PCSK9 inhibitors: Pharmacology, adverse effects, and use

INTRODUCTION — Elevated levels of circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with increased low-density lipoprotein (LDL) and worse cardiovascular outcomes. Antibodies to PCSK9 have been approved by regulatory agencies for the treatment of individuals with inadequately treated levels of LDL-cholesterol (LDL-C). They are capable of lowering LDL-C by as much as 60 percent in patients on statin therapy. In addition, they produce clinical benefits, such as reductions in the rates of stroke or myocardial infarction. (See 'PCSK9 antibodies' below.)

A second therapeutic approach for lowering PCSK9 uses a small interfering RNA. (See 'Small interfering RNA (inclisiran)' below.)

This topic will focus on information the clinician might need or be interested in when considering using these drugs. The potential indications for the use of these drugs are discussed separately. (See "Familial hypercholesterolemia in adults: Treatment", section on 'Third-line treatment' and "Treatment of drug-resistant hypercholesterolemia", section on 'PCSK9 inhibitors' and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

MECHANISMS OF ACTION — PCSK9, an enzyme (serine protease) encoded by the PCSK9 gene, is predominantly produced in the liver [1-3]. PCSK9 binds to the LDL receptor (LDL-R) on the surface of hepatocytes, leading to the degradation of the LDL-R and subsequently to higher plasma LDL-C levels [4,5]. (See "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'Low-density lipoprotein'.)

Antibodies to PCSK9 interfere with its binding of the LDL-R, leading to higher hepatic LDL-R expression and lower plasma LDL-C levels (figure 1) [6,7] (see 'PCSK9 antibodies' below). Alirocumab and evolocumab are fully humanized monoclonal antibodies that bind free plasma PCSK9, promoting degradation of this enzyme [8-11]. As a result, less free PCSK9 is available in plasma to bind to LDL-R. This results in a higher fraction of LDL-R recycling towards the hepatocyte surface. As a direct consequence, the liver has the capacity to remove more LDL-C from the circulation, resulting in lower LDL-C plasma levels. These antibodies are specific for PCSK9 and do not bind to other members of the PCSK enzyme superfamily [7,12,13].

Another method of interfering with PCSK9 is to block its synthesis, which is dependent on messenger RNA [14]. Inclisiran is one such antisense, silencing mRNA. (See 'Other studies' below.)

Circulating levels of PCSK9 are upregulated in the presence of statins, suggesting that inhibiting the PCSK9 pathway may complement the LDL-C lowering effect of statins. (See 'Drug interactions' below.)

PCSK9 ANTIBODIES — PCSK9 monoclonal antibodies are approved for use in many areas of the world. They are highly effective at lowering LDL-C when administered once or twice a month.

Patient surveys indicated a high rate of satisfaction with PCSK9 injection therapy, with very few injection site reactions and a willingness to self-inject using the subcutaneous pen injection device [15].

Among patients with cardiovascular disease (CVD) who are on effective statin therapy, PCSK9 inhibitors reduce LDL-C and short-term risk of cardiovascular events [16]. In an open-label extension study of the FOURIER trial, over 6600 patients with CVD on statin therapy who had been originally assigned to the PCSK9 inhibitor evolocumab or placebo were treated with open-label evolocumab [17]. At a median of five years, patients originally assigned to evolocumab had a lower risk of a composite of major adverse cardiovascular events and a lower risk of cardiovascular death than those originally assigned to placebo; adverse events were similar between the groups. These findings suggest that patients with CVD receiving combination therapy with a statin and a PCSK9 inhibitor derive long-term benefits with treatment.

Clinical effect — Among patients with atherosclerotic cardiovascular disease (ASCVD), randomized trials of the efficacy of PCSK9 inhibitors on secondary cardiovascular and mortality outcomes have been conducted [17,18]. The FOURIER outcome study with evolocumab found a significant reduction in major adverse cardiovascular events. As expected, after a short median follow-up of only 2.2 years, there was no CVD mortality or overall mortality benefit [17]. The post-hoc analysis of the ODYSSEY OUTCOMES (median follow-up of 2.8 years) demonstrated that alirocumab added to intensive statin treatment after acute coronary syndrome may reduce all-cause death in the long term (hazard ratio [HR] 0.85, 95% CI 0.73-0.98) [19]. Despite the lack of a mortality benefit in FOURIER, the risk of myocardial infarction (HR 0.73, 95% CI 0.65-0.82) and stroke (HR 0.79, 95% CI 0.66-0.95) was significantly lowered. In the open-label follow-up study called FOURIER-OLE, after a median of five years, patients with clinically evident ASCVD on stable effective statin therapy who had been originally assigned to evolocumab had a lower risk of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina or coronary revascularization (annualized incidence per 100 person-years 3.36 versus 3.96 percent; HR 0.85, 95% CI 0.75-0.96), a lower risk of cardiovascular death, myocardial infarction, or stroke (annualized incidence per 100 person-years 2.05 versus 2.58; HR 0.80, 95% CI 0.68-0.93), and a lower risk of cardiovascular death (annualized incidence per 100 person-years 0.68 versus 0.9; HR 0.77, 95% CI 0.60-0.99) [16]. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Clinical relevance of the inhibition of PCSK9 has been substantiated by Mendelian randomization studies, in which PCSK9 loss-of-function mutations were associated with both reduced LDL-C levels, as well as a significantly lower cardiovascular event risk [20-22]. Conversely, gain-of-function mutations of PCSK9 are associated with increased LDL-C levels and a higher risk of cardiovascular events [23-25]. Another study reported that HMG-CoA reductase mutations and PCSK9-mutations leading to lower LDL-C levels resulted in a cumulative impact of reduction in cardiovascular event rates, implying an additive effect of PCSK9 antibodies on top of statin (figure 2) [26,27].

Benefits of PCSK9 antibodies include:

●A reduction in LDL-C in a dose-dependent manner, by as much as 70 percent, and by as much as 60 percent in patients on statin therapy [28-38].

●A reduction in lipoprotein(a) levels by 18 to 36 percent, triglyceride levels by 12 to 31 percent, and a modest increase in high density lipoprotein cholesterol by 5 to 9 percent [37,39-44]. (See "Lipoprotein(a)", section on 'Management' and "Lipoprotein(a)", section on 'PCSK9 inhibitors'.)

●A decrease in percent atheroma volume [45], reduction of lipid-rich necrotic core [46], and increase in fibrous cap thickness [46], indicating stabilization of plaque phenotype.

●A significant (up to 50 percent) reduction in cardiovascular event risk in post-hoc analyses of early evolocumab and alirocumab studies [47-50].

A meta-analysis of 24 randomized trials (n = 10,159) in a variety of clinical situations (familial hypercholesterolemia; other hypercholesterolemia; statin-intolerant hypercholesterolemia; intensive, non-intensive, or no statin therapy) found that anti-PCSK9 abs reduced all-cause mortality (odds ratio [OR] 0.45, 95% CI 0.23-0.86), cardiovascular mortality (OR 0.50, CI 0.23-1.10), and myocardial infarction (OR 0.49, CI 0.26-0.93) [47]. There was no statistical heterogeneity found among the included trial results, suggesting that, as has been seen with statins, the relative benefits of anti-PCSK9 abs may be similar across a wide range of clinical situations and baseline risks of cardiovascular disease.

Another study published after the meta-analysis had similar findings. In two open-label trials of the monoclonal antibody evolocumab that were combined for analysis, 4465 patients who had completed one of twelve phase 2 or phase 3 trials of evolocumab were randomly assigned to evolocumab (140 mg injected subcutaneously every two weeks or 420 mg monthly) plus standard therapy, or standard therapy alone [48]. The patients in the underlying trials included those on statin therapy (approximately 70 percent), including high-intensity statin therapy (approximately 27 percent), as well as patients who were statin intolerant or who were on no other lipid lowering therapy, and the median duration of follow-up was 11.1 months. Patients treated with evolocumab had a lower rate of combined cardiovascular events (1.0 versus 2.2 percent; HR 0.47, 95% CI 0.28-0.78).

Our recommendations for the use of these drugs are discussed elsewhere. (See "Treatment of drug-resistant hypercholesterolemia", section on 'PCSK9 inhibitors' and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Pharmacology — The highlights of the pharmacokinetics and pharmacodynamics of evolocumab and alirocumab are presented in a table (table 1) [13,51-53].

PCSK9 antibodies bind free (ie, unbound to other proteins) PCSK9 rapidly, resulting in no free PCSK9 availability for two to three weeks after antibody administration (figure 3). When PCSK9 activity is suppressed, hepatocytes recycle and express a larger proportion of LDL-R surface receptors which more efficiently clear LDL-C from the plasma. When suppression of free PCSK9 levels falls below 75 to 85 percent, the opposite occurs, and plasma LDL-C rises (figure 3).

Absorption, distribution, and onset — Following an initial subcutaneous injection of alirocumab or evolocumab, systemic bioavailability is 85 and 72 percent, respectively. The apparent volume of distribution of both PCSK9 inhibitors is approximately 3.3 liters, suggesting limited tissue distribution. The onset of inactivation of PCSK9 enzyme occurs within four to eight hours following the first subcutaneous injection of PCSK9 monoclonal antibodies [52,53].

Metabolism and clearance — Formal metabolism studies were not conducted because PCSK9 monoclonal antibodies are composed of proteins and carbohydrates and elimination is expected to occur via saturable binding to PCSK9 enzyme and nonsaturable proteolysis to small peptides and amino acids. Estimates of exposure and clearance properties provided in the manufacturer labeling are based upon population analyses. The effective elimination half-life of the available PCSK9 inhibitors is 11 to 20 days. Half-life and is modestly reduced when administered with a statin [52,53]. (See 'Drug interactions' below.)

In patients with renal or hepatic impairment, dose adjustment of alirocumab or evolocumab is not felt to be necessary. However, no data are available in patients with severe renal or hepatic impairment.

Hepatic impairment — In patients with mild to moderate hepatic impairment (Child Pugh class A or B) (table 2), evolocumab exposure was decreased by 40 to 50 percent relative to patients without liver disease. Decreased exposure in patients with hepatic impairment was not associated with a change in time-course of PCSK9 inactivation and therefore no dose adjustment is recommended. The pharmacokinetics of alirocumab do not appear to be altered in patients with mild to moderate hepatic impairment. While PCSK9 inhibitors have not been studied in patients with severe or decompensated liver disease, we would consider using this class of drug, as they are cleared through saturable binding to PCSK9 enzyme and proteolysis [52-55].

Renal impairment — As monoclonal antibodies are not eliminated by the kidneys but rather cleared via the reticuloendothelial system, a significant alteration in exposure in patients with renal impairment is not expected. We would consider using PCSK9 antibodies in patients with severe renal impairment and in dialysis patients [56]. Most of our contributors use these drugs (added to statin therapy) in patients with an estimated glomerular filtration rate <15 mL/min/1.73m² and very high cardiovascular risk. Details of the pharmacokinetics of alirocumab and evolocumab are presented in a table (table 1).

A population analysis of evolocumab trials suggested no difference in pharmacokinetics in patients with mild or moderate renal impairment relative to those with normal renal functioning. Population analysis of data pooled from alirocumab trials showed an increased exposure time course of alirocumab by 22 to 50 percent in patients with mild to moderate renal impairment relative to patients with normal kidney functioning. The cause of this observation is unclear. No dose adjustment is recommended for PCSK9 inhibitors in patients with mild to moderate renal impairment. Clinical trials included few patients with severe renal impairment or end-stage kidney disease; in the few patients studied, exposure to alirocumab was approximately twofold higher than patients with normal renal functioning [52-55].

In the FOURIER trial, the absolute reduction in cardiovascular events with evolocumab therapy was greater with more advanced chronic kidney disease [57]. Absolute risk reductions at 30 days for the secondary endpoint (composite of cardiovascular death, myocardial infarction, or stroke) were -2.5 percent (95% CI -0.4 to -4.7 percent) for ≥stage 3 chronic kidney disease compared with -1.7 percent (95% CI 0.5 to -2.8 percent) with preserved renal function. There were no differences in the primary endpoint (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization) for patients with advanced kidney disease versus preserved renal function.

Drug interactions — Pharmacokinetic evaluation of drug-drug interactions have not been performed for both antibodies because there are no known interactions between immunoglobulin type G and small molecules. The manufacturers’ labeling provides a comparison of PCSK9 inhibitor exposure in patients receiving statin treatment to those receiving PCSK9 inhibitor alone based upon population analyses [52,53].

Statin use is associated with increased levels of circulating PCSK9 enzyme [58-61]. PCSK9 production is stimulated by statins through an increased release of sterol regulatory element-binding protein 2. These data suggest PCSK9 inhibition could be even more efficacious in high-intensity statin users compared with low-dose statin users. However, the percent LDL-C reduction with PCSK9 antibodies is independent of statin dosage, suggesting PCSK9 antibodies can override this concomitant effect of statins [37,39].

Adverse effects — The available PCSK9 inhibitors appear to be well tolerated [47-49,62]. In an analysis of pooled data from clinical trials the overall rate of adverse events with either PCSK9 inhibitor was similar to placebo [63]. Local injection site reactions that are usually mild (eg, erythema, pain, or bruising) are among the most commonly reported adverse effects occurring in 6 and 7 to 10 percent of evolocumab and alirocumab treated patients, respectively [52,53]. PCSK9 inhibitors do not appear to cause muscle toxicity or elevated liver enzymes [63].

PCSK9 clinical trials have evaluated safety for up to nearly five years [17,44,64-66]. Serious adverse effects appear uncommon.

Immunologic and allergic effects — Hypersensitivity reactions such as rash, pruritus, and urticaria have occurred with PCSK9 inhibitors. Serious allergic reactions have been described, rarely including nummular eczema, severe urticaria, and hypersensitivity vasculitis. Drug-neutralizing antibodies were detected in 1.2 percent of alirocumab treated patients. Patients who developed neutralizing antibodies to alirocumab had more frequent injection site reactions than those who did not develop neutralizing antibodies (10.2 versus 5.9 percent). However, consistent loss of LDL-C-lowering efficacy was not observed among patients who had neutralizing antibodies [53]. Drug neutralizing antibodies to evolocumab were not detected during clinical trials [52].

Neurocognitive toxicity — A few trials have reported a small (less than 1 percent) increase in neurocognitive symptoms in patients using alirocumab or evolocumab compared with placebo [48,49]. However, in a prospective neurocognitive sub study of the 1974 patients in the FOURIER trial (reported prior to peer review), 1974 patients no significant evidence of neurocognitive impairment was found [17,67]. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Muscle toxicity — Neither muscle toxicity nor creatine kinase elevations have been found in patients after administering PCSK antibodies [48,49,63,68]. Moreover, patients who already were using statins did not experience muscle toxicity after combination treatment with a PCSK9 antibody [48,49]. (See "Rhabdomyolysis: Epidemiology and etiology".)

Hepatitis C virus (HCV) infectivity — There is evidence that PCSK9 possibly can influence HCV infectivity, as it downregulates the HCV entry receptors (LDL-R and tetraspanin protein CD81) [69,70]. Theoretically, PCSK9 antibodies can boost HCV entry into the liver by upregulation of LDL-R and CD81 on hepatocytes [71]. Yet, evidence is conflicting and additional data are needed to confirm this theory. (See "Epidemiology and transmission of hepatitis C virus infection" and "Clinical manifestations and natural history of chronic hepatitis C virus infection".)

Colon tumors — The liver synthesizes bile acids from cholesterol [72]. As a result of more cholesterol uptake by the liver through upregulated LDL-R by PCSK9 antibodies, the liver produces more bile acids. It is demonstrated that high levels of bile acids in the intestine can promote colon tumors in rodents and are associated with colorectal cancer in humans [73-75]. However, no colon abnormalities were found in both rodent as well as non-rodent toxicity studies with evolocumab and alirocumab [76,77]. The potential increase in bile acid levels in the intestine after PCSK9 inhibition is probably not sufficient to be of clinical significance. (See "Pathology and prognostic determinants of colorectal cancer".)

Insulin resistance and diabetes — There is an association between statin therapy and the risk of type 2 diabetes [78]. The mechanism behind this is still incompletely understood.

Mouse studies show PCSK9 may be required for normal pancreatic function [79]. However, published clinical studies to date have not demonstrated any correlation between PCSK9 inhibition, insulin resistance, plasma glucose levels, pancreas insufficiency, or increased rates of diabetes [17,48,49,80]. (See "Insulin resistance: Definition and clinical spectrum".)

Administration — The PCSK9 antibodies alirocumab and evolocumab are available in a sterile, single-use, preservative-free solution for subcutaneous injection in a prefilled syringe or pen. It can be injected in the upper arm or leg or in the abdomen. Evolocumab is also available in an infusion patch pump that delivers the once monthly dose over a period of approximately 10 minutes.

Dosing in adults

Evolocumab

●For primary hyperlipidemia or secondary prevention of cardiovascular events, the recommended dosage of evolocumab is 140 mg subcutaneously every two weeks or 420 mg once monthly; both doses are clinically equivalent [38,52,81].

●For homozygous familial hypercholesterolemia (HoFH), evolocumab 420 mg subcutaneously once monthly is the recommended starting dose in the United States and most other countries. The dose may be increased after 12 weeks of treatment to 420 mg subcutaneously once every two weeks if a clinically meaningful response has not been achieved. HoFH patients on lipid apheresis may initiate evolocumab treatment as 140 mg once every two weeks to correspond with their apheresis schedule, ie, directly after apheresis [54,82-84].

Alirocumab

●For primary hyperlipidemia or secondary prevention of cardiovascular events, the optimal LDL-C lowering dose of alirocumab is either 150 mg once every two weeks or 300 mg once every four weeks. [11]. An optional dose of 75 mg every two weeks is available, albeit with a slightly reduced LDL-C-lowering effect.

LDL-C plasma levels should be measured within 4 to 12 weeks of initiating or changing the dose and every 3 to 12 months thereafter. For patients receiving 300 mg once every 4 weeks, the LDL-C should be measured just prior to the next scheduled dose.

●For patients with heterozygous familial hypercholesterolemia undergoing LDL apheresis, HoFH, or very high-risk with LDL-C levels >50 percent above their minimal acceptable LDL-C goal, we initiate therapy with alirocumab 150 mg once every two weeks. Alirocumab can be administered without regard to the timing of LDL apheresis.

Clinical use — The use of PCSK9 inhibitors is discussed separately. (See "Familial hypercholesterolemia in adults: Treatment", section on 'Second-line therapy' and "Treatment of drug-resistant hypercholesterolemia", section on 'PCSK9 inhibitors' and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

SMALL INTERFERING RNA (INCLISIRAN) — An alternative to monoclonal antibodies for PCSK9 lowering are the PCSK9-small interfering RNA molecules (siRNA) [85]. These molecules offer profound lowering of (intra- and extracellular) PCSK9 at a lower-dose frequency. (See 'PCSK9 antibodies' above.)

Use — Inclisiran can be used as an adjunct to diet and maximally tolerated statin therapy for treatment of heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease that requires further LDL-C lowering in the following patients:

●Those with allergic responses to both evolocumab and alirocumab

●Persons who have difficulty using a pen injector due to arthritis and/or weakness of the hands

It is a subcutaneous injection administered every three months for two doses, then every six months thereafter.

We await clinical endpoint data showing cardiovascular risk reduction before suggesting broader use of inclisiran for high-risk cardiovascular disease patients.

Efficacy — One siRNA (RNAi) inhibitor of PCSK9 synthesis (inclisiran) has undergone phase 1, 2, and 3 evaluation all within the context of the ORION trials [86-89].

The ORION-9, -10, and -11 phase 3 trials were published in 2020 [88,89]. In all studies, the coprimary endpoints were the placebo-corrected percentage change in LDL-C from baseline to day 510 and the time-adjusted percentage change in LDL-C from baseline after day 90 and up to day 540.

●IN ORION-9, 482 adults with heterozygous familial hypercholesterolemia (see "Familial hypercholesterolemia in adults: Overview" and "Familial hypercholesterolemia in adults: Treatment") and treated with maximally tolerated doses of statin were randomly assigned to subcutaneous injections of inclisiran or placebo on days 1, 90, 279, and 450 [88]. The mean baseline LDL-C was 153 mg/dL. At day 510, inclisiran reduced LDL-C by 47.9 percent (95% CI 42.3-53.5) and the corresponding time-adjusted reduction of 44.3 percent (95% CI 40.1-48.5).

●Results of the ORION-10 and -11 trials were published together [89]. In these two trials, statin-treated patients with cardiovascular disease (CVD) or at high risk were randomly assigned to receive inclisiran or placebo administered by subcutaneous injection on day 1, day 90, and every six months over a period of 540 days.

•In both trials, the mean baseline LDL-C was approximately 105 mg/dL (2.72 mmol/L).

•ORION-10 enrolled 1561 patients with CVD. At day 510, inclisiran reduced LDL-C by 52.3 percent (95% CI 48.8-55.7) and the corresponding time-adjusted reduction of 53.8 percent (95% CI 51.3-56.2).

•ORION-11 enrolled 1617 patients with CVD or at high risk. At day 510, inclisiran reduced LDL-C by 49.9 percent (95% CI 46.6-53.1) and the corresponding time-adjusted reduction of 49.2 percent (95% CI 46.8-51.6).

In a patient-level pooled analysis of these three trials (3660 participants), the placebo-corrected change in LDL-C with inclisiran at day 510 was -50.7 percent (95% CI -52.1 to -48.9 percent) [90]. In addition, significant reductions in lipoprotein(a), an independent risk factor for CVD, were seen. (See "Lipoprotein(a)" and "Lipoprotein(a)", section on 'Disease associations'.)

ORION-3 was a four-year open-label extension of the ORION-1 trial [91].

●One arm of the trial included 290 of the 370 patients originally allocated to inclisiran; these 290 patients continued to receive inclisiran 300 mg subcutaneously every six months. The other arm of the study included 92 of 127 patients originally allocated to placebo; these 92 patients were transitioned to evolocumab 140 mg subcutaneously every 14 days until day 360 and then transitioned to inclisiran twice yearly for the duration of ORION-3.

In the inclisiran-only arm, LDL-C was reduced by 47.5 percent. The evolocumab treatment group had reductions in LDL-C ranging from 62.2 to 77.8 percent. Thus, the PCSK9 inhibitor evolocumab was more effective in lowering LDL-C than inclisiran.

Adverse effects — Serious adverse events are relatively rare with inclisiran therapy.

●In a pooled analysis of 3660 patients in ORION 9, 10, and 11, injection-site adverse reactions occurred in 5 percent of those receiving the drug (compared with 0.7 percent in the placebo group), and most were generally mild [90].

●The ORION-3 extension study followed the original ORION-1 cohort (of whom 290 of 370 patients allocated to drug continued into the inclisiran-only arm and 92 of 127 patients allocated to placebo entered the switching arm) [91]. Adverse events at the injection site were equivalent in both arms of the study and were reported in 14 percent of patients. The incidence of treatment-emergent serious adverse events possibly related to the study drug was similar in both arms of the study and was reported in 1 percent of patients.

OTHER STUDIES — In late 2016, the cardiovascular outcome studies of a novel PCSK9 inhibitor bococizumab were halted by the manufacturer, citing attenuation of LDL-C lowering effect over time and greater-than-expected immunogenicity (high-titer antidrug antibodies) and injection site reactions [92,93]. In addition, there was wide variability in LDL-C lowering, even among patients who were antidrug antibody negative.

Multiple pharmaceutical companies are pursuing oral compounds against PCSK9 [94,95]. No oral PCSK9 inhibitor has been developed for human use.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lipid disorders in adults".)

SUMMARY AND RECOMMENDATIONS

●Mechanisms – Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme produced in the liver. PCSK9 binds to the low-density lipoprotein (LDL) receptor on the surface of hepatocytes, leading to its degradation and higher plasma LDL-cholesterol (LDL-C) levels. Blocking PCSK9 with antibodies leads to lower plasma LDL-C levels. (See 'Mechanisms of action' above.)

Alirocumab and evolocumab are fully humanized monoclonal antibodies that bind free plasma PCSK9. They have been approved for clinical use by regulatory agencies. (See 'Mechanisms of action' above.)

●Clinical effects – PCSK9 antibodies significantly lower LDL-C levels. Their use is associated with lower rates of myocardial infarction and stroke. Alirocumab in addition to intensive statin therapy may lead to reduced overall mortality risk after acute coronary syndrome in the long term [19]. (See 'Clinical effect' above.)

●Adverse effects – The most common adverse effect of evolocumab and alirocumab is injection site reactions. Other rates of adverse effects are comparable to those seen with placebo therapies. (See 'Adverse effects' above.)

●Our recommendations for the use of these drugs are found elsewhere. (See "Treatment of drug-resistant hypercholesterolemia", section on 'PCSK9 inhibitors' and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

ACKNOWLEDGMENT — The UpToDate editorial staff thank John J P Kastelein, MD, PhD, FESC, who contributed to earlier versions of this topic review.