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ACTOS® (pioglitazone HCl) Shows Sustained Efficacy Throughout Two-Year Period in Patients with Type 2 Diabetes

June 5, 2004

Studies presented at American Diabetes Association annual meeting underscore long-term, multiple effects of ACTOS

Orlando, FL, June 5, 2004 -- Long-term studies using the oral antidiabetic drug ACTOS® (pioglitazone HCl) alone, and in combination with other oral antidiabetic medications, found that it provided sustained improvements in glycemic control, insulin sensitivity and key lipid parameters over a 104-week period. The findings were presented today at the American Diabetes Association’s (ADA) 64th Annual Scientific Sessions.

“Given the clinical challenges of managing diabetes patients over time, and the fact that patients are living longer with diabetes, the data being presented today on ACTOS help physicians better understand the drug’s effectiveness over an extended period,” said Mehmood Khan, M.D., F.A.C.E., senior vice president for medical and scientific affairs, Takeda Pharmaceuticals. “Physicians are mindful that sustained improvements in A1C are essential to the long-term health of patients with type 2 diabetes.”

These studies, which were all conducted over a two-year period, compared the effects of ACTOS either alone or in combination with two other commonly used oral antidiabetic medications: a sulfonylurea (gliclazide) and metformin.

Effect of Combination Therapy on Fasting Insulin
In one study of 1,269 patients with type 2 diabetes, four different regimens were evaluated over two years of treatment: ACTOS (15-45 mg/day) or metformin (850-2550 mg/day), added to existing sulfonylurea therapy (gliclazide, 80-320 mg/day); and, using the same dosages, ACTOS or a sulfonylurea (gliclazide) added to existing metformin therapy.

Results showed that, whether combined with metformin or sulfonylurea, the addition of ACTOS produced the greatest reduction in fasting insulin; decreases were sustained over the two years. At 104 weeks, changes in serum insulin levels from baseline for the two arms of the study were:

ACTOS added to metformin: decrease of 2.6 µIU/mL; gliclazide added to metformin: increase of 1.9 µIU/mL
ACTOS added to gliclazide: decrease of 1.1 µIU/mL; metformin added to gliclazide: decrease of 0.2 µIU/mL.
“Since ACTOS helps the body use its insulin more efficiently, the reduction in fasting insulin suggests a reduced demand on the pancreatic beta cells,” noted Dr. Khan.

Effect of ACTOS on A1C Levels
The findings on decreases in insulin levels were complemented by another study that evaluated A1Cs (a measure of blood glucose levels over the previous 90 to 120 days) of patients with type 2 diabetes after two years of treatment on ACTOS and those on a sulfonylurea (gliclazide). Using repeated measures, the A1C at week 104 between the two groups differed significantly (ACTOS 7.3% vs. gliclazide 7.8%; p<0.0001).

A subset of 567 patients with type 2 diabetes was evaluated to measure the efficacy of ACTOS (up to 45 mg/day) compared to a sulfonylurea (gliclazide, up to 160 mg/day) in maintaining glycemic control for 104 weeks. All subset patients had an A1C of £9 percent prior to entry in this second year extension of a previous study. “Failure” was defined as an A1C level above 8 percent after 24 weeks. In this study, significantly more patients failed in the gliclazide group than in the ACTOS group. Similar results were seen when failure was more strictly defined as an A1C level above 7 percent.

“With the exploding prevalence of type 2 diabetes in younger adults, physicians today are increasingly challenged to effectively manage diabetes over extended periods of time,” said Dr. Khan. “We think these data are particularly relevant, as clinicians choose which combination therapies to use in managing type 2 diabetes.”

Effect of ACTOS on Lipid Levels
In addition to the data evaluating improvements in glycemic control, research from a study presented at the ADA Scientific Sessions investigated the effects of ACTOS on plasma lipid levels. A two-year study of almost 1,300 patients with type 2 diabetes measured plasma lipid levels when either ACTOS or metformin was added to sulfonylurea (gliclazide) therapy, and when either ACTOS or a sulfonylurea (gliclazide) was added to metformin therapy. Resulting lipid levels were measured and demonstrated the following (all differences were statistically significant):

Triglycerides : ACTOS added to a sulfonylurea resulted in a 17% decrease in triglycerides, while metformin addition resulted in a 9% decrease (p=0.001). ACTOS added to metformin resulted in a 23% decrease in triglycerides, while gliclazide added to metformin resulted in a 7% decrease (p=0.001).
HDL (“good”) cholesterol : ACTOS added to a sulfonylurea resulted in a 21% increase in HDL, while metformin addition resulted in a 15% increase (p=0.001). ACTOS added to metformin resulted in a 22% increase in HDL cholesterol, while gliclazide added to metformin resulted in a 7% increase (p=0.001).
LDL cholesterol : ACTOS added to a sulfonylurea resulted in a 5% decrease in LDL, while metformin addition resulted in an 11% decrease (p=0.001). ACTOS added to metformin resulted in a 2% increase in LDL cholesterol, while gliclazide added to metformin resulted in a 6% decrease (p=0.001).
These results suggest that ACTOS may target specific abnormalities associated with diabetic dyslipidemia.

ACTOS, an insulin sensitizer belonging to the thiazolidinedione (TZD) class of oral anti-diabetic medications, directly targets insulin resistance, a condition in which the body does not effectively use the insulin it produces. 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.com for complete Prescribing Information.

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