PROACTIVE Study: Pioglitazone Protects Against MI, Stroke, Death in High-Risk Type 2 Diabetics
In high-risk type 2 diabetic patients, the addition of the insulin sensitizer pioglitazone (ACTOS) to optimized therapy significantly reduces the combined risk of MI, stroke and death by 16%. That's according to results from the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) presented at the 41st European Association for the Study of Diabetes in Athens, Greece in Sept 2005.

"This study is the first to prospectively show that a specific oral glucose-lowering medication can significantly improve cardiovascular outcomes by helping to delay or reduce heart attacks, strokes and death in high-risk patients," said Dr. John Dormandy of St. George's Hospital, London, who presented the data.

Sponsored by pioglitazone drug maker Takeda Pharmaceuticals and Eli Lilly Company, the trial enrolled 5238 type 2 diabetic patients from 19 European countries to see whether pioglitazone, a thiazolidinedione with anti-inflammatory and vascular properties, could reduce cardiovascular morbidity and mortality in high-risk diabetics when added to optimized therapy, including statins, aspirin, antihypertensive medication and background diabetes medication.

Patients enrolled were a mean of 61.8 years of age, had type 2 diabetes for a mean of 9.5 years and had evidence of cardiovascular disease. More than half were taking metformin or a sulfonylurea and roughly one third were using insulin in addition to oral glucose-lowering drugs. Patients were randomized for an average of 3 years to pioglitazone or placebo and followed until the occurrence of a new event or death.

After approximately 175,000 patient-months of follow-up, the primary endpoint -- a combination of seven different macrovascular events (death, non-fatal MI, acute coronary syndrome, cardiac intervention, stroke, major leg amputation, bypass surgery or revascularization) -- was reduced by 10% but did not reach statistical significance by study end (p = 0.095).

However, Dr. Dormandy reported that for the principal secondary endpoint -- the individual components of the primary endpoint -- "there was a statistically significant 16% reduction in strokes, heart attacks and death" with pioglitazone versus placebo (p=0.027).

Moreover, with pioglitazone, the number of patients needing to have insulin added permanently to their treatment was reduced by greater than 50% (p < 0.001). The PROactive data also confirm pioglitazone's known favorable effects on blood glucose -- HbA1c levels fell significantly with pioglitazone compared with placebo (p < 0.001) -- and on diabetic dyslipidemia -- HDL-C increased and triglycerides decreased significantly relative to placebo (p < 0.001 for both).

Systolic BP was significantly reduced (p = 0.03) with a median change of 3 mm Hg more than placebo. Moreover, carotid intimal media thickness also decreased.

No new safety concerns emerged.

Summing up, the investigator said, before PROactive "we knew that pioglitazone decreases blood glucose, improves lipids, and affects known markers of cardiovascular risk. We did not know it actually reduced cardiovascular deaths, heart attacks and strokes and the need for permanent insulin therapy."

These results predict that 10 heart attacks, strokes or deaths will be prevented for every 500 high-risk type 2 diabetic patients treated with pioglitazone over 3 years.