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Clinical Question:
Does pioglitazone (Actos) reduce macrovascular morbidity and mortality in
high-risk patients with type 2 diabetes?
Bottom Line:
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.
Reference:
Dormandy JA, Charbonnel B, Eckland DJ, et al, for the PROactive
investigators. 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;366:1279-89.
Study Design:
Randomized controlled trial (double-blinded)
Synopsis:
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 gamma (PPAR gamma) 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. 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. 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. |