Takeda Pharmaceuticals Europe Ltd, is aware of the review of ACTOS® (pioglitazone HCl) data conducted by A. Michael Lincoff, M.D., and colleagues at the Cleveland Clinic, Cleveland, USA, published in the Journal of the American Medical Association which concluded that ACTOS® is associated with a significantly lower risk of heart attack, stroke, or death among a diverse population of patients with diabetes versus control therapy. This new meta-analysis reflects the depth and breadth of ACTOS® cardiovascular data: In clinical studies with ACTOS® conducted over the past 10 years in more than 16,000 patients, including short- and long-term trials, there is no evidence that ACTOS® is associated with an increased risk of heart attack, stroke, or death.

Meta-analyses are pooled data across a number of studies. Although not definitive, they can offer insight into aspects of a compound or product that may not be readily available from individual studies. The overall effect calculated from a group of like or similar randomized trials can provide an estimate of the drug's overall effects in an expanded population. This meta-analysis adds important information to the body of evidence regarding ACTOS® and macrovascular ischemic events, and supports the consistency of data from both observational and prospective studies.

Critical in this body of data is PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events), a trial of patients with type 2 diabetes who are at high risk for cardiovascular events. Results from this prospective, randomized, placebo-controlled outcomes trial - considered by scientists to be the most scientifically rigorous type of study - were added to the ACTOS® label. These data show no increase in mortality or total macrovascular events with ACTOS®. ACTOS® is the only thiazolidinedione (TZD) with safety data from a cardiovascular outcomes trial in its label.

Given the strength and consistency of the ACTOS® data as demonstrated by the prospective studies, meta-analysis, and observational studies, Takeda remains confident in the ACTOS® safety profile regarding the risk of macrovascular ischemic events.

To view the full clinical paper visit jamamedia.

About the PROactive Study

PROactive was a prospective, randomized, placebo-controlled outcomes trial. The PROactive study included 5,238 patients with type 2 diabetes and a history of macrovascular disease, who were force titrated up to 45 mg daily of either ACTOS® or placebo. In this study, there was no difference in the number of macrovascular events between standard of care and ACTOS®, and standard of care alone. Although the study failed regarding its primary endpoint, which was a composite of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, major leg amputation, coronary revascularisation and leg revascularisation, the results suggest that there are no long-term cardiovascular concerns regarding use of pioglitazone

The ACTOS® Summary of Product Characteristics was recently revised by the EMEA to include this reassuring cardiovascular safety data. ACTOS® is the only thiazolidinedione (TZD) with safety data from a cardiovascular outcomes trial in its label.

About ACTOS®

ACTOS® received its first regulatory approval in July 1999 in the United States. ACTOS® was originally approved by the European Medicines Agency for the treatment of type-2 diabetes in October 2000, the original label was most recently extended in January 2007. In Europe, ACTOS® is indicated in the treatment of type 2 diabetes mellitus as:

-- monotherapy
- in patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin is inappropriate because of contraindications or intolerance

-- dual oral therapy in combination with
- metformin, in patients (particularly overweight patients) with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin

- a sulphonylurea, only in patients who show intolerance to metformin or for whom metformin is contraindicated, with insufficient glycaemic control despite maximal tolerated dose of monotherapy with a sulphonylurea.

-- triple oral therapy in combination with
- metformin and a sulphonylurea, in patients (particularly overweight patients) with insufficient glycaemic control despite dual oral therapy.

Pioglitazone is also indicated for combination with insulin in type 2 diabetes mellitus patients with insufficient glycaemic control on insulin for whom metformin is inappropriate because of contraindications or intolerance

Takeda also manufactures COMPETACT® which combines two widely used diabetes treatments (metformin and pioglitazone) in a convenient single tablet, to be taken twice daily. COMPETACT® was first launched in Europe in October 2006.

COMPETACT® 15mg/850mg tablets contains 15mg pioglitazone as hydrochloride and 850mg of metformin hydrochloride. Indication: Treatment of type 2 diabetes mellitus patients, particularly overweight patients, who are unable to achieve sufficient glycaemic control at their maximally tolerated dose of oral metformin alone.

About Takeda in Europe

Takeda Pharmaceuticals Europe Ltd, based in London, UK, supervises the overall business activities of Takeda's subsidiaries in Europe through promoting pan-European strategies.

Takeda Global Research & Development Center, Inc., based in Deerfield, Ill., USA, and London, U.K., is a wholly owned subsidiary of Takeda Pharmaceutical Company Limited and is responsible for Takeda's clinical research and development in the U.S. and Europe.

Takeda Pharmaceutical Company Limited, located in Osaka, Japan, is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to striving toward better health for individuals and progress in medicine by developing superior pharmaceutical products. Additional information about Takeda is available through its corporate website, takeda

ACTOS® (pioglitazone HCl) is a registered trademark of Takeda Pharmaceutical Company Limited.



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