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Review
. 2018 Jul;12(7):191-202.
doi: 10.1177/1753944718775352. Epub 2018 May 24.

Alirocumab as add-on therapy to statins: current evidence and clinical potential

Johann Auer  1 , Robert Berent  2
Affiliations
Review

Alirocumab as add-on therapy to statins: current evidence and clinical potential

Johann Auer et al. Ther Adv Cardiovasc Dis. 2018 Jul.

Abstract

Atherosclerotic cardiovascular diseases (ASCVDs) are associated with a substantial mortality, physical morbidity, and mental disability. Elevated plasma low-density lipoprotein cholesterol (LDL-C) levels play a major role in the pathophysiology of ASCVDs. Statins have been shown to reduce ASCVD risk and associated events and are recommended as first-line therapy for treatment of hypercholesterolemia by current international guidelines. The key issue is to attain guideline-recommended LDL-C levels (below 70 mg/dl) for patients at very high cardiovascular risk. However, many high-risk and very-high-risk patients on statin therapy remain beyond treatment goals despite lifestyle modification and statins, and are exposed to a high risk of future cardiovascular events including myocardial infarction (MI), stroke, revascularization procedures, and death. This clearly emphasizes the urgent need for additional LDL-C reduction with new therapeutic strategies to target these highly atherogenic particles and to further reduce the burden of ASCVDs. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a major role as a key regulator of the hepatic LDL receptor recycling process. Developments over the past 15 years have demonstrated PCSK9 inhibition to be a novel therapeutic strategy to manage increased LDL-C levels. A number of clinical studies using humanized monoclonal antibody technology against PCSK9 have shown profound reductions of LDL-C levels when used either alone or in combination with statin therapy. Recently, the first cardiovascular outcome study demonstrated a significant reduction of ASCV events when evolocumab was added to a statin therapy. This review will discuss current knowledge about antibody-mediated PCSK9 inhibition as add-on therapy to statin and the clinical potential that may be expected.

Keywords: alirocumab; cholesterol metabolism; genetics; proprotein convertase subtilisin/kexin type 9 inhibition; statins.

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Conflict of interest statement

Conflict of interest statement: Within the last 36 months, J. Auer was advisor and member of the speakers bureau for Sanofi and Amgen.

Figures

Figure 1.
Figure 1.
Intracellular cholesterol depletion in hepatocytes as an effect of statin therapy. Activation of the sterol regulatory element binding protein 2 (SREBP-2) may result in an enhanced expression of both low-density lipoprotein cholesterol receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9).
Figure 2.
Figure 2.
Change in non-HDL-C levels over time [on-treatment (mITT) population]. The percent values represent the percent change from baseline at each time point. Pools 1–3 are on background statin therapy, pool 4 reveals no statin treatment in the control group. *p < 0.0001 versus control group. ApoB, apolipoprotein B; LS, least squares; mITT, modified intention to treat; non-HDL-C, non-high-density-lipoprotein cholesterol; Q2W, every 2 weeks; SE, standard error. Modified from Bays et al.
Figure 3.
Figure 3.
Change in ApoB levels over time [on-treatment (mITT) population]. The percent values represent the percent change from baseline at each time point. Pools 1–3 are on background statin therapy, pool 4 reveals no statin treatment in the control group. *p < 0.0001 versus control group. ApoB, apolipoprotein B; LS, least squares; mITT, modified intention to treat; non-HDL-C, non-high-density-lipoprotein cholesterol; Q2W, every 2 weeks; SE, standard error. Modified from Bays et al.
Figure 4.
Figure 4.
Percent of all patients (regardless of cardiovascular risk) achieving non-HDL-C levels of <100 mg/dl during the studies, overall and by cardiovascular risk [on-treatment (mITT) population]. Pools 1–3 are on background statin therapy, pool 4 reveals no statin treatment in the control group. *p < 0.0001 versus control group at all time points in all study pools and patient categories. mITT, modified intention to treat; non-HDL-C, non-high-density-lipoprotein cholesterol; Q2W, every 2 weeks. Modified from Bays et al.
Figure 5.
Figure 5.
Percent of patients with very-high-cardiovascular risk achieving non-HDL-C levels of <100 mg/dl during the studies, overall and by cardiovascular risk [on treatment (mITT) population]. Pools 1–3 are on background statin therapy, pool 4 reveals no statin treatment in the control group. *p < 0.0001 versus control group at all time points in all study pools and patient categories. mITT, modified intention to treat; non-HDL-C, non-high-density-lipoprotein cholesterol; Q2W, every 2 weeks. Modified from Bays et al.
Figure 6.
Figure 6.
Percent of patients with high cardiovascular risk achieving non-HDL-C levels of <100 mg/dl during the studies, overall and by cardiovascular risk [on-treatment (mITT) population]. Pools 1–3 are on background statin therapy, pool 4 reveals no statin treatment in the control group. *p < 0.0001 versus control group at all time points in all study pools and patient categories, except for pool 3 and pool 4 of the ‘high cardiovascular risk’ category where †p = 0.0030, ‡p = 0.0008, §p = 0.0159, and ‖p = 0.0220. mITT, modified intention to treat; non-HDL-C, non-high-density-lipoprotein cholesterol; Q2W, every 2 weeks. Modified from Bays et al.
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