Statin pleiotropy: a popular concept but clinical significance unclear.

Statins have a variety of effects beyond lowering low density lipoprotein cholesterol (LDL-C). These “pleiotropic” effects include significant effects on other lipid fractions as well as effects on numerous measures of inflammation, immunity, thrombosis, vascular, and renal function.[1–6] These effects have also been shown to vary by statin.[7, 8] However, the role of statin pleiotropy in reducing cardiovascular (CVD) risk is less clear. There are essentially four models for the role of statin effects on CVD risk (Fig. 1). Model 1 shows that the pleiotropic effects of statins are additive to LDL-C lowering and result in greater CVD risk reduction than would be expected from the reduction in LDL-C alone. Models 2 through 4 show a lesser reduction in CVD risk than Model 1, with pleiotropic effects playing no role in CVD risk reduction (Model 2); pleiotropic effects occurring downstream from and dependent upon LDL-C lowering (Model 3); and pleiotropic effects and LDL-C lowering playing joint roles in CVD risk reduction (Model 4). In a meta-analysis of placebo-controlled statin trials designed to evaluate Model 1, we found the reduction in coronary heart disease (CHD) risk from statins was similar to that of other treatments that primarily lower LDL-C (diet, bile-acid sequestrants, and ileal bypass surgery). [9] Nor did risk reduction vary by statin. Some evidence suggests that the pleiotropic effects of statins may play a more important role in the early benefit observed in the setting of ACS.[10] Although a meta-analysis of 14 ACS trials [11] did find a benefit at 4 months, the benefit at 2 years was the same as that observed at 2 years in a meta-analysis of 14 statin trials performed primarily in populations with stable CVD or diabetes. [12] These studies suggest that the pleiotropic effects of statins are not additive to the long-term benefit cardiovascular risk reduction benefit expected from LDL-C reduction. On the other hand, a post-hoc analysis of four intravascular ultrasound studies that used statins, suggested that high density lipoprotein cholesterol (HDL-C) increases were additive to LDL-C reduction for atherosclerotic regression. [13] Although these findings may provide some support for Model 1, it remains to proven whether these changes result in clinically meaningful reductions in cardiovascular events, and the previously cited metaanalyses suggest that they may not. Attention can next be turned to the more difficultto-distinguish relationship between pleiotropic effects and LDL-C reduction in Models 2 through 4. The paper by Mulder et al., in this issue, provides further support that Model 3 (pleiotropic effects are dependent upon the degree of LDL-C reduction) may not be the operative model whereby statins exert their cardioprotective effect. In this carefully performed study, the additional 24% reduction in LDL-C with atorvastatin 40 and 80 mg appeared to have no more effect than simvastatin 40 mg on a number of measures of oxidative stress, inflammation and thrombosis. These findings are consistent with the independence of Creactive protein reduction from LDL-C reduction at 14 days, [14] the lack of a dose response for C-reactive protein recently found for low and high doses of simvastatin [15] and meta-analysis of earlier studies evaluating C-reactive protein that also failed to identify a dose-dependent relationship. [16] Also consistent with the study by Mulder et al., this meta-analysis also found that statins did not affect fibrinogen levels, and had little effect on lipid oxidation, Cardiovasc Drugs Ther (2007) 21:81–83 DOI 10.1007/s10557-007-6021-7