Sweetless'n low LDL-C targets for PCSK9 treatment.


In their trial, Cannon et al. report the superiority of the anti-PCSK9 monoclonal antibody (mAb) alirocumab (SAR236553/REGN727; s.c. 75 mg every 2 weeks) over ezetimibe (oral 10 mg once a day) in the reduction of LDL-cholesterol (LDL-C) levels among 720 patients athigh cardiovascular risk whowere inadequately controlled despite maximally tolerated statin dosage. At week 24, mean reduction in LDL-C from baseline was 50.6% for alirocumab vs. 20.7% for ezetimibe (P , 0.001), while 77.0% of the alirocumab treatment arm achieved the recommended LDL-C target of , 1.8 mmol/L vs. 45.6% for ezetimibe (P , 0.001). Mean LDL-C at week 24 was 1.3 mmol/L for alirocumab comparedwith 2.1 mmol/L for ezetimibe, yielding an additional 30% lipid-lowering effect for patients treated with the anti-PCSK9. The findings of the ODYSSEY COMBO II trial add to the evidence of alirocumab as a safe and efficacious option for patients whose LDL-C is insufficiently controlled under maximally dosed statin therapy, as is the case for an increasing number of high-risk patients. Available data indicate that fully human antibodies targeting PCSK9 are very effective in reducing LDL-C, apolipoprotein B (apoB), and lipoprotein(a) [Lp(a)] concentrations. Their efficacy has been demonstrated alone or in addition to statins in hypercholesterolaemic patients. Used alone in the primary setting, anti-PCSK9 treatments yielded LDL-C reductions up to 70% greater than placebo. The ODYSSEY COMBO studies are among the longest duration placebo/ezetimibe-controlled trials of PCSK9 inhibitors in high-risk patients with poorly controlled LDL-C despite maximally tolerated statin treatment. ODYSSEY COMBO I reported the benefit of alirocumab (75 mg s.c. every 2 weeks) over placebo in patients poorly controlled despite maximally tolerated statin therapy or other concomitant lipid-lowering therapies. In ODYSSEY COMBO I, LDL-C levels , 70 mg/dL were reached more frequently for alirocumab than for placebo (75% vs. 9%, P , 0.001). ODYSSEY COMBO II compared alirocumab with the active substance ezetimibe. Using ezetimibe as the control substance is of particular interest in view of the IMPROVE-IT trial outcomes recently presented at the American Heart Association (AHA) 2014 congress. IMPROVE-IT is the first trial having demonstrated the benefit of adding a non-statin lipid-lowering agent (ezetimibe 10 mg) to a statin (simvastatin 40 mg), compared with a statin alone (simvastatin 40 mg) in patients with recent acute coronary syndrome (ACS) and LDL-C values , 125 mg/dL (3.2 mmol/L). Adding ezetimibe to the statin therapy further reduced LDL-C by an average of 0.4 mmol/L, yielding an additional improvement of 2% for the absolute rate of major composite cardiovascular endpoints. This result is remarkable in light of the fact that the study was intention-to-treat driven with a 40% drop-out rate, and all patients were already well controlled by optimal medical therapy. By treating 50 patients during 7 years, IMPROVE-IT demonstrated that the addition of a non-statin lipid-lowering agent to a statin could prevent one additional event. The relative risk reduction for IMPROVE-IT was, however, more modest (6%). As limitations, we can mention that patients in the control arms were not on a high-intensity statin therapy regimen as currently recommended by American and European guidelines. The adage ‘lower is better’ seems to be confirmed also for nonstatin lipid-lowering agents in the light of the ODYSSEY LONG TERM trial results (Figure 1) presented at the European Society of Cardiology 2014 congress and recently published. The ODYSSEY LONG TERM trial randomized 2341 patients with familial hypercholesterolaemia (FH) or coronary heart disease to alirocumab 150 mg every 2 weeks vs. placebo for 78 weeks. All participants had poorly controlled LDL-C at inclusion despite maximum tolerated statin dosages. At week 78, differences in LDL-C were significant (1.5 mmol/L for alirocumab vs. 3.2 mmol/L for placebo, P-value , 0.001), which translates into a significant additional 60% LDL-C reduction with PCSK9 inhibition. In a post-hoc analysis, the rate of

DOI: 10.1093/eurheartj/ehv056

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@article{Gencer2015SweetlessnLL, title={Sweetless'n low LDL-C targets for PCSK9 treatment.}, author={Baris Gencer and François Mach}, journal={European heart journal}, year={2015}, volume={36 19}, pages={1146-8} }