PROspective pioglitAzone Clinical Trial In macroVascular Events - PROactive


The goal of the trial was to evaluate the effect of treatment with pioglitazone compared with placebo on macrovascular complications among patients with type 2 diabetes.

Study Design

Study Design:

Patients Screened: 5,602
Patients Enrolled: 5,238
Mean Follow Up: Mean 34.5 months
Mean Patient Age: Mean age 62 years
Female: 34

Patient Populations:

Type 2 diabetes; age 35–75 years; HbA1c concentration > local laboratory equivalent of 6.5% for a Diabetes Control and Complications Trial-traceable assay (DCCT), despite existing treatment with diet alone or with oral glucose-lowering agents with or without insulin; evidence of extensive macrovascular disease, defined as MI or stroke at least 6 months before trial entry, percutaneous coronary intervention or coronary artery bypass surgery at least 6 months before recruitment, acute coronary syndrome at least 3 months before recruitment, or objective evidence of coronary artery disease or obstructive arterial disease in the leg


Type 1 diabetes; treatment with only insulin; planned coronary or peripheral revascularization; New York Heart Association class II heart failure or above; ischemic ulcers, gangrene, or rest pain in the leg; hemodialysis; or >2.5 times the upper limit of normal concentrations of alanine aminotransferase

Primary Endpoints:

Composite of all-cause mortality, nonfatal MI (including silent MI), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle

Secondary Endpoints:

Death from any cause, MI (excluding silent MI), and stroke; cardiovascular death; and individual components of the primary composite

Drug/Procedures Used:

Patients were randomized to oral pioglitazone titrated from 15 mg to 45 mg (n = 2,605) or matching placebo (n = 2,633). The study drug therapy was to be taken in addition to regular glucose-lowering drugs and other medications.

Concomitant Medications:

Metformin 62%, sulphonylurea 62%, and insulin 30%

Principal Findings:

Baseline characteristics were well balanced, with 47% of patients having a prior myocardial infarction (MI), 19% a prior stroke, and 48% having objective evidence of coronary artery disease. Median time since diabetes diagnosis was 8 years. Glycosylated hemoglobin (HbA1c) at baseline was 7.8% in the pioglitazone group and 7.9% in the placebo group. Study medication discontinuation was reported in 16% of the pioglitazone group and 17% of the placebo group.

HbA1c was reduced to a greater degree in the pioglitazone group compared with placebo (-0.8% vs. -0.3%, p < 0.0001), as were triglycerides (-11.4% vs. +1.8%, p < 0.0001). Low-density lipoprotein cholesterol increased by 7.2% in the pioglitazone group and 4.9% in the placebo group (p = 0.003). Need to add insulin to the glucose-lowering regimen occurred less often in the pioglitazone group (2.7% vs. 12.4%, p < 0.0001).

The primary composite endpoint occurred in 514 patients in the pioglitazone group and 572 patients in the placebo group (hazard ratio [HR] 0.90, p = 0.095). The secondary composite endpoint of death from any cause, nonfatal MI (excluding silent MI), or stroke occurred less frequently in the pioglitazone group compared with placebo (n = 301 vs. n = 358, HR 0.84, p = 0.027). There was no difference in mortality between groups (HR 0.96, 95% CI 0.78-1.18). Nonfatal MI trended lower in the pioglitazone group (HR 0.83, 95% CI 0.65-1.06), as did stroke (HR 0.81, 95% CI 0.61-1.07). Overall serious adverse events did not differ by treatment group (46% for pioglitazone vs. 48% for placebo, p = 0.11). However, occurrence of any heart failure occurred more often in the pioglitazone group (11% vs. 8%, p < 0.0001), as did heart failure requiring hospitalization (6% vs. 4%, p = 0.007).

Among the subgroup of patients with MI (n = 1,230 in the pioglitazone group and n = 1,215 in the placebo group), occurrence of a new nonfatal MI (excluding silent MI) occurred less often in the pioglitazone group (5.3% vs. 7.2%, HR 0.72, 95% CI 0.52-0.99, p = 0.045), as did acute coronary syndrome (2.8% vs. 4.3%, HR 0.63, 95% CI 0.41-0.97, p = 0.035). In the MI subgroup, as with the overall population, heart failure leading to hospitalization occurred more often in the pioglitazone group (7.5% vs. 5.2%).

As presented at the European Society of Cardiology Congress 2006, among the subgroup of patients with a history of prior stroke within 6 months of randomization (n = 984), treatment with pioglitazone compared with placebo was associated with a significant reduction in an additional stroke (n = 27 vs. n = 51, HR 0.53, p = 0.008), but results of the primary endpoint were similar to those of the overall trial (20.2% vs. 25.3%, HR 0.78, p = 0.067). Among patients without prior stroke, there was no difference in stroke (p = NS).


Among patients with type 2 diabetes, treatment with pioglitazone was not associated with a reduction in the primary composite event compared with placebo at an average follow-up of 3 years.

Pioglitazone, a part of the thiazolidinedione class of drugs, is an agonist of the peroxisome proliferator-activated receptor (PPAR gamma), which improves insulin sensitivity. While pioglitazone was not associated with a reduction in the primary composite event, which combined both coronary and peripheral events, it was associated with a reduction in the secondary composite endpoint of coronary events (death, MI, or stroke). Additionally, there was a reduction in the need to add insulin to glucose-lowering regimens.

Of note, the incidence of heart failure and heart failure hospitalizations was higher in the pioglitazone group compared with placebo. Pioglitazone is known to cause edema. The authors suggest this increase in edema may explain in part the higher heart failure rates in the pioglitazone group.


Dormandy JA, Charbonnel B, Eckland DJ, 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;366:1279-89.

Presented by Dr. Erland Erdmann at the American Heart Association Scientific Sessions, Dallas, Texas, November 2005.

Presented by R.G. Wilcox, European Society of Cardiology Scientific Congress, September 2006.

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Cardiac Surgery and Heart Failure, Hypertriglyceridemia, Lipid Metabolism, Acute Heart Failure, Interventions and ACS, Interventions and Coronary Artery Disease, Diet

Keywords: Coronary Artery Disease, Myocardial Infarction, Stroke, Acute Coronary Syndrome, Follow-Up Studies, Diabetes Mellitus, Type 2, Edema, Insulins, Insulin Resistance, Peroxisome Proliferator-Activated Receptors, Leg, Percutaneous Coronary Intervention, Glucose, Lipoproteins, LDL, Hemoglobin A, Glycosylated, PPAR gamma, Heart Failure, Hypoglycemic Agents, Diet, Triglycerides, Coronary Artery Bypass, Thiazolidinediones

< Back to Listings