Although safe, effective drugs are available for reducing circulating cholesterol concentrations, several epidemiologic studies have reported that most patients at high cardiovascular risk have low-density lipoprotein cholesterol (LDLc) values above the target levels recommended in clinical guidelines.1 This is an important issue, considering that patients reaching the therapeutic target have a lower risk of cardiovascular complications and death.2 There are several reasons for poor cholesterol control, such as poor treatment adherence among patients and treatment delays among physicians, but sometimes poor control is the result of ineffective lipid-lowering therapy.

In this regard, various patient subgroups may have difficulty reaching LDLc goals with the currently available drugs.3 These include the population of patients with familial hypercholesterolemia (FH), who generally show extraordinarily high LDLc concentrations that are difficult to reduce to recommended levels despite optimal lipid-lowering therapy,4,5 patients with partial or total statin intolerance, those unable to receive the recommended drugs,6 and numerous patients at very high cardiovascular risk who may require marked LDLc reductions that cannot be attained because of the considerable variability in the response to statins.7 Hence, it seems evident that new potent lipid-lowering agents are needed to replace statin therapy or be combined with these drugs.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that regulates cholesterol metabolism by controlling degradation of low-density lipoprotein (LDL) receptors.8 After binding to an LDL particle, the LDL receptor internalizes into the cytoplasm within structures known as endosomes. The LDL-LDL receptor complex then dissociates: LDL is processed for degradation within the lysosomes, whereas the LDL receptors are recycled toward the cell surface where they bind to new LDL particles. This recycling process occurs approximately 150 times for each receptor. LDL receptors that are bound to a PCSK9 molecule cannot be recycled and are instead processed for lysosomal degradation together with LDL particles. Thus, PCSK9 inhibition reduces the number of receptors that will be degraded and increases their numbers on the cell surface, which lowers the plasma cholesterol concentration.

Two human monoclonal antibodies able to block PCSK9, alirocumab and evolocumab, are currently available in Spain. These agents, which are administered by subcutaneous injection every 2 or 4 weeks, are able to immediately (within hours) block the circulating PCSK9. Reductions in LDLc are perceptible at 48hours after the start of treatment. Anti-PCSK9 antibodies reduce cholesterol concentrations in a dose-dependent manner, achieving decreases of up to 60% at a dose of 140 mg of evolocumab or 150 mg of alirocumab, administered every 2 weeks, with no significant adverse effects to date.9 In addition to reducing LDLc, both drugs can lower lipoprotein (a) levels by 20% to 30% and moderately lower triglyceride concentrations, with marginal elevations of high-density lipoprotein cholesterol levels. These reductions are cumulative to those obtained with statins or any other lipid-lowering drug.

Evolocumab and alirocumab have been approved by the Spanish Ministry of Health to be dispensed in the hospital setting for patients with the following indications, based on therapeutic positioning reports: patients with FH and LDLc plasma concentrations >100 mg/dL despite the use of maximum statin doses, patients with established cardiovascular disease (ischemic heart disease, ischemic cerebrovascular disease, and peripheral arterial disease) and uncontrolled LDLc (>100 mg/dL) with maximum tolerated statin doses, and any patients within these 2 groups who are intolerant to or have contraindications for statin use, and whose LDLc levels are >100mg/dL.

The Spanish Society of Cardiology has decided to establish a series of recommendations to position this therapeutic option, while being aware that clinical trials investigating the related morbidity and mortality are needed to provide a definitive basis for the indications. The complete document derived from this study is available on the Spanish Society of Cardiology website.10

The patient populations with priority to receive PCSK9 treatment and the LDLc concentrations above which PCSK9 would be indicated were established by consensus at participatory meetings. PCSK9 should probably only be used in patients who have already received optimal lipid-lowering therapy; that is, potent statins at the maximum tolerated doses with or without ezetimibe (if a patient exclusively treated with statins is far from achieving the therapeutic goals, anti-PCSK9 can be started if the attending physician considers that these goals will not be reached solely with the addition of ezetimibe).

With the availability of new, highly effective lipid-lowering drugs such as PCSK9 inhibitors, the recommended LDLc target levels will be reached in a large number of patients (Figure). It is anticipated that the use of these agents will significantly decrease overall cardiovascular risk and mortality. Completion of ongoing clinical trials using several of these new monoclonal antibodies and investigation of morbidity and mortality will enable more accurate delineation of patient populations that will benefit from this therapy and will provide cost-effectiveness analyses.

Figure.

Recommendations for PCSK9 inhibitor use in patients with high/very high cardiovascular risk (primary prevention) and patients with a clinical diagnosis of ischemic heart disease (secondary prevention). HeFH, heterozygous FH; HoFH, homozygous FH; LDL, low-density lipoprotein.

(0.45MB).

Although the situations described in this document refer exclusively to atheromatous coronary heart disease, the same conclusions can be applied to other atherosclerosis-related conditions, such as peripheral arterial disease and cerebrovascular disease.

M. Anguita Sánchez has received honoraria from Amgen for writing/revising manuscripts and for presentations. A. Cordero has received honoraria for consultancy work, expert testimony, and presentations from MSD, AstraZeneca, Menarini, Amgen, and Sanofi. J.M. Mostaza has received honoraria for consultancy work, talks, and educational presentations from Amgen and Sanofi. R.M. Lidón has received honoraria for consultancy work from AstraZeneca, and for expert testimony and presentations from Amgen and Ferrer. J.L. López-Sendón has received grants from Sanofi, Pfizer, Bayer, and GlaxoSmithKline, honoraria for participation in manuscript revisions from Pfizer, Bayer, and Merk, for writing/revising manuscripts from Amgen, for consultancy work from Bayer, and for presentations from Menarini, Servier, Novartis, and Merck, and funding for travel expenses from Servier. X. García-Moll has received honoraria for presentations from Sanofi, Amgen, and MSD, and funding for travel expenses from Sanofi. J.J. Gómez Doblas has received honoraria for presentations from Amgen. A. Castro has received honoraria for consultancy work from GOC Networking and for presentations from Amgen. L. Rodríguez Padial has received honoraria for par ticipation in manuscript revisions from Amgen and Sanofi and for manuscript preparation from Rovi, Amgen, and MSD. J.R. González-Juanatey has received honoraria for presentations from Amgen, Sanofi, MSD, Boehringer-Ingelheim, Novartis, AstraZeneca, Ferrer, Servier, Bayer, and Menarini.