PROactive: Pioglitazone reduces CAD events in patients with diabetes

Susan Jeffrey

September 12, 2005

Athens, Greece - Results of a randomized trial of pioglitazone in high-risk patients with type 2 diabetes showed a nonsignificant 10% reduction in the study's primary end point of all macrovascular events[1]. However, there was a significant 16% reduction in the secondary end point of death, MI, and stroke with treatment.

Prof Erland Erdmann (Source: https://www.proactive-results.com)

The results, from the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive), were presented today at the 41st meeting of the European Association for the Study of Diabetes (EASD).

Prof Erland Erdmann (University of Cologne, Germany), a principal investigator and member of the study's executive committee, told renalwire that the primary end point was affected by a lack of effect on end points such as amputation above the ankle and revascularization of peripheral arterial disease. "My feeling is that the most important thing is that the trial was positive on end points that there is no debate about," he said, that is, the secondary "hard" end points of death, MI, and stroke.

The study was funded by Takeda Pharmaceutical Company Ltd, maker of pioglitazone (ACTOS), and Eli Lilly and Company.

High-risk patients

The PROactive study was a randomized, double-blind, placebo-controlled outcomes study in 5238 patients with type 2 diabetes at high risk for cardiovascular events because of the presence of macrovascular disease, including previous stroke, MI, revascularization, or peripheral artery disease, and objective evidence of coronary artery disease. Erdmann, who presented the study design and background in Athens, told renalwire that the estimated risk for cardiovascular events in these patients was approximately 6% per year.

HbA1c had to be above the upper limit of normal despite existing treatment with diet or glucose-lowering agents. Patients receiving insulin as their only therapy were excluded, but insulin could be used in combination with oral glucose-lowering drugs.

The study randomized patients to placebo or to 45 mg/day of pioglitazone in addition to standard medications in accordance with guidelines, including use of antihypertensive medications such as ACE inhibitors and beta blockers; glucose-lowering medications such as metformin, sulfonylureas, and insulin; antiplatelet drugs including aspirin; and lipid-lowering medication including statins and fibrates. "We in fact encouraged the investigators during the study to improve treatment," Erdmann noted, pointing out that the use of statins, for example, increased from 43% at baseline to 55% at study end.

Prof John Dormandy (Source: https://www.proactive-results.com)

The primary end point was the time from randomization to one of a composite end point including all-cause mortality, nonfatal MI (including silent MI), stroke, major leg amputation (above the ankle), acute coronary syndrome, cardiac intervention including CABG or PCI, or leg revascularization. Secondary end points were prespecified, he noted. The "principal" secondary end point was the time from randomization to one of all-cause mortality, nonfatal MI, this time excluding silent MI, and stroke. This secondary end point was selected, Erdmann said, because it was "less dependent on the decision of the treating doctor."

Results were presented by Prof John Dormandy (St George's Hospital, London, UK), chair of the steering committee. Mean follow-up was 2.8 years; only two patients were lost to follow-up. Pioglitazone 45 mg was well tolerated by 93% of patients, he noted.

There was a 10% reduction in the primary end point with pioglitazone therapy, Dormandy noted, a finding that was not statistically significant. "Interestingly, this does not mean that pioglitazone did not significantly benefit patients in terms of serious macrovascular events," he said. The principal predefined secondary end point was significantly reduced by pioglitazone treatment by 16%.

PROactive: Primary and secondary end points

End point Placebo, n (%) Pioglitazone, n (%) HR (95% CI) p
Primary composite end point 572 (23.5) 514 (21.0) 0.904 (0.802-1.018) 0.0951
Death, MI (excluding silent MI) and stroke 358 (14.4) 301 (12.3) 0.841 (0.722-0.981) 0.0273

"We believe that from the patient's point of view it is this 16% reduction in death, MI, and stroke that really matters," Dormandy said. The effect appeared to persist across subgroups, he noted.

Metabolic and safety data

Metabolic effects of the drug relative to placebo, presented separately, included a decrease in HbA1c, a 50% reduction in progression topermanent insulin use, improved diabetic dyslipidemia, including an increase in HDL, and a reduction in blood pressure.

Dr Pierre Lefèbvre (Source: https://www.proactive-results.com)

Adverse events with treatment were presented by Dr Pierre Lefèbvre (CHU, France). Any serious adverse event occurred in 46.2% of pioglitazone patients, compared with 48.4% of placebo patients.

We believe that from the patient's point of view it is this 16% reduction in death, MI, and stroke that really matters.

Heart failure (HF) occurred more often with pioglitazone, in 5.7% of patients compared with 4.1% of placebo patients. "It should be noted that all of these end points were not adjudicated by the end-point adjudication committee," Lefebvre said. "Heart failure may have been to a certain extent overdiagnosed in pioglitazone-treated patients due to the increased incidence of edema," he said. However, HF death was similar between groups.

PROactive: Heart-failure events

End point Pioglitazone, n (%) Placebo, n (%)
Reported HF (nonadjudicated) 281 (10.8) 198 (7.5)
HF leading to hospitalization 149 (5.7) 108 (4.1)
HF leading to death 25 (0.96) 22 (0.84)

There was no difference in the total number of malignancies between groups, but bladder cancer occurred in 14 patients on pioglitazone vs six cases with placebo. Two independent experts examined these data and suggested that since eight patients in the pioglitazone group and three in the placebo group had their bladder cancer diagnosed when they had been treated for less than one year, it was "extremely unlikely" there was a causal link between the two events, Lefebvre said, leaving six cases in the pioglitazone-treated patients vs three in the placebo group.

Pioglitazone treatment was also associated with more nonserious hypoglycemia, edema in the absence of heart failure, and weight gain leading to cessation of the drug. There was no increase in liver enzymes with treatment.

Summing up the findings, Dormandy said, "Adding pioglitazone to the medications of 1000 patients would avoid 21 first myocardial infarctions, deaths, or strokes over three years. Or in other words, 48 patients would need to be treated for three years to avoid a first major cardiovascular event."

Erdmann speculated on the mechanism of additional benefit seen with the addition of pioglitazone to standard treatments in these high-risk patients. "I can only speculate, but this drug lowers glucose, increases HDL, lowers the triglycerides, lowers inflammation and CRP, and decreases the intima-medial thickness of the arteries," he told renal wire . "So it has many actions that we thought before making the study might be beneficial."

A webcast and the full results of the study are available at https://www.proactive-results.com, a website supported by an unrestricted grant by Takeda/Eli Lilly.

The "next big thing"

Dr Christopher P Cannon (Harvard Medical School, Brigham and Women's Hospital, Boston, MA) told renal wire , "Based on this landmark trial, I think the use of 'glitazones may be the 'next big thing' in the treatment of atherosclerosis. This class of drugs has a profound (40%-50%) reduction in CRP, and this may be one of the mechanisms by which the benefit is achieved."

"We all look forward to learning more," he added, "but we all need to look very carefully at this 'sea-change' trial."

Erdmann received an honorarium for acting as a member of the study's executive committee but reports he has no other financial interest.



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