A new study of pioglitazone (Actos, Takeda Pharmaceuticals) suggests
that it can prevent progression of atherosclerosis and produce
meaningful improvements in cardiovascular risk factors over 18
months, as compared with glimepiride (Amaryl, Sanofi-Aventis) [1].
Experts say results of the Pioglitazone Effect on Regression of
Intravascular Sonographic Coronary Obstruction Prospective
Evaluation (PERISCOPE) trial, presented here at the American College
of Cardiology 2008 Scientific Sessions, raise new questions about
how best to lower blood sugar levels in type 2 diabetics.

Dr Steven Nissen (Cleveland Clinic, OH), who presented the results
during a late-breaking trial session here, called the results
a "huge surprise."

"What we saw was that the people who got one of the most widely used
therapies--glimepiride, a sulfonylurea--had unequivocal progression
of coronary atherosclerosis by [intravascular ultrasound] IVUS,
while pioglitazone had a little less plaque at the end of the study,
and the difference between the two therapies was highly
statistically significant. . . . To our knowledge, this is first
time that a diabetes study has been shown to slow progression of
coronary atherosclerosis."

Nissen emphasized that while no one study should change clinical
practice, particularly one based on a surrogate end point--in this
case, atherosclerosis progression as measured by IVUS. The trial did
not address impact on clinical events. But Nissen also pointed out
that the PERISCOPE results come in the wake of PROACTIVE, which
showed a nonsignificant 10% reduction in its primary end point of
all macrovascular events and a significant 16% reduction in its
secondary end point of death, MI, and stroke with pioglitazone. "I
think the totality of information suggests this is a beneficial
therapy, but PERISCOPE alone doesn't answer all the questions," he
said.

But commenting on the study for heartwire, Dr Roger Blumenthal (John
Hopkins University, Baltimore, MD) warned against making too much of
a small imaging study on top of a larger clinical trial that failed
to meet its primary end point. "We need more supportive data. Right
now the totality of evidence is not enough to change guidelines," he
said. "The chance of this having a significant impact on clinical
practice is the same as a snowball's chance in Hades."

The PERISCOPE results have also been published online March 31, 2008
in the Journal of the American Medical Association.

All eyes on PERISCOPE

In PERISCOPE, 543 patients with type 2 diabetes underwent coronary
IVUS and then were randomized to receive either glimepiride (1-4 mg)
or pioglitazone (15-45 mg) for 18 months, at which time IVUS studies
were repeated. According to study investigators, mean percent
atheroma volume decreased by 0.16% in pioglitazone-treated subjects
but increased by 0.73% in glimepiride-treated patients. When the
analysis was repeated to include patients who had not completed the
study, the results also showed an increase for glimepiride and a
decrease for pioglitazone. Both agents lowered glycohemoglobin and
fasting insulin levels, although pioglitazone's effects on these end
points were statistically greater. Pioglitazone also produced
statistically meaningful changes in HDL and triglyceride levels.

Adverse events in the trial were clearly different between the two
drugs. More patients taking glimepiride developed hypoglycemia and
angina, while patients taking pioglitazone were more likely to
develop edema, gain weight, or suffer bone fractures.

Commenting on the study, Dr Salim Yusuf (McMaster University,
Hamilton, ON) highlighted the fracture results, which occurred in 3%
of the pioglitazone-treated patients.

"This was a significant excess in fractures with pioglitazone, and
no matter how good a surrogate end point, even if it is truly
related to the outcome you're interested in, which may be CV events,
it doesn't tell you the totality of the benefit/risk," he said.

Likewise, Dr Darren McGuire (UT Southwestern, Dallas, TX), speaking
with heartwire, also acknowledged that the fracture rate
was "surprisingly high"--higher than the signal of fracture risk
seen before with this drug.

"I think it is something to pay attention to," he said. "These drugs
are not completely benign, but in total their benefit-to-risk ratio
in select patients remains favorable."

Indeed, McGuire points out that PERISCOPE is not a standalone
imaging study, because of the promising secondary results in
PROACTIVE. "What the PERISCOPE study does is provide proof of
principle that the drug is to some degree modifying atherosclerosis."

Several observers have pointed out that the absolute changes in
atherosclerosis progression are small, a comment Nissen rejects. He
cites research in progress at his own institution that is examining
clinical outcomes in relation to IVUS results from statin trials. "I
can tell you that, with a p value with a lot of zeros before the
one, that changes of around 0.8% to 1.0% are associated with a very
substantial reduction in hard end points across all the trials we've
done. The differences we saw here are really very statistically
robust and they will translate into clinical benefits," he said.

Indeed, an editorial [2] by Drs P Gabriel Steg (Centre Hospitalier
Bichat-Claude Bernard, Paris, France) and Michel Marre (Universite
Paris VII, France) points out that, while small, the apparent affect
of pioglitazone is "well within the range of what is achieved with
some therapies demonstrated to improve cardiovascular outcomes, such
as high-dose statins."

A glimpse of things to come

Following Nissen's presentation, one of the session moderators, Dr
Greg Brown (University of Washington, Seattle), asked Nissen if the
PERISCOPE results have "changed [his] opinion about the glitazone
class," referring to the 2007 hullabaloo over rosiglitazone, sparked
in large part by a meta-analysis that Nissen coauthored.

Nissen called this a "fair question" but emphasized that, while
technically in the same class, rosiglitazone and pioglitazone affect
different genes. "They both affect a gene that is involved in
lowering blood sugar, but they have otherwise extraordinarily
different effects. We have to study each of these compounds
individually."

In the press conference, Nissen acknowledged that he and his
coauthors cannot yet explain the mechanism by which pioglitazone
alters atherosclerosis progression but that its effects on blood
pressure, lipids, triglycerides, and CRP are major candidates. "What
this study now tells us is: we must do a comparator effectiveness
trial looking at different diabetes treatment strategies. We can't
just focus on pricking the finger, getting the blood sugar down, and
saying, that's the goal of therapy. The goal in therapy is to
prevent complications of diabetes, and the most feared, most serious
complication is heart disease, which will kill 75% of diabetics."

Nissen SE, Nicholls SJ, Wolski L, et al. Comparison of pioglitazone
vs glimepiride on progression of coronary atherosclerosis in
patients with type 2 diabetes. JAMA 2008;
DOI:10.1001/jama.299.13.1561. Available at: http://www.jama.com.
Steg PG, Marre M. Does PERISCOPE provide a new perspective on
diabetic treatment? JAMA 2008; 299:1603-1604.