The role of ezetimibe in the prevention of cardiovascular disease: Where do we stand after ARBITER 6-HALTS

Abstract

Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, rapidly became one of the most widely drugs in the US following its approval by the FDA in 2002. Due to its capacity to significantly lower LDL-C with few side effects, ezetimibe has been very useful in enabling patients who were statin intolerant to reach their recommended therapeutic goal for LDL-C. In addition, ezetimibe also reduces non-HDL-C and raises HDL-C, further enhancing its effectiveness in clinical practice. A significant preponderance of evidence supports the reduction of LDL-C and non-HDL-C as the most effective therapy to prevent or reverse atherosclerotic cardiovascular disease (ASCVD). However 3 recent clinical trials, ENHANCE, SEAS, and ARBITER 6-HALTS have raised questions about the efficacy and safety of ezetimibe and have led to a re-examination of its clinical use as a drug for managing lipid risk factors to prevent or manage ASCVD. An in-depth analysis of these three trials reveals methodological deficiencies and concerns with the statistical methods used which significantly diminish their indictment of the clinical utility of ezetimibe. In contrast, The SANDS trial has confirmed the effectiveness of ezetimibe in managing both LDL-C and non-HDL-C, and also demonstrated this drug’s ability to improve carotid atherosclerosis by producing regression of CIMT. One of the important conclusions of the SANDS Trail is that ezetimibe remains an effective adjunctive medication for use in patients who do not reach their LDL-C goals on statin monotherapy. However, as a significant residual risk for ASCVD remains even after aggressive goals for LDL-C and non-HDL-C are reached, current treatment strategies should emphasize managing of all cardiac risk factors and increasing HDL in addition to the attainment and maintenance of recommended goals for LDL-C and non-HDL-C. Hence, ezetimibe should be considered as an important component of broad-spectrum management of lipid risk factors with therapy that includes statins, niacin, bile acid sequestrants, fibrates and Omega 3 fatty acids in appropriate combinations in addition to therapeutic life change.