Abstract
By inhibiting 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase, the statins reduce hepatocyte cholesterol levels, which results in up-regulation of low-density lipoprotein (LDL) receptors and, consequently, increased clearance of LDL-cholesterol (LDL-C) from the plasma. Structural differences among the available statins partially account for differences in their capacity to inhibit HMG-CoA reductase and their lipid-lowering efficacy, and for variability in other biological properties, such as their pharmacokinetic characteristics and their tolerability and propensity to interact with other drugs. In terms of pharmacokinetic properties, the synthetic (type II) HMG-CoA analogue atorvastatin exhibits a number of characteristics that are different to those of other members of the class, including a longer plasma half-life and metabolites that have an ability to inhibit HMG-CoA reductase equivalent to that of the parent drug. These characteristics are postulated to be responsible for a more prolonged inhibition of HMG-CoA reductase, and, hence, for the greater efficacy of atorvastatin in decreasing total and LDL-C levels relative to other statins (with the exception of rosuvastatin) noted in clinical trials in patients with dyslipidaemias. From the available clinical trial data, atorvastatin can be considered one of the most effective statins, not only by taking into account its effects on LDL-C and ability to meet recommended treatment guidelines for this parameter, but also its effect on triglyceride levels and capacity to modify lipoprotein composition in a non-atherogenic manner. Clinical studies with atorvastatin have also shed some light on the question as to whether it is better to focus on obtaining maximal reduction of LDL-C in at-risk patients or on cardiovascular outcomes. Cardiovascular event rates have been shown to be substantially lower in patients attaining LDL-C levels between 1.0 and 1.6 mmol/L (40-60 mg/dL) or < or =1.0 mmol/L (< or =40 mg/dL) compared with higher levels (>2.1-2.6 mmol/L [>80-100 mg/dL]). This finding reinforces the update of the National Cholesterol Education Programme's clinical practice guidelines, which recommend LDL-C levels <2.6 mmol/L (100 mg/dL) to be the goal of antihyperlipidaemic drug therapy in high-risk patients with CHD, with an optional therapeutic target of <1.8 mmol/L (70 mg/dL) in patients at very high risk.
