New analyses of PROactive Trial data show that pioglitazone reduces the rate of major adverse cardiovascular events and delays the need for insulin in high-risk patients with type 2 diabetes, according to presentations at the annual meeting of the American Diabetes Association. Major adverse cardiovascular events included symptomatic myocardial infarction, nonfatal stroke, acute coronary syndrome, and cardiovascular death.

The first new analysis demonstrated statistically significant risk reductions with pioglitazone compared with placebo for myocardial infarction, major adverse cardiovascular events, and additional endpoints including all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, or acute coronary syndrome.

At the end of the study, 339 patients (13 percent) in the pioglitazone group had a first event that contributed to one of the additional endpoints compared with 409 (15.5 percent) in the placebo group. Additionally, 108 (4.1 percent) pioglitazone patients had a myocardial infarction compared with 140 (5.3 percent) in the placebo group, excluding a silent myocardial infarction.

The other two new analyses related to drug effects on need for insulin and mean daily insulin dose in patients requiring insulin to control blood glucose.

In the first of these analyses, the one third of patients using insulin at baseline (pioglitazone, 864; placebo, 896) were evaluated: A rapid and sustained decrease in insulin doses was observed among drug patients compared with progressively larger insulin doses among placebo patients. By study end, mean insulin dose was statistically lower with pioglitazone (42 U/day) than with placebo (55 U/day), and insulin had been discontinued in 9 percent of pioglitazone patients versus 2 percent in the placebo group.

In the second analysis, the two thirds of pioglitazone patients (1741) and placebo (1737) patients no using insulin at baseline were evaluated. Pioglitazone delayed the need for permanent insulin use - defined as daily use for greater than or equal to ninety days, or ongoing use at death or final visit. In fact, twice as many placebo patients progressed to permanent insulin use as pioglitazone patients (362 and 183, respectively) with projected rates for time to permanent insulin use 11 percent and 21 percent for pioglitazone and placebo groups, respectively.

Overall, progression to permanent insulin use was reduced by 50 percent at three years active drug versus placebo, and better glycemic control was seen with pioglitazone. The incidence of hypoglycemia was higher among pioglitazone patients than placebo patients.

"What is unique about these new data is that while earlier PROactive results found a combined risk reduction of heart attack, stroke, and death by 16 percent in high-risk patients treated with ACTOS, we saw a greater risk reduction when we looked at the wider scope of major adverse cardiovascular events,, in this high-risk population," said Erland Erdmann, MD, chairman of the PROactive Executive Committee, and director of the Clinic III for Internal Medicine, University of Cologne, Germany.

"Separate analyses suggest a significant decrease in the amount of insulin needed, as well as a delay in the need for permanent insulin use among patients taking ACTOS," said Robert Spanheimer, MD, medical director for diabetes and metabolism at Takeda Pharmaceuticals North America, Inc. "As type 2 diabetes is a progressive disease requiring multiple therapies, many patients eventually need supplementary insulin to manage their condition. For patients with type 2 diabetes and established cardiovascular disease, these results could lead to the potential for less dependence on daily insulin use."