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PROactive Study Shows Takeda's ACTOS(R) (pioglitazone HCl) Reduces Heart Attacks, Strokes and Deaths

Athens, Greece (ots/PRNewswire)

Landmark data from the PROactive
Study, presented today at the 41st meeting of the European
Association for the Study of Diabetes (EASD) demonstrated that
ACTOS(R) (pioglitazone HCl) significantly reduces the combined risk
of heart attacks, strokes and death by 16% in high risk patients with
type 2 diabetes.
"The PROactive study is the first in the world to prospectively
show that a specific oral glucose lowering medication, namely
pioglitazone, can significantly improve cardiovascular outcomes by
helping to delay or reduce heart attacks, strokes and death in
high-risk patients," said John Dormandy, M.D., professor of Vascular
Sciences at St. George's Hospital, London, UK, and chairman of the
PROactive Study Steering Committee. "This groundbreaking study gives
new hope to people with type 2 diabetes who, despite their attempts
to control blood glucose and take medications, fear these
life-threatening events."
PROactive (PROspective PioglitAzone Clinical Trial In
MacroVascular Events) was a randomised, double blind,
placebo-controlled outcome study to determine the effects of ACTOS on
mortality and morbidity associated with cardiovascular disease
progression in more than 5,000 high risk patients with type 2
diabetes when added to standard of care treatment. Standard of care
included the routine use of anti-hypertensives such as ACE inhibitors
and beta blockers; glucose-lowering agents such as metformin,
sulphonylureas and insulin; antiplatelet drugs such as aspirin, and
lipid-modifying medicines such as statins and fibrates.
Compelling Study Results
This study focused on two key endpoints: a primary combination
endpoint of seven different macrovascular events of varying clinical
importance; and a principal secondary combination endpoint of
life-threatening events including death, heart attack and stroke.
The primary endpoint was reduced by 10% but had not reached
statistical significance by study end (p=0.095). The principal
secondary endpoint of life-threatening events showed that
pioglitazone significantly reduced the risk of heart attacks, strokes
and death by 16% (p=0.027).
According to Professor Dormandy, these results predict that 10
heart attacks, strokes or deaths will be prevented for every 500
high-risk patients treated with ACTOS over three years.
Additional PROactive study results of ACTOS(R) showed:
  • HbA1c levels (a measurement of long-term blood glucose control) were significantly reduced as compared to placebo (p<0.001).
  • Lipid profiles significantly improved by increasing HDL cholesterol ("good" cholesterol) by 9% more than placebo (p<0.001), and reducing triglycerides (a known cardiovascular risk factor) by 13% more than placebo (p<0.001).
  • The LDL/HDL cholesterol ratio ("bad" to "good" cholesterol) was significantly improved (p<0.001). A 2% increase in LDL cholesterol ("bad" cholesterol) was observed compared to placebo (p=0.003).
  • Systolic blood pressure was significantly decreased (p=0.03); median change of 3 mmHg more than produced by placebo.
  • The number of patients needing to have insulin added permanently to their treatment was 50% less than placebo (p<0.001).
The PROactive Study was also designed to further examine the
safety of ACTOS in this high-risk patient group. The results
demonstrated that adverse events reported in this study were
consistent with the known safety profile. Known side effects of
ACTOS, including weight gain, oedema, non-serious hypoglycaemia and
heart failure were observed more frequently compared to placebo.
However, the benefits of ACTOS in the study outweighed the risks. In
addition, there were no reports of acute liver toxicity.
"ACTOS has demonstrated a unique profile in earlier comparative
clinical studies by providing benefits beyond glycaemic control on
markers of cardiovascular risk," commented Dr Kitazawa, a member of
the board of Takeda Pharmaceutical Company, Osaka, Japan. "However,
the clinical significance of these effects of pioglitazone was
unknown until we knew the exciting news from the PROactive Study.
Additional clinical studies are being funded by Takeda to further
improve our understanding of how ACTOS enables the results we have
seen in the PROactive study, specifically the reduction in risk of
heart attacks, strokes and deaths."
Professor Dormandy added, "Until we know how pioglitazone works to
provide these life-saving benefits, the beneficial results of
PROactive should not be generalized to any other oral glucose
lowering medication."
Editors Notes
  • The PROactive Study was funded by Takeda Pharmaceutical Company Limited, the makers of pioglitazone (marketed under the trade name ACTOS(R)) and Eli Lilly and Company.
  • The PROactive Study involved 5,238 patients in 19 European countries who had experienced one or more cardiovascular events such as a heart attack, coronary artery bypass surgery or stroke. Each patient was randomly assigned to ACTOS(R) (pioglitazone HCl) or placebo in addition to the best standard of usual care and treatments.
  • The results in slide format and other information on the PROactive Study are available on the global PROactive website, This website is supported by an unrestricted educational grant by Takeda Pharmaceutical Company and Eli Lilly and Company.
Takeda is the originator of thiazolidinedione derivatives, and
ACTOS(r) (pioglitazone HCl) is a member of the thiazolidinedione
class of "insulin-sensitizing" agents. Insulin sensitizers help
improve the body's ability to effectively use its own insulin by
reducing insulin resistance - a defect identified as a possible cause
of type 2 diabetes.
ACTOS received its first regulatory approval in July 1999 in the
United States. By April 2004, more than 32 million prescriptions for
ACTOS had been filled for over 4.5 million patients in the United
States alone.
ACTOS was originally approved by the European Commission for the
treatment of type 2 diabetes in October 2000 and the label extended
in 2003. In Europe, ACTOS is indicated for use as:
  • oral monotherapy treatment at doses up to 45 mg in type 2 diabetes mellitus patients, particularly overweight patients, inadequately controlled by diet and exercise for whom metformin is inappropriate.
  • oral combination treatment at doses up to 45mg in patients with insufficient glycaemic control despite maximum tolerated doses with either metformin (particularly in overweight patients) or sulphonylurea (in patients for whom metformin is not tolerated or is contraindicated).
About Eli Lilly & 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.
About Takeda
Takeda is an R & D oriented global company with its main focus on
pharmaceuticals. As the largest pharmaceutical company in Japan and
one of the leaders in the world, Takeda is committed to strive toward
better health for individuals and progress in medicine by developing
superior pharmaceutical products.


Jocelyn M. Gerst, Takeda Pharmaceuticals North America,
+33-674-030-359 (on site mobile), +1-847-383-3696 (office); Alexander
Watson, Ketchum London, +44(0)7712-675990 (on site mobile), Tina
Parisi, Ketchum New York, +44(0)7801-127-412 (on site mobile)