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

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.

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.

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.

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.

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.

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.

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.