The PROactive and DREAM Studies

US Endocrinology, 2006;(2): DOI:


These two large studies, PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) and Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM), had very different aims. PROactive asked whether the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone could decrease macrovascular morbidity and mortality in people with type 2 diabetes who were already taking maximum preventive treatment.1 DREAM asked whether rosiglitazone and ramipril (PPARγ agonist and angiotensin-converting enzyme (ACE) inhibitor, respectively), either in combination or individually, could decrease the rate of progression to diabetes in people with abnormal glucose tolerance.2,3

The former was based on a hypothesis that most clinicians would regard as optimistic. The latter was a composite of wishful thinking.

Pioglitazone improves the lipid profile as well as lowering blood glucose levels and increasing insulin sensitivity, and hence the drug could have beneficial effects on atherosclerosis. People with type 2 diabetes at high risk of cardiovascular events will already be taking a statin, antihypertensives, and aspirin. The PROactive study examined the effect of adding pioglitazone to such therapy. It was well designed, apart from a primary end-point that was a mixture of actual events (myocardial infarction (MI), stroke, allcause mortality) and therapeutic procedures such as coronary stenting.

The primary end-point was not statistically different in those given active treatment or placebo, although a widening gap appeared to be developing by the end of the study. The main secondary end-point of allcause mortality,MI, and stroke was reached in 11.5% of patients on pioglitazone and 13.5% on placebo, and this was statistically significant. However, if a doctor offered their patient an additional tablet that would change risk of problems over three years from about 13% to about 12%, and may cause weight gain (4kg) and ankle swelling, the patient might not be tempted.
  1. 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: pp. 1279–1289.
  2. Dream: Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a roandomised controlled trial”, Lancet (2006);368: pp. 1096–1105.
  3. Dream: Effect of ramipril on the incidence of diabetes”, N Engl J Med (2006);355: pp. 1551–1562.
  4. Yki-Jarvinen H,“The PROactive study: some answers, many questions”, N Engl J Med (2005);366: pp. 1241–1242.
  5. Sleight P,Yusuf S, Pogue J, Psuyuki R, Probstfield J, “Blood pressure reduction and cardiovascular risk in HOPE study”, Lancet (2001);358: pp. 2130–2131.
  6. Svensson P, de Faire U, Sleight P,Yusuf S, Ostergren J, “Comparative effects of ramipril on ambulatory and office blood pressures.A HOPE substudy”, Hypertension (2001);38: pp. E28–E32.
  7. Taylor R,“Conundrum of the HOPE study”, BMJ (2003);327: pp. 681–682.
  8. Taylor R, “How large studies may mislead: the HOPE study”, Practical Diabetes (2001);18: pp. 208–211.
  9. Berkowitz K, Peters R, Kjos SL et al.,“Effect of troglitazone on insulin sensitivity and pancreatic beta cell function in women at high risk for NIDDM”, Diabetes (1996);45: pp. 1572–1579.
  10. Xiang AH, Peters RK, Kjos SL et al.,“Effect of pioglitazone on pancreatic beta-cell function and diabetes risk in Hispanic women with prior gestational diabetes”, Diabetes (2006);55: pp. 517–522.
  11. UKPDS, “Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group”, Lancet (1998);352: pp. 854–865.