Elsevier

The Lancet

Volume 366, Issue 9493, 8–14 October 2005, Pages 1279-1289
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(05)67528-9Get rights and content

Summary

Background

Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor γ (PPAR γ) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes.

Methods

We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993.

Findings

Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34·5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0·90, 95% CI 0·80–1·02, p=0·095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0·84, 0·72–0·98, p=0·027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups.

Interpretation

Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.

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

References (18)

  • MN Feinglos et al.

    Therapy of type 2 diabetes, cardiovascular death, and the UGDP

    Am Heart J

    (1999)
  • NA Roper et al.

    Excess mortality in a population with diabetes and the impact of material deprivation: longitudinal, population based study

    BMJ

    (2001)
  • J Stamler et al.

    Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Interventional trial

    Diabetes Care

    (1993)
  • K-T Khaw et al.

    Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and Nutrition (EPIC-Norfolk)

    BMJ

    (2001)
  • SM Haffner et al.

    Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction

    N Engl J Med

    (1998)
  • MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial

    Lancet

    (2003)
  • Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)

    Lancet

    (1998)
  • H Yki-Jarvinen

    Drug therapy: thiazolidinediones

    N Engl J Med

    (2004)
  • A Pf˚tzner et al.

    Improvement of cardiovascular risk markers by pioglitazone is independent from glycemic control: results from the Pioneer study

    J Am Coll Cardiol

    (2005)
There are more references available in the full text version of this article.

Cited by (0)

Investigators listed at end of paper

View full text