Letter by Settergren 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:
It is well established that statins improve the prognosis of patients with coronary artery disease. However, it is still unclear whether the protective effects of statins relate to lipid lowering only or whether other so-called pleiotropic effects may contribute. Experimental data support the pleiotropic effects of statins, but knowledge on their clinical relevance is limited.
We read with great interest the recent article by Liu et al.1 The authors compared the effect of simvastatin 40 mg/d, and the combination of simvastatin 10 mg and ezetimibe 10 mg and placebo, in 3 groups of patients with low-density lipoprotein cholesterol >130 mg/dL and <2 cardiovascular risk factors. The groups were compared relative to changes in the Rho-associated coiled-coil containing protein kinase activity as the primary and endothelial function as a secondary end point. They concluded that a high dose of statin given as monotherapy induces a greater reduction in Rho-associated coiled-coil containing protein kinase activity and improvement in endothelial function measured by flow-mediated dilation compared with the combination of the statin in a low dose combined with ezetimibe. The authors claim that this discovery provides evidence for the pleiotropic effects of the statin in humans. This finding may appear to contrast our recent article,2 in which there were no differences in the improvement of endothelial function between 2 groups of patients with dysglycemia and coronary artery diseases treated with simvastatin 80 mg or simvastatin 10 mg in combination with ezetimibe 10 mg. The reduction in low-density lipoprotein cholesterol was similar in the 2 groups (45% to 50%), supporting the conclusion that lipid-lowering rather that pleiotropic effects are of importance for the improvement of flow-mediated dilation.
These 2 studies have important differences. The patients in the study by Liu et al were at a considerably lower cardiovascular risk, the patients were not all naive to statin treatment, and patients with diabetes mellitus were excluded. The low-density lipoprotein reduction in the combination group was less pronounced than in our and other studies3 with simvastatin/ezetimibe 10/10 mg/d (35% versus 50%), although this discrepancy is not discussed by Liu et al. A pronounced reduction in low-density lipoprotein cholesterol may be more important than a possible pleiotropic effect for endothelial function. Additionally, it is not clear whether the change in endothelial function differed significantly between the 2 treatment groups. Although only the high-dose simvastatin group reached statistically significant improvement, a statistical analysis of the difference in change in flow-mediated dilation between the treatment groups would be helpful.
An increasing number of published studies are investigating the pleiotropic effects of statins, with diverging results.1,2,4,5 These results stress the need for a larger multicenter study to shed more light on this important mechanistic issue.
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.
Landmesser U, Bahlmann F, Mueller M, Spiekermann S, Kirchhoff N, Schulz S, Manes C, Fischer D, de Groot K, Fliser D, Fauler G, Marz W, Drexler H. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation. 2005; 11: 2356–2363.