Letter by Tershakovec et al Regarding Article, “Evidence for Statin Pleiotropy in Humans: Differential Effects of Statins and Ezetimibe on Rho-Associated Coiled-Coil Containing Protein Kinase Activity, Endothelial Function, and Inflammation”
To the Editor:
The article in Circulation by Liu et al1 claims that statin monotherapy provides greater “pleiotropic effects” than low-dose statin with ezetimibe due to the effects on Rho-kinase activity, which is postulated to play a role in flow-mediated dilation (FMD), a surrogate marker for endothelial function. We believe this article has significant limitations related to its design, presentation, and conclusions.
Ezetimibe would not be expected to directly influence Rho-kinase activity, so the treatment group differences in Rho-kinase activity in this study are expected. However, the clinical significance of changes in Rho-kinase activity with respect to cardiovascular risk is entirely speculative.
The utility of FMD assessment in clinical research remains unknown, compounded by the difficulties in obtaining accurate and reproducible data. Liu et al failed to provide an accurate description of the variability in the percentage of FMD change observed. More than 40% of the data points represent changes in FMD of ≥40%. Such variability limits the reliability of the FMD findings and their interpretation. Moreover, studies of positive drug effects on endothelial function should enroll subjects with baseline endothelial dysfunction. The subjects in this trial had relatively high baseline FMD, suggesting fairly normal baseline endothelial function, and subjects in the ezetimibe/simvastatin group had higher baseline FMD than patients taking statin monotherapy or placebo, thus leaving less opportunity to demonstrate improvement. Also, the authors fail to consider 2 other studies with ezetimibe or ezetimibe plus statin that showed a positive effect on FMD.2,3 Proper interpretation of the reported new finding requires accurate assessment of the existing literature.
To appropriately compare the effects of low-density lipoprotein cholesterol (LDL-C) lowering on FMD for 2 therapies, it would be necessary to achieve equivalent changes and levels of LDL-C across the treatment groups. This goal was not accomplished in the study by Liu et al. The LDL-C changes observed in this study also differ significantly from that observed in other studies, possibly related to the small sample size, lack of compliance, or other factors.
Extrapolating the results of this study to explain the results of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study is not scientifically reasonable. Evidence from the Atorvastatin Versus Simvastatin on Atherosclerosis Progression (ASAP) Extension, the atorvastatin monotherapy arm of Rating Atherosclerotic Disease Change by Imaging With a New CETP Inhibitor (RADIANCE) 1, Carotid Atorvastatin Study In Hyperlipidemic Post-Menopausal Women: A Randomized Evaluation of Atorvastatin Versus Placebo (CASHMERE), and other analyses suggests that previous aggressive statin treatment and relatively normal baseline carotid intima-media thickness status profoundly limit the utility of change in intima-media thickness as a surrogate for the effects of lipid-lowering medication on clinical risk.4,5 Furthermore, a secondary analysis from the Stop Atherosclerosis in Native Diabetics Study (SANDS) using a more appropriate patient cohort to assess carotid intima-media thickness change recently demonstrated the utility of ezetimibe-mediated LDL-C lowering in producing intima-media thickness regression.6
The primary goal of the prevention of atherosclerotic disease is LDL-C lowering, which is affirmed by decades of research supporting the link between LDL-C lowering achieved through a broad range of mechanisms and decreased risk of cardiovascular disease. Although many claims have been made about the pleiotropic effects of statins, the clinical relevance of such effects remains theoretical and unproven.
Drs Pasternak and Tershakovec are employees of Merck and Co Inc, and they own stock and stock options in the company. Dr Veltri is an employee of Schering-Plough Corporation and owns stock and stock options in the company.
Liu PY, Liu YW, Lin LJ, Chen JH, Liao JK. Evidence for statin pleiotropy in humans: differential effects of statins and ezetimibe on rho-associated coiled-coil containing protein kinase activity, endothelial function, and inflammation. Circulation. 2009; 119: 131–138.
Olijhoek JK, Hajer GM, van der Graaf Y, Dallinga-Thie GM, Visseren FL. The effects of low-dose simvastatin and ezetimibe compared to high-dose simvastatin alone on post-fat load endothelial function in patients with metabolic syndrome: a randomized double-blind crossover trial. J Cardiovasc Pharmacol. 2008; 52: 145–150.
Vergeer M, Zhao R, Duivenvoorden R, Koglin J, Mitchel YB, Huijgen R, Sapre A, Bots ML, Pasternak RC, Gagne C, Marais AD, Ballantyne CM. Carotid intima media thickness is modest in statin-treated familial hypercholesterolemic patients: results from a patient level meta-analysis of 1257 patients. Circulation. 2008; 118: S687. Abstract.
Fleg JL, Mete M, Howard BV, Umans JG, Roman MJ, Ratner RE, Silverman A, Galloway JM, Henderson JA, Weir MR, Wilson C, Stylianou M, Howard WJ. Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial. J Am Coll Cardiol. 2008; 25: 2198–2205.