New Data Showed Actos (pioglitazone HCl) Prevented Progression of Atherosclerotic Plaque Volume in Patients with Type 2 Diabetes

Data expands body of evidence in high risk population using IVUS, a unique marker for coronary atherosclerosis

CHICAGO, March 31, 2008 - New data from a clinical trial using intravascular ultrasound (IVUS) technology found that in patients living with type 2 diabetes, ACTOS(r) (pioglitazone HCl) reduced the atherosclerotic burden in the coronary arteries compared to the sulphonylurea glimepiride, and prevented progression compared to baseline.

Results from the PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) trial have today been simultaneously presented as a late breaker at the 57th Annual Scientific Session of the American College of Cardiology and published on-line by the Journal of the American Medical Association (JAMA).

PERISCOPE is the first clinical trial to examine the effects of an oral antidiabetic medication on the development of coronary atherosclerosis in patients with type 2 diabetes using IVUS technology. IVUS measures the volume of plaque build-up in the coronary arteries, a marker of coronary atherosclerosis. The 18-month trial, involving 543 patients, was conducted in 97 centres in the USA, Canada and Latin America.

The analysis demonstrated a statistically significant difference in percent change in coronary artery atheroma volume (PAV) in favour of ACTOS treatment compared to glimepiride treatment. The data showed that patients treated with glimepiride exhibited progression of coronary atherosclerosis, whilst in contrast the ACTOS arm showed no progression of coronary atherosclerosis over the 18-month period from the initial baseline measurement.

"The findings of PERISCOPE represent a fundamental observation demonstrating that pioglitazone, in addition to controlling blood sugar, favourably influences the development of coronary artery atherosclerosis, the process that is responsible for the premature death of 80 percent of type 2 diabetic patients", commented Mark Kearney, Professor of Cardiology, University of Leeds, UK.

"This is further robust evidence that pioglitazone has a beneficial effect on coronary atherosclerosis in patients with diabetes. Importantly, this effect is seen on top of good treatment with statins and other cardiovascular drugs", added Martin Cowie, Professor of Cardiology, National Heart & Lung Institute, Imperial College London.

Cardiovascular safety data was collected by looking at macrovascular events and episodes of congestive heart failure (CHF). The number of episodes of a common cardiovascular endpoint of cardiovascular mortality, non-fatal MI, or non-fatal stroke was 6 (2.2 percent) in glimepiride patients and 5 (1.9 percent) in ACTOS-treated patients. The number of hospitalisations due to CHF were equivalent in both arms. In the ACTOS-treated group, eight patients experienced a bone fracture, none involving the hip or spine.

This trial adds to the body of cardiovascular data for ACTOS. ACTOS studies, conducted over the past 10 years in more than 16,000 patients, including short- and long-term trials, as well as prospective and observational studies, have shown no evidence that ACTOS is associated with an increased risk of heart attack, stroke, or death.

The data are consistent with the findings of the CHICAGO (Carotid intima-media tHICkness in Atherosclerosis using pioGlitazOne) trial. Both PERISCOPE and CHICAGO support the findings of the PROactive (PROspective PioglitAzone Clinical Trial In MacroVascular Events) trial, which showed that ACTOS was not associated with an increased risk of heart attack, stroke or death.

Atherosclerosis is a condition that leads to reduced or blocked blood flow, and is accelerated in patients with type 2 diabetes. Atherosclerosis-related cardiovascular disease is the leading cause of death and disability in people with type 2 diabetes. Published data shows that slowed progression and reductions in atheroma volume lessens the incidence of a second heart attack.

-Ends-

Contacts:

Richard Kenyon Helen Crow

Takeda Pharmaceuticals Europe Ketchum

+44 (0) 207 632 9351 (E.U. office) +44 (0) 207 611 3654

helen.crow@ketchum.com

Note to Editors

CHICAGO

The CHICAGO (Carotid intima-media tHICkness in Atherosclerosis using pioGlitazOne) trial, published in JAMA in 20061, demonstrated that ACTOS significantly slowed progression of carotid intima-media thickness (CIMT) in patients with type 2 diabetes, compared with the sulphonylurea glimepiride, over an 18-month period. CIMT is a marker of coronary atheroscelerosis and independently predicts subsequent cardiovascular events.

PROactive

In PROactive, a cardiovascular outcome study, 5238 patients with type 2 diabetes mellitus and preexisting major macrovascular disease were randomised to pioglitazone or placebo in addition to existing antidiabetic and cardiovascular therapy, for up to 3.5 years2. 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. However, the incidences of oedema, weight gain and heart failure were increased. No increase in mortality from heart failure was observed.

ACTOS(r) (pioglitazone HCl)

In Europe, pioglitazone 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.

Pioglitazone is contraindicated in patients with:

- Hypersensitivity to the active substance or to any of the excipients

- Cardiac failure or history of cardiac failure (NYHA stages I to IV)

- Hepatic impairment

- Diabetic ketoacidosis.

Some patients with long-standing type 2 diabetes mellitus and heart disease or previous stroke who were treated with Actos and insulin experienced the development of heart failure. Patients should consult their doctor as soon as possible if they experience signs of heart failure such as unusual shortness of breath or rapid increase in weight or localised swelling (oedema).

Takeda also manufactures Competact(r), which combines two widely used diabetes treatments (metformin and pioglitazone) in a convenient single tablet, to be taken twice daily. COMPETACT(r) was first launched in Europe in October 2006. Competact(r) 15mg/850mg tablets contain 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.

Takeda Global Research & Development Center

Based in Deerfield, USA, and London, Takeda Global Research & Development Center, Inc. is a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, the largest pharmaceutical company in Japan. Takeda Global Research & Development was established in 2004 and is responsible for Takeda's clinical research and development in the U.S. and Europe, supporting clinical and product development activity for Takeda commercial organizations in the U.S. - Takeda Pharmaceuticals North America, Inc, and in Europe: six sales and marketing companies, respectively. With a robust pipeline of compounds in development for diabetes, cardiovascular disease and other conditions, Takeda rapidly brings innovative products to market to improve patient health and enhance the practice of medicine. To learn more about the company, visit www.tgrd.com <http://www.tgrd.com/> .

References

1. Mazzone T, Meyer P, Feinstein SB et al. Effect of Pioglitazone Compared with Glimepiride on Carotid Intima-Media Thickness in Type 2 Diabetes. JAMA 2006; 296: 2572-2581 2. Dormandy JA, Charbonnel B, Eckland DJA et al. Secondary Prevention of Macrovascular Events in Patients with Type 2 Diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A Randomised Controlled Trial. Lancet 2005; 336:1279-89

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Posted: April 2008

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