Letter by Westerink and Visseren 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:
For daily clinical practice, it is important to know which lipid-lowering strategy for reaching recommended low-density lipoprotein cholesterol treatment goals is most effective in lowering cardiovascular risk: high-dose statin or low-dose statin in combination with inhibiting intestinal cholesterol uptake. Both strategies lead to a similar 40% to 50% low-density lipoprotein cholesterol reduction. To date, there are no prospective cohort studies with hard clinical end points addressing this issue. In their study, Liu et al1 show that low-risk patients randomized to simvastatin 40 mg had higher flow-mediated dilation (FMD) compared with patients receiving simvastatin 10 mg in combination with ezetimibe 10 mg after 4 weeks of treatment.
The results of the Liu et al article are not in line with other studies. If the effect on endothelial function is solely due to the statin, it would be expected that higher doses of simvastatin would have larger effects on endothelial function. The authors cite an article in which patients with coronary artery disease and either impaired glucose tolerance or type 2 diabetes mellitus were treated with simvastatin 80 mg or simvastatin 10 mg in combination with ezetimibe 10 mg.2 After 6 weeks of treatment, there was no difference in low-density lipoprotein cholesterol or high-sensitivity C-reactive protein whereas both treatments improved FMD to a similar degree. In a recently published cross-over study in patients with the metabolic syndrome, who are more comparable in cardiovascular risk to the patients in the study by Liu et al, patients were randomized to simvastatin 80 mg or simvastatin 10 mg in combination with ezetimibe 10 mg.3 After 6 weeks of treatment, the FMD in both groups was the same, and there were similar changes in lipids, high-sensitivity C-reactive protein, and other proinflammatory markers. In another recent study, patients with coronary artery disease were randomized to either atorvastatin 80 mg or atorvastatin 10 mg in combination with ezetimibe 10 mg.4 After 8 weeks of treatment, the high-dose statin group had a greater increase in FMD than the combination group.
So far, the results from the FMD studies with high-dose statins versus low-dose statins in combination with inhibiting intestinal cholesterol uptake show mixed results. These are all single-center studies with differences in FMD technique, choice of statin, and study population. Results from the FMD studies can also be influenced by concomitant medication, especially in the high-risk populations. Strictly controlled multicenter studies are needed to give more definitive answers to this important and clinically relevant question.
For the clinician, the following question remains: Which lipid-lowering therapy is the best for the vasculature given equal low-density lipoprotein cholesterol reduction? At the moment, there is no evidence of advantage for either high-dose statins or a combination of low-dose statins with inhibition of intestinal cholesterol uptake.
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.
Settergren M, Bohm F, Ryden L, Pernow J. Cholesterol lowering is more important than pleiotropic effects of statins for endothelial function in patients with dysglycaemia and coronary artery disease. Eur Heart J. 2008; 29: 1753–1760.
Olijhoek JK, Hajer GR, 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.
Ostad M, Eggeling S, Tschentscher P, Schwedhelm E, Böger R, Wenzel P, Meinertz T, Munzel T, Warnholtz A. Flow-mediated dilation in patients with coronary artery disease is enhanced by high dose atorvastatin compared to combined low dose atorvastatin and ezetimibe: results of the CEZAR study. Atherosclerosis. 2008; 205: 227–232.