London, UK - Results of a randomized trial of pioglitazone (Actos, Takeda Pharmaceutical Company) in patients with type 2 diabetes at high risk for macrovascular events showed a nonsignificant 10% reduction in the study's primary end point of all macrovascular events vs placebo but found a significant 16% reduction in the secondary composite end point of death, MI, and stroke with pioglitazone treatment [1].

The results, from the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) trial, are published in the October 8, 2005 issue of the Lancet. The findings were presented in September at the 41st meeting of the European Association for the Study of Diabetes (EASD) in Athens, Greece and reported by heartwire at that time.

When the study was presented, Prof Erland Erdmann (University of Cologne, Germany), a principal investigator and member of the study's executive committee, told heartwire that the primary end point was influenced 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, myocardial infarction, and stroke.

The study was funded by Takeda Pharmaceutical Company Ltd and Eli Lilly and Company. First author on the paper is Prof John Dormandy (St George's Hospital, London, UK), chair of the steering committee.

Pioglitazone is a peroxisome proliferator-activated receptor- (PPAR-) agonist used to treat type 2 diabetes. It has a variety of actions that could potentially positively affect cardiovascular risk, including reduction of glucose, triglycerides, and C-reactive protein and raising of HDL.

In this randomized, double-blind, placebo-controlled study, investigators recruited 5238 patients with 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.

HbA1_c had to be above the upper limit of normal despite existing treatment with diet or glucose-lowering agents. Patients receiving insulin as sole 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, sulfonylurea, 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.

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, the main one being the time from randomization to one of all-cause mortality, nonfatal MI, this time excluding silent MI, and stroke.

Mean follow up was 2.8 years; two patients were lost to follow-up. At that point, there was a 10% reduction in the primary end point with pioglitazone therapy, the authors report, a finding that was not statistically significant. However, the principal predefined secondary end point was significantly reduced by pioglitazone treatment by 16%.

"When the protocol was devised, we thought that the need for amputation or cardiac or leg revascularization was likely to indicate macrovascular deterioration and would respond to therapy in a similar way to stroke and myocardial infarction," Dormandy et al write. "The hypothesis did not prove correct in the case of cardiac and leg revascularization, perhaps because these end points are in part determined by the decision to intervene being based on local surgical or medical practice," they point out.

Metabolic effects of the drug relative to placebo included a decrease in HbA1_c, a 50% reduction in progression to permanent insulin use, improved diabetic dyslipidemia including an increase in HDL, and a reduction in blood pressure.

Overall safety and tolerability of the drug was good, they report, with no change in the known safety profile of pioglitazone identified. There was a significantly higher number of reported but unadjudicated heart-failure events with pioglitazone (p<0.0001) and hospitalization for heart failure (p=0.007), but mortality rates from heart failure were similar between groups, they write.

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 judged that these tumors "could not plausibly" be related to treatment, the authors write, leaving six cases in the pioglitazone-treated patients vs three in the placebo group. Of these, four and two patients in each group had other risk factors that could account for their cancer.

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.

Dormandy et al conclude that adding pioglitazone to the medications of 1000 patients would avoid 21 first myocardial infarctions, deaths, or strokes over three years. "In other words, 48 patients would need to be treated for three years to avoid one first major cardiovascular event."

Dr Hannele Yki-Järvinen (University of Helsinki, Finland) was the invited discussant when the PROactive results were presented at the EASD meeting and also the author of a Commentary article that accompanied the trial's publication [2].

In her editorial, Yki-Järvinen says that this "important study leaves us with some good news, some bad news, and some unknowns."

The good news is that pioglitazone reduced the composite of all-cause mortality, nonfatal MI, and stroke in this population; she called the inclusion criteria "brave," as these patients had extensive evidence of macrovascular disease; one third were on insulin and were already taking drugs known to reduce the risk of CVD. In addition, patients with liver-enzyme elevations were excluded. "This principle might have excluded patients who respond best to glitazones, as the main mechanism of action of these drugs is a reduction in the fat content of the liver and in hepatic insulin resistance," she writes.

From the patient's perspective, is it better to have healthy arteries in the heart than a failing heart?

However, she expressed greater concern about the increase in heart failure as well as edema not associated with heart failure that was seen with pioglitazone treatment, the "bad news." In her talk at the time of the presentation, she joked that her views might cause her to "lose my contacts with the company that sponsored the study."

The question she raises is the overall impact of pioglitazone on health—there were 58 fewer primary end points with pioglitazone but 115 more heart failures and 221 more episodes of edema. "From the patient's perspective, is it better to have healthy arteries in the heart than a failing heart?" she writes, pointing out the prognosis of heart failure is particularly poor in patients with type 2 diabetes.

"When presenting the results, the investigators emphasized that heart failure was not a centrally adjudicated event and that increased reporting of heart failure was at least partly caused by a diagnostic bias because of increased edema," Yki-Järvinen points out. "The cardiologists were keen to comment that heart failure induced by pioglitazone is not as dangerous as other types of heart failure, although no data are presented to support this comment in the study."

In addition, more weight gain was seen with pioglitazone that could further increase the risk of heart failure. Some of the patients were also taking both insulin and glitazones, a combination that is contraindicated in Europe because of an increased risk of heart failure; it would have been informative to have stratified patients at baseline on whether or not they were on this combination, she noted.

"The clinician, of course, wants to know who should be treated with pioglitazone," Yki-Järvinen concludes. "Unfortunately, the study does not provide such answers. It showed that pioglitazone is beneficial in patients with type 2 diabetes and preexisting macrovascular disease who do not develop heart failure."