JACC: Avandia, Altace do not improve outcomes in pre-diabetics without CV disease

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In people with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) without cardiovascular disease and diabetes, treatment with ramipril had a neutral effect on carotid intima-media thickness (CIMT), whereas rosiglitazone modestly reduced CIMT progression, according to the STARR trial results released June 2 issue in the Journal of the American College of Cardiology.

Eva M. Lonn, MD, from the department of medicine at McMaster University in Hamilton, Ontario, and colleagues said that the aim of STARR (STudy of Atherosclerosis with Ramipril and Rosiglitazone) was to evaluate effects of the angiotensin-converting enzyme (ACE) inhibitor ramipril (Altace from King Pharmaceuticals) and the thiazolidinedione (TZD) rosiglitazone (Avandia from GlaxoSmithKline) on CIMT in people with IGT and/or IFG.

The researchers randomized 1,425 people with IGT and/or IFG but without cardiovascular disease or diabetes to ramipril 15mg per day, or its placebo, and to rosiglitazone 8mg per day, or its placebo.

The primary study outcome was the annualized change of the aggregate maximum CIMT, computed as the average of the maximum CIMTs across 12 carotid arterial segments, according to the authors. The secondary study outcome was the annualized change of the mean far wall left and right common CIMT. The median follow-up was three years, and they obtained carotid ultrasound exams at baseline and yearly thereafter.

The investigators found that there were no differences in the primary and secondary outcomes between the ramipril and placebo groups.

Compared with placebo, the STARR researchers reported that rosiglitazone reduced the primary CIMT outcome, but the difference was not statistically significant (difference = 0.0027mm per year) and significantly reduced the secondary CIMT outcome (difference = 0.0043mm per year).

In an accompanying editorial, Juan Carlos Kaski, MD, and Gillian W. Cockerill, PhD, from St. George's University of London wrote that although STARR trial is "the largest of its kind thus far to examine CIMT progression in individuals with IGT or IFG but without cardiovascular disease, the clinical implications are not extremely clear at present, particularly in view of the neutral effects of ramipril and the modest effects of rosiglitazone on CIMT in pre-diabetic patients found in the trial."

Kaski and Cockerill also noted that because rosiglitazone is "under close scrutiny after the results of the meta-analysis by Nissen and Wolski in 2007 and TZDs in general continue to be monitored in view of reports showing that these drugs can increase the risk for heart failure, the possible clinical application of the STARR findings remains uncertain."

Despite the beneficial actions of TZDs in clinical and experimental studies in diabetic and nondiabetic populations, "the true effects of these drugs on ischemic CV events and all-cause mortality and their role in clinical practice regarding CV disease prevention still require further ad hoc investigation," Kaski and Cockerill wrote. "Perhaps the development of new pharmacological agents able to overcome the limitations of TZDs, particularly in relation to their potentially adverse CV effects, and a better understanding of the mechanisms leading to CV events in pre-diabetic individuals might offer better options for patient management in the not so distant future."

However, the STARR researchers concluded that the use of rosiglitazone in high-risk populations may deserve further study, specifically examining clinical outcomes.