ArticlesSecondary 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
Introduction
Patients with type 2 diabetes are at high risk of fatal and non-fatal macrovascular events. These events are the main reason for their decreased life expectancy, which is about 8 years shorter in a 40-year-old patient newly diagnosed with diabetes than in the general population.1 There is a two-fold to four-fold increased risk of a macrovascular event in patients with, compared with those without, diabetes.2, 3 Haffner and colleagues4 noted that the risk of a cardiovascular complication in a patient with diabetes was similar to that of a patient without diabetes who had had a myocardial infarction. In the Heart Protection Study,5 patients with diabetes and a history of cardiovascular disease at entry had almost a three-fold higher risk of a new cardiovascular event than did those without such a history.
Intensive control of glycaemia decreases microvascular complications, such as retinopathy and nephropathy, but has no great effect on macrovascular complications or all-cause mortality. However, in the UK prospective diabetes study (UKPDS),6 findings of a retrospective analysis in a subgroup of 342 overweight patients who received metformin showed a significant decrease in cardiovascular disease and total mortality.
Pioglitazone is an agonist of peroxisome proliferator-activated receptor γ (PPAR γ) used to treat type 2 diabetes.7 The overall pattern of changes induced by pioglitazone suggests a general improvement in various risk factors that might reduce cardiovascular morbidity and mortality. Additionally, pioglitazone reduces the levels of various inflammatory markers, such as highly sensitive C-reactive protein (hsCRP), independently of its effect on glycaemic control.8
Our aim was to ascertain whether pioglitazone reduces cardiovascular morbidity and mortality in patients with type 2 diabetes, and to assess the safety and tolerability of such treatment.
Section snippets
Patients
The PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) protocol has been described in detail previously.9 Between May, 2001, and April, 2002, we recruited patients from primary-care practices and diabetic or cardiovascular specialist departments in hospitals to a randomised controlled trial. We included patients with type 2 diabetes who were aged 35–75 years if they had an haemoglobin A1c (HBA1c) concentration greater than the local laboratory equivalent of 6·5% for a
Results
Figure 1 shows the trial profile. 5238 patients from 321 centres in 19 European countries were randomly assigned to either pioglitazone (n=2605) or placebo (n=2633); 1681 patients were recruited from the community and 3557 from hospitals. All patients commenced study medication and all received their intended treatment. 16% of patients assigned pioglitazone and 17% of those assigned placebo discontinued study medication before death or final visit (figure 1). We completed final visits between
Discussion
Our findings show that pioglitazone non-significantly reduces the risk of the composite primary endpoint—death from any cause, non-fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, leg amputation, coronary revascularisation, or revascularisation of the leg. The pre-defined main secondary endpoint—all-cause mortality, myocardial infarction, or stroke—was also reduced, significantly, in the pioglitazone group. Kaplan-Meier estimates indicate
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