Editorial Seeking Alternatives to Hard End Points Is Imaging the Best APPROACH ?

Patients with diabetes mellitus are at increased risk of death resulting from cardiovascular disease, but the best strategy to control excess cardiovascular risk is not yet clear. Although the use of statins and angiotensin antagonists has been successful, treatment of diabetes mellitus itself, especially from the standpoint of degree of glycemic control and type of antidiabetic agents, remains an area of ongoing investigation. Once touted as having the potential for atheroprotection because of their favorable effects on inflammatory biomarkers, endothelial function, carotid intimal-medial thickness, and even macrophage and lipid deposition, the thiazolidinediones (TZD) have become substantially controversial after a meta-analysis suggested an increase in the risk of myocardial infarction in patients treated with rosiglitazone.1 Although this notion was not confirmed in an interim analysis of the prospective study Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD), owing to several serious limitations of this report and several unanswered questions,2 studies such as Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Type 2 Diabetes Patients with Cardiovascular History (APPROACH)3 become important. Taking a leaf from the statin playbook, the APPROACH was to see whether imaging the atheroma in the coronary vasculature could explain some of the outcome data with rosiglitazone. This prospective, multicenter, double-blind, randomized study compared potentially glucose-independent effects of rosiglitazone with those of a sulfonylurea (glipizide) on progression of coronary atherosclerotic disease in 672 patients with type 2 diabetes mellitus. Patients underwent baseline intravascular ultrasound (IVUS) of the longest and least angulated nonintervened epicardial artery with noncritical plaque at baseline and 18 months later. Atheroma, as measured by IVUS, did not progress significantly in either arm over time; the primary end point of the trial— change in percent atheroma volume ( PAV)—in individuals treated with rosiglitazone ( 0.21%) was not significantly different from that in the glipizide group ( 0.43%). Several issues raised by this study deserve discussion.