November 14, 2008 (New Orleans, Louisiana) — 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 .
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.
Change in Volumetric End Points by IVUS in Glipizide and Rosiglitazone Groups
|End point||Glipizide, n=339||Rosiglitazone, n=333||Difference||p|
|Change in PAV* (%)||+0.43||-0.21||-0.64||0.12|
|Change in atheroma volume (mm3)||+1.2||-3.9a||-5.2||0.04|
|Change in atheroma volume (at the most diseased 10-mm vessel segment) (mm3)||-3.6b||-5.3b||-1.7||0.13|
*Primary end point PAV=percent atheroma volume a. p=0.05 vs baseline b. p<0.0001 vs baseline
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.
Subgroups Showing Primary-End-Point Differences Between Rosiglitazone and Glipizide Groups
|Subgroup||Difference between treatments (mm3) (95% CI)||p|
|Age >60 y||-1.39 (-2.54 to -0.25)||0.07|
|Diabetes duration longer than median of 4.9 y||-1.83 (-2.98 to -0.69)||0.005|
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.
Adverse Effects in APPROACH
|Mean weight change vs baseline (kg)||1.4||2.6||0.02|
|Hemoglobin decrease >3 g/dL (%)||3||8||0.01|
|Peripheral edema (%)||7||9||0.48|
|Bone fracture (%)||0.6||2||0.17|
Nesto reports being on the speakers' bureau for GlaxoSmithKline and Takeda and a consultant for GlaxoSmithKline. The APPROACH coauthors include at least two employees of GlaxoSmithKline. Rodriguez said she had no disclosures.
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.
Heartwire from Medscape © 2008 Medscape
Cite this: Steve Stiles. AHA 2008: APPROACH: Rosiglitazone Doesn't Affect Atherosclerosis Progression in Diabetics With CV Disease - Medscape - Nov 14, 2008.