CHICAGO: Pioglitazone Slows Progression of Carotid Atherosclerosis vs Glimepiride

Susan Jeffrey

November 13, 2006

November 13, 2006 (Chicago) — Results of a head-to-head comparison of 2 antidiabetes drugs have shown an advantage for pioglitazone ( Actos, Takeda Pharmaceuticals North America) over glimepiride ( Amaryl, Anakena Healthcare) in reducing progression of carotid intima-media thickness (CIMT) in patients with type 2 diabetes. After 18 months of treatment, both mean and maximal progression of CIMT was significantly less among patients receiving pioglitazone compared with those on glimepiride.

Results of the Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone (CHICAGO) study are published online November 13 in the Journal of the American Medical Association to coincide with presentation here at the American Heart Association 2006 Scientific Sessions.

"What this means is that pioglitazone could be part of a novel strategy to manage residual cardiovascular risk in patients with type 2 diabetes," Theodore Mazzone, MD, from the University of Illinois College of Medicine, in Chicago, principal investigator for the trial, told a press conference here.

The study was funded by Takeda Pharmaceuticals North America Inc.

Different Mechanisms

CIMT is a marker of coronary atherosclerosis and predicts subsequent cardiovascular events, the authors write. Both pioglitazone, a thiazolidinedione, and glimepiride, a sulfonylurea, are antidiabetic agents and about equally efficacious in reducing blood glucose but work through different mechanisms, Dr. Mazzone said.

Pioglitazone, though, has other effects that might be expected to translate into potential reduction of cardiovascular risk, including reductions in markers of systemic inflammation and fatty-acid levels, he noted. Thiazolidinediones have also been shown to reduce atherosclerotic plaque in animals independently of glucose or lipid levels.

The CHICAGO study was a randomized, double-blind, comparator-controlled trial, conducted at 28 clinical sites in a multiracial/ethnic Chicago metropolitan area. The 462 patients with type 2 diabetes were randomized to receive 72 weeks of treatment with 1 of 3 doses of each agent: 15 to 45 mg per day of pioglitazone, or 1 to 4 mg per day of glimepiride, titrated to the HbA1 c target.

Patients had a mean duration of diabetes of 7.7 years and a mean HbA1 c value of 7.4%, indicating well-controlled diabetes. Blood pressure was also well controlled, and about 55% of both groups were receiving statins. They were either newly diagnosed or treated at enrollment with diet and exercise, sulfonylurea, metformin, insulin, or a combination of agents. Patients were excluded if they already had significant cardiovascular or cerebrovascular disease.

CIMT images were captured by a single ultrasonographer at 1 center and read by a single reader blinded to treatment assignment using automated edge-detection technology.

The main outcome measure was the absolute change from baseline to the final visit at 72 weeks in the mean posterior-wall CIMT of the left and right common carotid arteries.

Dr. Mazzone reported that CIMT was less with pioglitazone vs glimepiride at all time points — weeks 24, 48, and 72. The primary end point of progression of mean CIMT was less with pioglitazone, with a difference between groups of 0.013 mm favoring the pioglitazone group.

CHICAGO: Progression of Mean CIMT at Week 72 With Pioglitazone vs Glimepiride

End Point
Pioglitazone
Glimepiride
Difference (95% CI)
P
Primary end point (mm)
-0.001
+0.012
-0.013 (-0.024 to 0.002)
.02

Similarly, pioglitazone slowed progression of maximum CIMT compared with glimepiride.

CHICAGO: Progression of Maximum CIMT at Week 72 With Pioglitazone vs Glimepiride
End Point
Pioglitazone
Glimepiride
Difference (95% CI)
P
Progression of maximum CIMT (mm)
+0.002
+0.026
-0.024 (-0.042 to 0.006)
.008

The beneficial effect of treatment was similar across prespecified subgroups based on age, sex, systolic blood pressure, duration of diabetes, HbA1 c value, and statin use, Dr. Mazzone noted.

There was a highly significant increase in HDL cholesterol seen with pioglitazone, "and this certainly could have contributed to the beneficial effects on CIMT that we observed," he said. There was also a significant decrease in triglycerides in the pioglitazone group.

Adverse events occurred in approximately 89% of patients in both groups; serious adverse events occurred in 25 of the pioglitazone patients (10.9%) vs 30 (13.2%) of those taking glimepiride.

The study was not powered to look at clinical outcomes, Dr. Mazzone stressed. There was 1 death in the study that occurred in the pioglitazone group, an 80-year-old woman who died of pancreatic cancer.

A numerically higher incidence of clinical events occurred in the glimepiride group (10, vs 4 in the pioglitazone group), with coronary revascularization accounting for most of these events, 8 and 3 revascularizations in the groups, respectively. There was 1 nonfatal MI and 1 nonfatal stroke with glimepiride.

Congestive heart failure occurred in 1 pioglitazone patient, an effect that has been seen and caused some concern in other trials of this agent. Peripheral edema and weight gain were also more common with pioglitazone, as was previously observed, he added.

Not a Clear-Cut Answer

The PROactive trial, comparing pioglitazone with placebo in addition to usual care, published last year, was powered to look at clinical end points (Dormandy JA et al. Lancet. 2005;366:1279-1289). "PROactive showed a significant effect in its principal secondary end point (death, MI, and stroke)," Dr. Mazzone told Medscape, "but because the primary end point (a composite end point that included peripheral artery revascularization end points) was not positive, it wasn't as clear-cut an answer as we'd like. So we need additional data from studies like CHICAGO and PERISCOPE. Had we found no effect on CIMT, I think it would have been more difficult to accept the positive end-point results in PROactive."

He said it was unlikely, however, that there will be more definitive end-point trials with pioglitazone. "So what we're going to be left with as clinicians is that we’re going to have to assess the best evidence out there for clinical end points and for surrogates — and we do this all the time when we decide about the use of drugs in individual patients, to decide on the benefits and costs for each patient and move on from there."

Reassuring Signals

Invited discussant for the trial here was Peter Wilson, MD, from Emory University in Atlanta, Georgia. He felt that CHICAGO had fairly answered the question it set out to address and that the results are believable based on previous evidence.

The results also provide more data on safety concerns that had been raised with this agent: peripheral edema and weight gain was seen more often, but there was no liver toxicity, which he said was reassuring, given the previous experience with troglitazone, which was withdrawn from the market.

In terms of the heart failure finding, Dr. Wilson pointed out, the CHICAGO investigators "preselected a group that were not likely to get into heart failure concerns, so perhaps this opens the window a little wider to where we can use these agents."

He advocated further research with these agents to prevent atherosclerotic progression, including more trials with clinical end points and focusing on other vascular territories.

Asked for comment by Medscape, cardiologist Darren McGuire, MD, from the University of Texas Southwestern, in Dallas, called the results "a very favorable signal in the right direction, especially with the apparent safety demonstrated regarding the very low incident CHF."

However, Dr. McGuire pointed out that although IMT is validated as a marker of risk, it is not a validated surrogate, as it was described in the presentation. "To validate the surrogate would require parallel data on clinical outcomes tracking concordantly with the IMT change," he pointed out. With the exception of LDL cholesterol, there are no other validated surrogates in cardiovascular medicine, "so it's unlikely, but not impossible, that IMT change will prove to be another."

Up PERISCOPE

An ongoing study of pioglitazone, called PERISCOPE, is using intravascular ultrasound to look at atherosclerotic progression in coronary arteries. PERISCOPE is also funded by Takeda, and the principal investigator is Steve Nissen, MD, from the Cleveland Clinic Foundation in Ohio.

Dr. Nissen declined to comment on the CHICAGO results because of his participation in the PERISCOPE trial but pointed out that while PERISCOPE is very similar in design, it is being conducted in a secondary-prevention and therefore higher-risk cohort.

Like CHICAGO, PERISCOPE is not powered to assess clinical end points, but events are nevertheless being adjudicated. "They had an interesting trend, and you could expect us to probably combine the 2 trials to look at clinical outcomes, which gives us a little more power," Dr. Nissen noted. PERISCOPE is expected to report at the American College of Cardiology meeting in 2008, he said.

John Yates, MD, president of Takeda Pharmaceuticals global research and development, confirmed to Medscape that no further end-point trials are planned with pioglitazone. "However, we are actively performing a meta-analysis to examine at all the randomized controlled studies that have been sponsored by Takeda to look specifically at the question of whether cardiovascular events occur less frequently in patients on pioglitazone relative to a comparator agent. That study is ongoing, and we hope to have the data to present and publish in the near future."


In JAMA, Dr. Mazzone reports serving as a consultant for Amylin, Merck, Novartis, Pfizer, and Takeda and receiving speaking honoraria from Merck, Novartis, Pfizer, and Takeda. Disclosures for the coauthors appear in the paper.


JAMA . Published online November 13, 2006.

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