PROactive: Pioglitazone Reduces Recurrent Stroke in Patients with Diabetes

Susan Jeffrey

September 04, 2006

September 4, 2006 — In a prespecified subgroup analysis of the previously published Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive), researchers report that treatment with pioglitazone (Actos, Takeda/Eli Lilly and Co.) reduced stroke risk in patients with type 2 diabetes, but only among those with a history of stroke; no significant difference with treatment was seen in patients without a prior stroke.

Recurrent stroke was reduced by 47% in patients with a prior history of stroke who received pioglitazone compared with those treated with placebo in the trial, Robert G. Wilcox, MD, from the School of Medicine and Surgical Sciences, Nottingham, United Kingdom, told attendees at the World Conference of Cardiology 2006 in Barcelona, Spain.

However, pioglitazone had no effect in reducing the risk of first strokes over this time course compared with placebo, although it did improve biochemical parameters, including reductions in HbA1c, blood pressure, and triglycerides and increased HDL cholesterol.

"Whether longer-term therapy with pioglitazone would similarly benefit diabetic patients without prior stroke, or perhaps indeed nondiabetic patients with prior stroke, awaits further inquiry," Dr. Wilcox said.

The PROactive study was funded by Takeda Pharmaceutical Company Ltd and Eli Lilly and Co.

End Points

Effective secondary prevention therapies in stroke are antihypertensive therapy, antiplatelet agents, and lipid-lowering treatment, Dr. Wilcox told attendees here. "To date, however, there's no conclusive evidence about the benefit of a glucose-lowering therapy in patients with diabetes on their incidence of stroke," he said.

Pioglitazone is a peroxisome proliferator-activated receptor- γ (PPAR- γ ) agonist, approved as an antiglycemic agent for the treatment of type 2 diabetes. This agent has effects in addition to glucose lowering, including reductions in triglycerides and C-reactive protein and increased HDL cholesterol, all of which may positively affect cardiovascular risk.

The main PROactive study was a randomized, double-blind, placebo-controlled trial in 5238 patients with type 2 diabetes considered at high risk for cardiovascular events because of the presence of macrovascular disease, including previous stroke, MI, revascularization, or peripheral artery disease, and objective evidence of coronary artery disease.

Patients were randomized to 45 mg/day of pioglitazone or placebo given on top of standard medications recommended in this patient population, including antihypertensive drugs; glucose-lowering medications such as metformin, sulfonylurea, and insulin; antiplatelet drugs including aspirin; and lipid-lowering agents such as statins and fibrates.

The main study results, published in October 2005 (Lancet. 2005; 366:1279-1289), showed a nonsignificant 10% reduction in the study's primary end point, a composite of all-cause mortality, nonfatal MI (including silent MI), stroke, major leg amputation (above the ankle), acute coronary syndrome, cardiac intervention including CABG or PCI, or leg revascularization. However, there was a significant 16% reduction in the secondary composite end point of death, MI (excluding silent MI), and stroke seen with pioglitazone.

Stroke End Points

In the overall trial, stroke was reduced by 19% with pioglitazone treatment; 86 strokes occurred with treatment vs 107 with placebo (HR, 0.81; 95% CI, 0.67 – 1.07), a trend in favor of treatment that did not reach statistical significance.

In the prespecified subgroup analysis presented here, the PROactive investigators looked at the stroke end points in patients with (n=984) and without (n=4254) a prior history of stroke.

Dr. Wilcox reported that the risk of recurrent stroke was reduced among patients with a history of stroke for those treated with pioglitazone relative to those not treated, from 10% to about 5% in treated patients, a significant reduction.

ProACTIVE: Fatal and Nonfatal Stroke With Pioglitazone Treatment vs Placebo in Patients With Prior History of Stroke

End Point
Pioglitazone, n=486
Placebo, n=498
Hazard Ratio (95% CI)
Recurrent stroke
0.53 (0.34 – 0.94)

The combined risk of death, MI, or stroke was reduced by 28% (P < .05) with pioglitazone vs placebo in this group with prior stroke, he noted.

However, there was no significant reduction in new strokes seen in those without a prior history of stroke, where the overall risk for stroke was much lower.

Biochemical and diabetic changes from baseline showed a greater reduction in HbA1c, systolic and diastolic BP, and triglycerides, even more of an increase in HDL cholesterol and more of a decrease in the LDL/HDL ratio with pioglitazone treatment, Dr. Wilcox said. Very similar changes were seen in the same parameters among patients without prior stroke.

Multivariate analysis showed that prior stroke itself was the strongest predictor of recurrent stroke in the entire cohort of patients (HR, 2.88; P < .0001), he noted. Use of pioglitazone and statins were the only factors that had significant effect on the risk of stroke or recurrent stroke in patients with previous stroke.

For patients without prior stroke, major risk factors included HbA1c, creatinine clearance, and the presence of peripheral vascular disease.

There were similar reports of adverse events in patients with and without previous stroke, Dr. Wilcox noted. More patients on pioglitazone were admitted to the hospital with clinical features consistent with heart failure — similar to findings in the overall trial that had raised some concern about this treatment in this population — but the mortality in all groups was the same, he added.

Astrology and Clinical Trials

Invited discussant for the trial update presented here was Lars Rydén, MD, from the Karolinska Institute in Stockholm, Sweden. He cautioned the investigators about the perils of subgroup analysis, harking back to the now-famous subgroup analysis of data from ISIS II by Peter Sleight, MD, and colleagues at Oxford University, in the United Kingdom, showing that for MI patients born under the astrological signs of Libra and Gemini, aspirin therapy was associated with harm, "and who believes that actually?" Dr. Rydén said. "There are similar examples of sub-sub-subgroup analysis ending up like that."

Relative to this PROactive subanalysis, Dr. Rydén expressed concern that, given the similar changes seen in biomarkers such as blood pressure and cholesterol fractions with pioglitazone treatment, these findings of a different result among those who did and did not have prior stroke were "difficult to understand" and have no obvious biologic explanation.

The main results of the overall trial were good, Rydén concluded, and he congratulated the PROactive investigators on those findings. "Please remain pleased with that," he said. "It is encouraging enough."

World Congress of Cardiology 2006. Presented September 3, 2006.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.