Cardiovascular Risk, Diabetes
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The PROactive and DREAM Studies

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Published Online: Jun 6th 2011 US Endocrinology, 2006;(2): DOI:
Authors: Roy Taylor
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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.


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. The good news from PROactive concerns the lack of serious side effects. Eighty-nine per cent of patients tolerated the 45mg daily dose of pioglitazone. There was no difference in fatal heart failure (1% in each group) although confusion has been caused by referring to ankle edema as ‘heart failure.’ By using such loose terminology, the significant difference in ‘any heart failure’ (11% versus 8%) has been taken to suggest that pioglitazone harmed more people than it saved.4 This does not reflect real clinical experience. A small and non-significant excess of bladder tumors did not allow a conclusion of any direct effect of pioglitazone, but longer-term data are required.

One other point deserves mention.The associated army of statisticians and trialists stopped the trial early (34.5 instead of 48 months) and this prevented the primary end-point reaching significance, assuming the observed trends continued. Although this would hardly change the practical interpretation of the study results, this error seems curious.

This study arose from the claim made by the investigators in the Heart Outcomes Prevention Evaluation (HOPE) study that ramipril decreased the rate of developing diabetes;5 and this was one of a number of unsupportable claims from that study.6,7 Placebo-treated patients were admitted to the hospital more, and hence had more blood glucose testing and more discovery of asymptomatic diabetes.8 In DREAM,the chance of detecting any effect upon rate of development of diabetes was maximized by using a very large dose of ramipril (15mg), 50% more than that licensed in the UK. In view of the interest in PPARγ agonists potentially acting upon the pancreas to prevent the development of diabetes,9,10 DREAM was set up with a 2×2 design to test the effect of both ramipril and rosiglitazone. The study population comprised people with impaired glucose tolerance or impaired fasting glucose.

The high dose of ACE inhibitor had no effect on the rate at which diabetes developed (18.1% versus 19.5%). Use of the glucose lowering agent rosiglitazone brought about lowering of glucose (10.6% versus 25.0% crossed the threshold for diabetes).This effect could have hardly surprised the investigators. It is, after all, what oral hypoglycemic agents are designed to do. The only conceivable interest will come from analysis of the wash-out phase of the study, as a biologically important effect of three years’ treatment with PPARγ agonist on β-cell function should persist at least for two months after the hypoglycemic agent is withdrawn.This analysis has been promised. It should be noted that in this three-year study there was no effect of PPARγ agonist on cardiovascular events (2.9% on rosiglitazone and 2.1% on placebo).

What do the Results Mean for PPARγ Agonists?
These agents are generally well tolerated, although weight gain is problematic in some patients and ankle edema is sometimes troublesome. Both of these effects were known before.

Pioglitazone has a small effect upon the rate of development of macrovascular disease additional to statins, antihypertensives, and aspirin.

Rosiglitazone lowers blood glucose, but the concept of using this drug on asymptomatic people who may spontaneously revert to normal glucose tolerance does not stand up to close examination.

Implications for Clinical Practice
Even though hindsight is a wonderful thing, it has to be said that the basic questions posed by each of these highly expensive studies were not well thought through. If a group of practicing physicians had been consulted in advance, they may have pointed out issues of real clinical importance that required addressing. For instance, as metformin is thought to confer some advantage in preventing coronary heart disease,11 a direct comparison with pioglitazone as monotherapy would be important.The lack of benefit of rosiglitazone on macrovascular events, albeit in a low-risk population, raises the issue of the deleterious effect of this agent upon plasma lipids in contrast to the beneficial lipid effects of pioglitazone.

Practicing diabetologists may well view these two trials as being divorced from clinical practice, merely the spoor of evidence-based gurus in pursuit of evidence.


  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.

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