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Clinical Question: Is Pioglitazone reduce fatal and
non-fatal myocardial infarction (MI), and stroke in patient with type 2
diabetes mellitus?
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: 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.Dormandy JA,
Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM,
Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L,
Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, Laakso M, Mokan M,
Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz
O, Skrha J, Smith U, Taton J; PROactive investigators.
Study Design: Randomised Controlled Trial (prospective)
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. They 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.
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