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LANDMARK STUDY SHOWS PIOGLITAZONE REDUCES HEART ATTACKS AND STROKES IN PATIENTS WITH TYPE 2 DIABETES

Landmark data from the PROactive Study*, presented today at the 41st meeting of the European Association for the Study of Diabetes (EASD) demonstrated that pioglitazone significantly reduces the risk of heart attacks (also known as myocardial infarction or MI), strokes and death in high risk patients with Type 2 Diabetes.

This result is a breakthrough for these patients who are at high risk from heart attacks, strokes or premature death, as it is the first time that an oral diabetes medication has shown significant reductions in these macro-vascular events.

“The PROactive Study found that pioglitazone has the potential to save lives and help delay or reduce the risk of cardiovascular events such as heart attacks or strokes in people with Type 2 Diabetes. It is the first study in the world designed to show that a specific diabetes medication, namely pioglitazone, normally used to control blood glucose, can also significantly improve patient outcomes associated with cardiovascular disease in patients with Type 2 Diabetes” said John Dormandy, M.D., Professor of Vascular Sciences at St. George’s Hospital, London, UK, and chairman of the PROactive Study steering committee.

John Dormandy further explained, “The significant effects of pioglitazone seen in this trial were incremental to the existing standards of care seen in clinical practice. These included the use of anti-hypertensives such as ACE inhibitors and Beta blockers, oral anti-diabetic agents such as metformin, sulphonylureas and insulin, antiplatelet drugs such as aspirin and clopidogrel and lipid-modifying medicines such as statins and fibrates”.

Type 2 Diabetes affects over 150 million people worldwide with the prevalence predicted to nearly double within the next 15 years. Type 2 Diabetes is associated with an increased risk of coronary heart disease, heart attacks, strokes and premature death, and that life expectancy for patients with Type 2 Diabetes is as much as 10 years shorter than in the general population, mainly because of increased cardiovascular mortality.

Summary of key results from the PROactive Study.

• Pioglitazone significantly reduced the risk of heart attacks, strokes and premature death (the principal secondary endpoint**) by 16% (p=0.027). Therefore allocating 1000 patients to pioglitazone would avoid 21 first heart attack, stroke or death in three years.
• Pioglitazone, on top of normal standard of care, reduced blood glucose, in a sustained manner, over the three years of the PROactive Study (HbA1c reduced by 0.5% more than placebo).
• Pioglitazone on top of normal standard of care improved diabetic dyslipidaemia by increasing HDL cholesterol (commonly known as good cholesterol) by 19% (9% more than placebo) and reducing triglycerides (a known cardiovascular risk factor) by 11% (13% more than placebo) over the three years of the PROactive Study.
• There was a significant (p=0.03) decrease in systolic blood pressure (median change 3 mmHg more than produced by placebo) in the patients treated with pioglitazone over the three years of the PROactive Study.
• The primary composite endpoint*** was reduced by 10% but had not reached statistical significance by study end (p=0.095).
• There were no unexpected adverse events with pioglitazone treatment.

“Earlier comparative clinical studies have already demonstrated that pioglitazone has a unique profile by providing benefits beyond glycaemic control on certain markers of cardiovascular risk, for example by improving the atherogenic lipid profile” commented Professor Dormandy. “However, until the new and exciting results of PROactive were announced, the clinical significance of these effects of pioglitazone was unknown”.

Professor Dormandy concluded, “pioglitazone significantly reduces the risk of heart attacks, strokes and premature death in high risk patients with Type 2 Diabetes and importantly there were no unexpected adverse events with pioglitazone treatment. Despite the size and duration of the study it was notable that only 2 patients were lost to follow up, which is exceptional in the conduct of large cardiovascular outcome studies.”

About the PROactive Study.

• *The full name of the PROactive Study is “PROspective PioglitAzone Clinical Trial In MacroVascular Events Study”.
• The PROactive Study was initiated as a randomised, double blind, placebo-controlled outcome study, to determine the effects of pioglitazone (ACTOS®) on mortality and morbidity associated with cardiovascular disease progression in patients with Type 2 Diabetes.
• **The principal secondary endpoint was defined as time from randomization to any of the following: heart attack (defined as MI excluding silent MI), stroke and death (all cause mortality).
• ***The primary composite endpoint was defined as time from randomisation to any of the following composite: all-cause mortality, non-fatal MI (including silent MI), stroke, acute coronary syndrome, coronary revascularisation, revascularisation in the leg or amputation above the ankle. Within this endpoint whilst the most serious events (such as MI, stroke and death) were significantly reduced with pioglitazone treatment, some of the other more subjective events, requiring physician judgment or intervention were affected to a lesser extent, reducing the overall difference observed.
• 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 pioglitazone or placebo in addition to their best standard of usual care and treatments.
• The PROactive Study was funded by Takeda Pharmaceutical Company Limited, the makers of pioglitazone (marketed under the trade name ACTOS®) and Eli Lilly and Company.
• The results from the landmark three year PROactive Study were presented at the 41st European Association for the Study of Diabetes (EASD) Annual Meeting, by Professor John Dormandy and other members of the PROactive Executive Steering Committee.
• These results are expected be published in The Lancet on September 17th 2005. The Lancet paper will be on-line on September 12th 2005.
• The results in slide format are available on the global PROactive website www.proactive-results.com

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