Has atorvastatin more than a DUAAL face?

The search for potent and efficacious inhibitors of the enzyme HMG-CoA reductase (HMGRIs) has long been the focus of considerable research. Atorvastatin calcium, one of the first synthetically designed HMGRIs, was created in 1985 and, due to a large number of trials showing positive clinical effect, especially in the field of acute coronary syndromes (ACS), has since obtained a leading role in the worldwide drugs market, with 2008 sales of US$12.4 billion making it the top-selling branded pharmaceutical in the world. In addition to its clinical efficacy, leading to profound reduction in LDL cholesterol and in major cardiac events, another merit of this innovative drug has been the contribution of atorvastatin research protocols to the development of the so-called ‘pleiotropic’ effects concept, e.g. the effects of HGMRIs independent from (or unrelated to) their main action, namely the reduction of serum cholesterol. A large amount of clinical evidence (including the ARMYDA studies) has indeed underscored several beneficial clinical actions of this drug that apparently go beyond the LDL cholesterol effect: it is effective in reducing post-percutaneous coronary intervention (PCI) myonecrosis, contrast-induced acute renal failure, and even in reducing disease activity in rheumatoid arthritis. Similarly, in vitro studies have shown an anti-inflammatory effect of HMGRIs. However, no simple unifying mechanisms have been put forward to explain these achievements, and proposed explanations vary widely, from microcirculatory effects to plaque-stabilizing capabilities, to a direct antiplatelet action. Inhibition of prenylation of several proteins such as the small GTP-binding proteins Ras and Rho, and the disruption, or depletion, of cholesterol-rich membrane microdomains (membrane rafts) have been proposed as pathways through which HMGRIs may modulate the immune response, fine-tuning cytokine levels, and affecting the function of cells involved in both innate and adaptive responses. Atorvastatin, specifically, has been observed to reduce the frequency of a specific subtype of T-helper lymphocyte, the CD4 + CD28null subtype, potentially implicated in the transition from stable to unstable plaque, in patients with unstable angina. Deanfield and colleagues have investigated another interesting face of atorvastatin in the DUAAL trial, i.e. its direct anti-ischaemic effect. The idea is not novel, as in 1999 the AVERT study first suggested that an aggressive medical therapy including high doses of atorvastatin is at least as effective as eliminating an epicardial stenosis with angioplasty. The DUAAL study supports the notion that optimal medical therapy is an effective strategy in stable angina patients and that high doses of HMGRIs may significantly affect prognosis in ischaemic heart disease. Some interesting points can be extrapolated from Deanfield’s work.