Atherosclerosis progression as gauged by intravascular ultrasound
(IVUS) was unaffected by a year and a half of treatment with
rosiglitazone (Avandia, GlaxoSmithKline), compared with more
conventional treatment with the sulfonylurea glipizide (Glucotrol,
Pfizer) in diabetics with CV disease, reported investigators at the
American Heart Association 2008 Scientific Sessions [1].

In their international trial, called Assessment on the Prevention of
Progression by Rosiglitazone on Atherosclerosis in Type 2 Diabetes
Patients with Cardiovascular History (APPROACH), there were no
suggestions of any of a host of potential clinical hazards and
adverse effects that have been attributed to rosiglitazone over the
past 18 months, as covered extensively by heartwire. In particular,
the trial, with fewer than 700 patients, showed no significant
differences between the two antidiabetic therapies with respect to
risk of CV death, new MI, heart failure, peripheral edema, or bone
fracture.

Despite the trial being negative for its primary end point, its
investigators pointed to secondary suggestions that the controversial
thiazolidinedione (TZD) may have had an antiatherosclerotic effect
among the trial's CV patients with more established diabetes.

"I do think it's reassuring as far as the effect of the drug on the
coronary arteries," APPROACH principal investigator Dr Richard W
Nesto (Lahey Clinic Medical Center, Burlington, MA), who presented
the trial at the meeting, said at a press conference. The data
suggest that rosiglitazone is not proatherosclerotic, at least, "and
I think the data suggest it could be antiatherosclerotic."

Also at the press briefing, Dr Beatriz Rodriguez (Pacific Health
Research Institute, Honolulu, HI), the assigned discussant for
Nesto's formal presentation, acknowledged the recent controversies
about rosiglitazone, including suggestions in a controversial meta-
analysis from 2007 that suggested the drug increases the risk of MI
and CV death. APPROACH, on the other hand, "suggests that
rosiglitazone may be associated with a reduction in the total
atheroma volume," she said, referring to another secondary
observation. "But we need to be cautious with this interpretation."

APPROACH randomized 672 patients with type 2 diabetes and indications
for coronary angiography or PCI, at least one clinically significant
coronary lesion, and 10% to 50% narrowing of at least one untreated
coronary artery. They could be on up to three antidiabetic agents and
had to have an LVEF of at least 40% and be free of heart failure.

Among the 339 patients who received glipizide at 15 mg/day and the
333 who took rosiglitazone at up to 8 mg/day, 54% were on one and 28%
were on two other antidiabetic agents. Other medication use by the
end of the trial included aspirin in about 84%, beta blockers in 67%,
ACE inhibitors or angiotensin-receptor blockers in about 74%, statins
in about 80%, and metformin in about 66% of patients.

When atherosclerosis progression over 18 months was measured in terms
of "percent atheroma volume" (PAV) in the study's primary analysis,
there was no significant difference between the treatment groups.

There were no significant differences in a composite clinical end
point that included death from any cause, nonfatal MI, or stroke,
revascularization, or hospitalization for ischemia; a composite end
point including CV death or nonfatal MI or stroke; death from any
cause; or new congestive heart failure, Nesto reported.

Prespecified subgroup analyses suggested that any rosiglitazone
antiatherosclerotic effect may be stronger in patients with longer-
established diabetes, and there was a favorable trend in older
patients.

Neither APPROACH nor another study that used IVUS to assess disease
progression in TZD-treated diabetics with CV disease, called
PERISCOPE, were large enough to say much conclusively about the
drugs' safety or efficacy in that population, Dr Mark A Creager
(Brigham and Women's Hospital, Boston, MA), who wasn't part of either
trial, told heartwire. Creager has been a member of the writing
committees for a range of guidelines from the North American
cardiology societies on the use of coronary interventions and the
treatment of acute coronary syndromes and arrhythmic and valvular
diseases.

As reported by heartwire, PERISCOPE tracked the same IVUS metric used
in APPROACH in 543 patients treated with either pioglitazone (Actos,
Takeda Pharmaceuticals) or the sulfonylurea glimepiride (Amaryl,
Sanofi-Aventis). But unlike APPROACH, the trial showed a significant
slowing of atherosclerosis progression compared to the more
traditional drug.

Nesto RW. Assessment on the Prevention of Progression by
Rosiglitazone on Atherosclerosis in Type 2 Diabetes patients with
Cardiovascular History (APPROACH). American Heart Association 2008
Scientific Sessions; November 12, 2008; New Orleans, LA. Late
Breaking Clinical Trials Session 4.