Premise

Evidence spanning from the pathogenesis of atherosclerosis to epidemiological studies consistently support the direct association of elevated plasma low-density lipoprotein-cholesterol (LDL-C) with the increased risk of cardiovascular disease (CVD). Meta-analysis of 14 trials of statin therapy, with more than 90,000 participants, has shown that each 1mmol/l (39mg/dl) of LDL-C reduction results in a 20–25% reduction in coronary heart disease (CHD) and stroke over five years. Finally, from the many outcome studies it has been established that for each 1% reduction in LDL-C, independent of mode of therapy, there was at least a 1% reduction in CVD events. On the basis of these premises, the Adult Treatment Panel (ATP) III and European guidelines have both recommended an LDL-C goal of <100mg/dl for patients at high risk of CHD. More recently, based on the later trials with statins, the ATP III has established LDL-C lowering as a primary goal in cholesterol treatment and has considered a more aggressive LDL-C goal of <70mg/dl in the highest risk CHD patients.

Despite the benefit of statin therapy and recommendations from international guidelines, LDL management remains suboptimal and many patients do not achieve recommended target goals. Several reasons could explain the failure of statin monotherapy to achieve the recommended LDLC goal, including extrinsic (e.g. poor compliance, time and uptitration of the dose, concomitant drug therapy, diet) and intrinsic (genetic of lipoprotein metabolism/pharmacokinetics, poor responders) factors. The significant gap between guideline recommended treatment goals and the lipid levels actually achieved in clinical practice highlights the urgent need for new management strategies, particularly for high-risk patients.

Safety Issue

The more recent clinical trials addressing the benefits of high doses of statins versus standard lipid-lowering therapy in high CHD risk patients have shown additional clinical benefits in terms of reduction of cardiovascular risk as related to LDL-C lowering, but also have pointed out an increased risk of side effects including liver toxicity, myopathy and noncardiovascular deaths. It is important to mention also the PRIMO (Prediction of Muscular Risk in Observational) study, a countrywide observational survey conducted in 7,924 hyperlipidaemic patients receiving high doses of statins in a usual care, outpatient setting in France. Patients were included if they were taking a high dosage of statins (fluvastatin 80mg, simvastatin 40 or 80mg, atorvastatin 40 or 80mg, pravastatin 40mg) for at least three months. Overall, 832 patients (10.5%) have reported muscular symptoms with a median onset of one month after the beginning of statin therapy. Altogether, the PRIMO trial demonstrated that mild to moderate muscular symptoms with high dosage of statin therapy are more common and exert a greater impact on daily life than previously appreciated. Based on this evidence, the safety issue has become a major concern in terms of the potential use of high-dose statins in CHD patients, and strongly supports the use of combination therapy.

Figure 1 represents the pharmacological effect of statins as related to the doses. As shown in the figure, at the recommended clinical doses of statins, when doubling the dose you can achieve only a 6% additional reduction of LDL-C (i.e. the additional pharmacological benefits are minimal, getting close to the steady state), while the toxicity is increasing from minor to major.

The failure of statin monotherapy to achieve LDL-C goals, as well as the safety issue, a major concern in the potential use of high-dose statins in CHD patients, strongly support the use of combination therapy as a practical, effective and safe option to bring more patients to their LDL-C goal.