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Combination Therapy with ACTOS® (pioglitazone HCl) Shown to Improve Components of Diabetic Dyslipidemia

April 30, 2004

Addition of insulin sensitizer provides lipid benefits for patients with type 2 diabetes

BOSTON, April 30, 2004 - Time 9:00 a.m. EST - Results of three studies show that the oral anti-diabetic agent ACTOS® (pioglitazone HCl), in combination with a sulfonylurea, metformin or insulin, resulted in triglyceride decreases and high-density lipoprotein (HDL) cholesterol increases that demonstrated statistically significant improvements from baseline.

These studies also showed that, in addition to increasing low-density lipoprotein (LDL) cholesterol particle size, ACTOS can significantly increase the size and buoyancy of HDL particles. The findings were presented today at the 13th Annual Meeting and Clinical Congress of the American Association of Clinical Endocrinologists (AACE) in Boston.

“The data are important because they underscore the additional lipid benefits of ACTOS beyond its ability to effectively manage glucose levels and positively affect triglyceride and HDL cholesterol levels,” said Mehmood Khan, M.D., F.A.C.E., senior vice president for medical and scientific affairs, Takeda Pharmaceuticals North America.

“While it’s well-established that increases in LDL cholesterol particle size are associated with ACTOS therapy, these new data show that HDL or ‘good’ cholesterol particles are similarly affected, which may further expand the lipid benefits of ACTOS.”

People with diabetes are about twice as likely as those without diabetes to have high triglyceride and low HDL cholesterol levels, a condition commonly referred to as diabetic
dyslipidemia. Studies have shown that the presence of large, buoyant HDL particles instead of small, dense particles may be associated with reduced cardiovascular risks.

In addition, people with diabetes tend to have a higher proportion of small, dense LDL particles, which may lead to an increase in cardiovascular risk. Smaller, more dense LDL particles are thought to more easily penetrate arterial walls to form atherosclerotic plaque.

Study Design
These studies were conducted to evaluate the effects of ACTOS, an insulin sensitizer belonging to the thiazolidinedione (TZD) class of oral anti-diabetic medications, on the lipid subspecies and subparticle profiles of patients with diabetic dyslipidemia when administered in conjunction with other diabetes therapies.

Three randomized, double-blind, multi-center trials studied the effect of ACTOS 30 mg or 45 mg plus either a sulfonylurea, metformin or insulin on HDL and LDL levels and subclass particle size profile in patients with type 2 diabetes over a 24-week period. More than 250 patients in the three studies were randomized to one of the following treatment arms:

ACTOS 30 mg + sulfonylurea, metformin or insulin;
ACTOS 45 mg + sulfonylurea, metformin or insulin.

Study Results
After 12 and 24 weeks of treatment, findings showed ACTOS, at either 30 mg or 45 mg doses in combination with sulfonylurea, metformin or insulin, resulted in significant increases in average and peak LDL particle size. The LDL particle size increase was accompanied by a decrease in particle density. Similarly, comparable shifts were seen in HDL particle size and density.

“While earlier generations of medications for type 2 diabetes effectively lowered glucose levels, studies are suggesting that medications like ACTOS have additional properties that address the lipid abnormalities associated with the disease, such as dyslipidemia common in patients with type 2 diabetes,” noted Dr. Khan.

ACTOS is known as an insulin sensitizer because it directly targets insulin resistance, a condition in which the body does not effectively use the insulin it produces. As an adjunct to diet and exercise, it is taken once daily, and is approved for use as monotherapy and in combination 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.

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.com for complete Prescribing Information. For company information, visit Takeda Pharmaceuticals North America’s Web site at www.tpna.com .

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