The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive)

Can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5,238 patients

  1. Bernard Charbonnel, MD1,
  2. John Dormandy, FRCS(ED), FRCS(ENG), DSC2,
  3. Erland Erdmann, MD, FESC, FACC3,
  4. Massimo Massi-Benedetti, MD4,
  5. Allan Skene, PHD5 and
  6. PROactive Study Group
  1. 1Clinique d’Endocrinologie, Nantes Cedex, France
  2. 2Department of Vascular Surgery, St. George’s Hospital, London, U.K
  3. 3Klinik III für Innere Medizin, Köln, Germany
  4. 4Dipartimento di Medicina Interna, Università di Perugia, Perugia, Italy
  5. 5Nottingham Clinical Research Limited, Isaac Newton Centre, Nottingham Science and Technology Park, Nottingham, U.K
  1. Address correspondence and reprint requests to Professor Bernard Charbonnel, MD, PROactive, Clinique d’Endocrinologie, Hotel Dieu, Place Alexis Ricordeau, 44093 Nantes Cedex 1, France. E-mail: bernard.charbonnel{at}


OBJECTIVE—The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) assesses the effect of pioglitazone, a peroxisome proliferator-activated receptor agonist, with anti-inflammatory and vascular properties, on the secondary prevention of macrovascular events in type 2 diabetes.

RESEARCH DESIGN AND METHODS—PROactive is an on-going randomized, double-blind outcome study in patients with type 2 diabetes managed with diet and/or oral blood glucose-lowering drugs (combination of oral agents with insulin is permitted) who have a history of macrovascular disease. Patients are randomized to receive pioglitazone (forced titration from 15 to 30 to 45 mg, depending on tolerability) or placebo in addition to existing therapy. The primary end point is the time from randomization to occurrence of a new macrovascular event or death. Follow-up is estimated to span 4 years.

RESULTS—A total of 5,238 patients have been randomized from 19 countries. At entry into the study, patients enrolled are a mean age of 61.8 years, with type 2 diabetes for a mean of 9.5 years; 60.9 and 61.5% are taking metformin or a sulfonylurea, respectively; and 33.6% are using insulin in addition to oral glucose-lowering drugs. The majority of patients are men (66.1%). Patients are required to meet one or more of entry criteria, as follows: >6 months’ history of myocardial infarction (46.7%); coronary artery revascularization (30.8%), stroke (18.8%), or acute coronary syndrome for >3 months (13.7%); other evidence of coronary artery disease (48.1%); or peripheral arterial occlusive disease (19.9%). One-half (48.5%) of the patients have two or more of these risk factors. Three-quarters (75.4%) have hypertension, and 58.8% are current or previous smokers.

CONCLUSIONS—The cohort of patients enrolled in PROactive is a typical type 2 diabetic population at high risk of further macrovascular events. The characteristics of this population are ideal for assessing the ability of pioglitazone to reduce the cardiovascular risk of patients with type 2 diabetes.


  • A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

    • Accepted April 5, 2004.
    • Received October 5, 2003.
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