|IVUS study investigated Avandia's ability to reduce progression of plaque build-up. Image Source: UMC St. Radboud|
NEW ORLEANS—Rosiglitazone (Avandia), a member of the thiazolidinedione (TZD) class of diabetes drugs, did not meet its primary endpoint for reducing progression of plaque buildup in coronary arteries in a study comparing it with glipizide, according to the APPROACH trial presented during the late-breaking clinical trials at the 2008 American Heart Association (AHA) Scientific Sessions.
Richard W. Nesto, MD, PhD, principal investigator of the study, chair of the division of internal medicine at Brigham and Women’s Hospital in Boston presented the results of APPROACH (Assessment on the Prevention of Progression by Rosiglitazone On Atherosclerosis in type 2 diabetes patients with Cardiovascular History) trial.
In December 2007, a study in the Journal of the American Medical Association found that TZDs, primarily with rosiglitazone, were associated with an increased risk of congestive heart failure, acute MI and mortality when compared with other combination oral hypoglycemic agent treatments. Since that time, wrongful death lawsuits have been filed due to the adverse effects.
In an intravascular ultrasound (IVUS) study of diabetic patients with established coronary artery disease, Nesto said the study sought to determine if the choice of diabetes drugs could affect the progression of atherosclerosis as measured by IVUS.
The comparison drug, glipizide, is from the sulfonylurea class of insulin secretagogues that makes the pancreas secrete more insulin.
Nesto said that the prospective, randomized, double-blind study followed 672 diabetic patients, average age 61, undergoing clinically necessary coronary angiography or PCI at 92 medical centers in 19 countries.
During the procedures, the researchers used IVUS to measure plaque burden in a 40 mm segment of a non-intervened artery with atherosclerosis at a level considered too low to require treatment. The participants were then randomized to one of the two study drugs with dosages adjusted to achieve similar levels of glucose control in each group.
After 18 months of treatment, Nesto reported that the 333 patients receiving RSG had high-density lipoprotein (HDL) levels of 49 mg/dL, nearly 8 percent higher than the 45.4 mg/dL level in the 339 patients randomized to glipizide.
Researchers also found beneficial directional effects on blood pressure, triglycerides and hs-CRP in the rosiglitazone group and also a modest increase in low-density lipoprotein (LDL) of 2.8 mg/dL.
At the end of the treatment period, the researchers performed a second IVUS to determine the study’s primary endpoint, defined as the change in percentage of atheroma in the segment of non-intervened artery. They found that Avandia seemed to stall or possibly reverse atherosclerotic progression with a 0.21 percent reduction in the primary outcome of percentage of plaque volume in RSG patients, compared to a 0.43 percent increase in plaque in glipizide patients.
The difference in drug effect did not achieve statistical significance. However, Nesto said that they found a significant 5.12 mm3 decrease in normalized total atheroma volume in favor of the Avandia group.
The researchers found no statistically significant differences in the secondary endpoint of major cardiovascular events between groups, although the study was not powered to evaluate clinical outcomes, Nesto said.
However, they found statistically significant differences in adverse events with 28 percent of participants taking glipizide experiencing a low-blood-sugar incident compared to 8 percent of those in the Avandia group. In addition, the Avandia group had multiple measures indicating fluid retention, although there was no difference in the risk of congestive heart failure.
Nesto noted that the results from the APPROACH trial are in line with similar and statistically significant results from an earlier, slightly smaller PERISCOPE trial, which used two different diabetes drugs, pioglitazone and glimepiride, from the same two classes.