The final word about LDL-cholesterol lowering

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In this year, the saga of the ‘cholesterol hypothesis’, which stipulates ‘lower is better’ in terms of lowering LDL cholesterol for improvement of cardiovascular risk, has finally been completed. With the publication of the FOURIER study [1], the year 2017 in lipidology will be known as the year that gave us the final word about lowering LDL cholesterol. FOURIER was a randomized, double-blind, placebo-controlled trial enrolling 27 564 patients with stable atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg/dl or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or placebo. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, MI, or stroke, and the median duration of follow-up was 2.2 years. Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point by 15% and the key secondary end point by 20%. Impressively, LDL-cholesterol concentrations of less than 19 mg/dl were achieved in 2669 patients and their primary efficacy end point event rate was reduced to 10.3% per 3 years [2]. There was no significant difference in adverse events between the study groups and in a substudy, neurocognitive adverse events were documented and found to be the same in both study arms [3]. Conversely, this study also provided an estimate of the minimum residual risk associated with the maximum LDL lowering, and it was considerably high for the type of patient enrolled. Furthermore, findings regarding adverse events were limited by the duration of the study and the type of adverse events documented. In this issue, authors will review data on the use of alternative lipoprotein targets to address residual risk after LDL lowering, and discuss a lesser well known adverse risk of LDL-lowering therapy.

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