Study highlights:
• This comparison of the diabetes drug, rosiglitazone, with glipizide (in another class of diabetes drugs) did not meet its primary endpoint (a significant difference in percent atheroma, or plaque, buildup in coronary arteries) in a multi-national coronary IVUS (intravascular ultrasound) study of 672 diabetic patients.
• Rosiglitazone did increase levels of “good” cholesterol, improved blood pressure and reduced hs-CRP, a marker of inflammation.
• There was a significant difference in a secondary endpoint, the absolute atheroma volume, and fewer patients had hypoglycemia (low blood sugar) with rosiglitazone.

NEW ORLEANS, La., Nov. 12 — Rosiglitazone — a member of the thiazolidinedione 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 research presented at the American Heart Association’s Scientific Sessions 2008. Results of The APPROACH Trial – Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Type 2 Diabetes Patients with Cardiovascular History were presented as a late-breaking clinical trial.

In the world’s largest intravascular ultrasound (IVUS) study of diabetic patients with established coronary artery disease, researchers sought to determine if the choice of diabetes drugs could affect the progression of atherosclerosis as measured by IVUS, said Richard W. Nesto, M.D., Ph.D., principal investigator of the study, an associate professor of cardiovascular medicine at Lahey Clinic in Burlington, Mass., and chair of the division of internal medicine at Brigham and Women’s Hospital in Boston.

People with diabetes, a disorder that interferes with blood sugar metabolism, face increased risks of atherosclerosis, heart attack and stroke.

Rosiglitazone (RSG), which has been in use for less than a decade, is a member of the thiazolidinedione class of diabetes drugs. It makes the body’s cells more sensitive to insulin, the hormone created in the pancreas that’s essential for proper blood sugar metabolism. It also produces beneficial effects on blood pressure, HDL (“good”) cholesterol and indices of inflammation.

The comparison drug, glipizide, is from the sulfonylurea class of insulin secretagogues that makes the pancreas secrete more insulin. It has been used clinically for more than 40 years.

The prospective, randomized, double-blind study followed 672 diabetic patients, average age 61, undergoing clinically necessary coronary angiography or percutaneous coronary intervention (PCI) at 92 medical centers in 19 countries.

During those 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, the 333 patients receiving RSG had high-density lipoprotein (HDL) levels of 49 milligrams per deciliter (mg/dL), nearly 8 percent higher than the 45.4 mg/dL level in the 339 patients randomized to glipizide. HDL is often called the “good” cholesterol carrier because it is thought to help carry cholesterol away from the arteries and back to the liver, where it is passed from the body.
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, “bad” cholesterol) of 2.8 mg/dL.

At the end of the treatment period, researchers performed a second IVUS to determine the study’s primary endpoint, defined as the change in percentage of plaque build-up (atheroma) in the segment of non-intervened artery. They found that RSG 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.

This difference in drug effect did not achieve statistical significance. However, researchers found a significant 5.12 millimeter cubed (mm3) decrease in normalized total atheroma volume in favor of the RSG group.

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, he said. They did find 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 RSG group. In addition, the RSG group had multiple measures indicating fluid retention, although there was no difference in the risk of congestive heart failure.

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, Nesto said.

The mechanism is probably multifactorial by affecting several cardiovascular risk factors, one of which may be raising the levels “good” cholesterol by nearly 8 percent.

Co-authors include Christopher P. Cannon, M.D.; Hertzel C. Gerstein, M.D., M.Sc.; Robert E. Ratner, M.D.; Patrick W. Serruys, M.D., Ph.D.; Gerrit-Anne van Es, Ph.D.; Nikheel S. Kolatkar, M.D. M.P.H.; Barbara G. Kravitz, M.S.; Allen R Wolstenholme, Ph.D.; Andrew Zalewski, M.D.; Peter J. Fitzgerald, M.D. Ph.D.; Hector Garcia, M.D., M.Sc.; Diane Miller, Ph.D.; and Chun Huang, Ph.D. Individual author disclosures can be found on the abstract.

The study was funded by Glaxo Smith-Kline, King of Prussia, Pa.

Statements and conclusions of study authors that are presented at American Heart Association scientific meetings are solely those of the study authors and do not necessarily reflect association policy or position. The association makes no representation or warranty as to their accuracy or reliability. The association receives funding primarily from individuals; foundations and corporations (including pharmaceutical, device manufacturers and other companies) also make donations and fund specific association programs and events. The association has strict policies to prevent these relationships from influencing the science content. Revenues from pharmaceutical and device corporations are available at http://www.americanheart.org/corporatefunding.

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NR08-1165 (LBCT-SS-08/Nesto)
 

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