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Therapy and clinical trials.

DOI:10.1097/MOL.0000000000000225 The cardiovascular risk reduction of lipid-lowering therapies added to statins has been controversial over the past 2 decades. This uncertainty led the most recent practice guidelines from the American College of Cardiology/American Heart Association to center exclusively on moderate-to-high statin therapy for all at-risk groups, disregarding combination therapies and ‘treat-to-target’ goals, based on a perceived lack of efficacy of ‘add-on’ lipid-lowering agents and that treatment targets make no point if there is no effective therapy beyond statins [1]. However, recent lipid-lowering clinical trials may make ‘current’ guidelines become rapidly obsolete. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease synthesized primarily in the liver, which binds to hepatic LDL receptors and targets them for degradation. Treatment with a monoclonal antibody that inhibits PCSK9 activity, or anti-PCSK9, reduces LDL cholesterol (LDL-C) concentration in statin-treated patients and has opened a new horizon in the management of dyslipidemia [2 & ,3 & ]. Two recent studies provide additional evidence about their overall safety and longer-term efficacy in lowering LDL-C when added to statin therapy. In the first one [Long-term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy (ODYSSEY LONG TERM) trial] [4 && ], 2341 patients at high risk for cardiovascular events on maximum statin-tolerated doses were randomized (2 : 1 ratio) to receive alirocumab 150 mg (as a 1-ml subcutaneous injection every 2 weeks) or placebo. This led at 24 weeks (primary efficacy endpoint) to a 60.7% reduction in LDL-C (from 123 to 48 mg/dl; P<0.001 vs. placebo), similar to prior shorter-term studies [2 & ,3 & ], remaining within this range over a period of 78 weeks. Post-hoc analysis revealed that major cardiovascular events [death from coronary heart disease (CHD), nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization] were 48% lower with alirocumab compared to that with placebo [1.7 vs. 3.3%, hazard ratio 0.52, 95% confidence interval (CI), 0.31–0.90, P1⁄40.02]. Treatment was overall well tolerated, although alirocumab was associated with more injection-site reactions (5.9 vs. 4.2%), myalgia (5.4 vs. 2.9%), neurocognitive