Proactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) study

PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events)

• aimed to find out whether pioglitazone reduced cardiovascular (CV) morbidity and mortality in high-risk patients with type 2 diabetes
• randomised controlled trial in 5,238 patients with type 2 diabetes and existing CV disease, excluding patients with heart failure (1)
  • patients were randomised to pioglitazone (titrated from 15mg to 45mg) or placebo, taken in addition to their existing glucose-lowering and other medications
  • average follow up was 34.5 months
  • primary endpoint was a composite of all-cause mortality, non-fatal myocardial infarction (MI), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle
• study results:
  • no statistically significant difference between the groups in the primary composite endpoint: 19.7% of patients in the pioglitazone group and 21.7% of patients in the placebo group had at least one primary event (HR 0.90, 95% CI 0.80-1.02, P=0.095)
  • a statistically significant difference between the groups in the main secondary endpoint, a composite of all-cause mortality, non-fatal MI and stroke. In the pioglitazone group 11.6% of patients had one of these events, compared with 13.6% in the placebo group (HR 0.84, 95% CI 0.72-0.98, P=0.027, NNT=49). This means that 49 patients would need to be treated with pioglitazone, together with glucose-lowering and other medications, for 34.5 months, to prevent one person experiencing death, nonfatal MI or stroke
  • no significant difference between pioglitazone and placebo in the overall incidence of serious adverse events (46% vs. 48%, respectively, P=0.110)
    • however, the number of patients with heart failure increased significantly with pioglitazone compared to placebo (10.8% vs. 7.5%, p<0.0001, NNH=31) i.e. for every 31 patients treated with pioglitazone for 34.5 months, one suffered heart failure (mortality rates from heart failure did not differ significantly between the groups)
• interpretation of results:
  • the study was only powered for analysis of the primary endpoint and conclusions based on a secondary outcome should normally only be used to generate, not prove, a hypothesis - it remains uncertain whether pioglitazone reduces the risk of death, MI and stroke in patients with type 2 diabetes who are already at high risk of these events (2)
  • on examination of the patients entered onto the study it should be noted that there were risk factors that could have been addressed in terms of reducing their CV risk e.g. mean body mass index was >30kg/m2, over 13% were smokers, 71% had blood pressure >140/85 mmHg, only 43% were taking a statin

Applicability to clinical practice in the UK:

• note that in over 30% of patients treated with pioglitazone, they were also treated with insulin (+/- metformin, +/- sulphonylurea) which, at the time of publication, was not a licensed combination in the UK

Notes:

• "...the interpretation of the effect of pioglitazone therapy is further complicated by the 0.6% difference in HbA1c between the 2 groups. Although glycaemic control generally has not been shown to reduce macrovascular events, it is clear that the placebo group did not have adequate glycaemic therapy to match that of the active treatment group... see this study primarily as a confirmation of concerns about fluid retention and weight gain with glitazones, and not about clear evidence of cardivoascular event reduction ....(4)"
• a review concerning the use of pioglitazone in diabetes management has been undertaken (5)
  • twenty-two trials which randomised approximately 6200 people to pioglitazone treatment were identified
    • longest duration of therapy was 34.5 months
    • published studies of at least 24 weeks pioglitazone treatment in people with type 2 diabetes mellitus did not provide convincing evidence that patient-oriented outcomes like mortality, morbidity, adverse effects, costs and health-related quality of life are positively influenced by this compound
    • HbA1c as a surrogate endpoint did not demonstrate clinically relevant differences to other oral antidiabetic drugs. Occurrence of oedema was significantly raised
    • results of the single trial with relevant clinical endpoints (PROactive study) have to be regarded as hypothesis-generating and need confirmation
    • authors concluded that until new evidence becomes available, the benefit-risk ratio of pioglitazone remains unclear

Reference:

1. Dormandy JA 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 Oct 8;366(9493):1279-89.
2. MeReC Extra (January 2006); 20:1
3. Isley WL. Commentary. Evidence Based Medicine 2006;11:47.
4. Richter B et al. Pioglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD006060