbearing age, talk to your doctor before taking ACTOS because it could increase your chance of becoming pregnant.

Some people taking ACTOS may experience cold and flu-like symptoms, mild to moderate swelling of legs and ankles, and anemia. Occasionally, blood sugar levels increased during clinical trials. When taking ACTOS with insulin or sulfonylureas, you may be at risk for low blood sugar.

Takeda Pharmaceuticals North America, Inc.
Based in Lincolnshire, Ill., Takeda Pharmaceuticals North America, Inc. is a wholly-owned subsidiary of Takeda Chemical Industries, Ltd. (Osaka, Japan). Takeda is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the industry’s leaders worldwide, Takeda is committed to strive toward better health for individuals and progress in medicine by developing superior pharmaceutical products. For company information, visit Takeda Pharmaceuticals North America’s Web site at www.tpna.com .

Eli Lilly and Company
Lilly, a leading innovation-driven corporation, is developing a growing portfolio of first-in-class and best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers—through medicines and information—for some of the world’s most urgent medical needs. Additional information about Lilly is available on www.lilly.com .

Final Notes
ACTOS is a registered trademark of Takeda Chemical Industries, Ltd. and used under license by Takeda Pharmaceuticals North America, Inc. and Eli Lilly and Company. Please visit the ACTOS Web site at www.actos.comfor complete Prescribing Information.

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