By Harold L. Karpman, MD, FACC, FACP
Clinical Professor of Medicine, UCLA School of Medicine
Dr. Karpman reports no financial relationships relevant to this field of study.
SYNOPSIS: When added to statin therapy at the maximum tolerated dose, the PCSK9 inhibitor alirocumab reduced low-density lipoprotein cholesterol levels by 62% and also reduced the rate of occurrence of cardiovascular events.
SOURCE: Robinson JG, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-1499.
Cardiovascular disease (CVD) caused by coronary artery atherosclerosis continues to be the leading single cause of death in industrialized countries. High serum lipid levels, and especially high low-density lipoprotein cholesterol (LDL-C), have been demonstrated in numerous epidemiological studies to strongly and directly correlate with CVD risk. Moreover, large prospective clinical outcome trials have revealed that lowering LDL-C decreases cardiovascular morbidity and mortality.1 However, despite the use of highly effective lipid-lowering therapy, such as statins and ezetimibe, a significant percentage of patients remain at high risk for CVD.
Monoclonal antibodies to pro-protein convertase subtilisin/kexin type 9 (PCSK9) have been demonstrated to reduce LDL-C levels in patients who are being treated with statins. The PCSK9 inhibitor alirocumab effectively reduces LDL-C by 40%-70% when added to background statin therapy.2-4 Robinson et al conducted a randomized trial involving 2341 patients who were at high risk for cardiovascular events, who had LDL-C levels of ≥ 70 mg/dL and who were receiving treatments with statins at the maximum tolerated dose.5 Either alirocumab (150 mg) or a placebo was injected every 2 weeks for 78 weeks. The primary efficacy endpoint measured was the percentage change in calculated LDL-C from baseline to week 24. Alirocumab, when added to the maximum tolerated dose of statin therapy, significantly reduced LDL-C, and a post-hoc analysis revealed evidence of a reduction in the rate of cardiovascular events.
PCSK9 is linked to serum LDL-C levels by binding to and down-regulating LDL receptor levels on hepatocytes. The resulting reduction in receptor function results in reduced hepatic cellular uptake of LDL-C and, consequently, results in higher levels of LDL-C in serum. By contrast, if PCSK9 is inhibited or made inactive pharmacologically, the result is to cause an increase in the number of hepatocyte LDL receptors, causing an increase in LDL uptake from the circulation into the liver, resulting in lower levels of LDL-C. In the ODYSSEY LONG TERM trial,5 performed by Robinson et al, the PCSK9 inhibitor alirocumab reduced LDL-C by 62% in high-risk patients when added to statin therapy at the maximum tolerated dose. This effect was determined to be consistent over the entire 78 weeks of therapy. The efficacy of the drug was similar across various subgroups, including those defined according to the presence or absence of heterozygous familial hypercholesterolemia. The data from a post-hoc safety analysis revealed that the rate of major adverse cardiovascular events was 48% lower among the patients who received alirocumab than it was among those who received placebos during the 78 weeks of follow-up. These findings were similar to those of another PCSK9 inhibitor trial in which the LDL-C levels decreased by 52%-57%.7,8 It must be recognized that the duration of follow-up therapy in the ODYSSEY LONG TERM trial was relatively short and that longer-term studies, which include careful assessment of neurocognitive drug effects and cardiovascular outcomes, are needed.
In summary, this carefully performed trial in 2341 high-risk cardiovascular patients produced results with a new drug, which could potentially offer a major advance in cholesterol-lowering therapy with a possible secondary significant reduction in cardiovascular events. In effect, PCSK9 inhibitors may be a major new addition to our cardiovascular drug armamentarium.
- Baigent C, et al. Efficacy and safety of more intensive lipid-lowering of LDL cholesterol: A meta-analysis of data from 170,000 participants in 26 randomized trials. Lancet 2010; 376:1670-1681.
- McKenney JM, et al. Safety and efficacy of a monoclonal antibody to pro-protein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Card 2012;59:2344-2353.
- Roth EM, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012;367:1891-1900.
- Stein EA, et al. Effects of a monoclonal antibody to PCSK9, RGEN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomized controlled trial. Lancet 2012;380:29-36.
- Robinson JG, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-1499.
- Abifadel M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154-156.
- Blom, DJ, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 2014;370:1809-1819.
- Koren MJ, et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open – Label Study of Long – Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation 2014;129:234-243.