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.

PROactive investigators have evaluated whether Pioglitazone ( Actos ) reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes.

A prospective, randomised, controlled trial enrolled 5238 patients with type 2 diabetes who had evidence of macrovascular disease.

Patients were assigned to oral Pioglitazone titrated from 15 mg to 45 mg ( n=2605 ) or placebo ( n=2633 ), to be taken in addition to standard therapy.

The 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.
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; 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; p=0.027 ).

Six percent ( 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.

According to authors, 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.

Nick Freemantle, an editorial adviser to the British Medical Journal, has expressed reservations about the study’s conclusions.

Members of the steering committee of the prospective Pioglitazone clinical trial in macrovascular events ( PROactive ) presented the results at the European Association for the Study of Diabetes meeting in Athens. The audience, which overflowed from the meeting room, heard John Dormandy, chair of the steering committee, conclude that the trial had shown that Pioglitazone, " Reduces the composite of all cause mortality, non-fatal myocardial infarction, and stroke." He commented: " We have now shown for the first time that oral glucose lowering medication can prevent macrovascular events."
The audience seemed excited by these results and a consensus emerged that the results would change practice.
The presentation was certainly positive and upbeat. Unfortunately, these conclusions are not based on robust standards for the interpretation of evidence from clinical trials.

According to Freemantle:

- the results for the primary composite outcome measure were insignificant, and

- conclusions based on the secondary outcome do not have sufficient statistical strength to prove an association.

“ … if Pioglitazone really reduces macrovascular events, it is surprising that it had no effect on all cause mortality, especially given that over 350 deaths were observed in the trial, “ Freemantle said.

Source:

1) The Lancet, 2005

2) British Medical Journal, 2005


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