Introduction
Evolocumab (Repatha®) is a fully human monoclonal antibody that represents a significant advancement in lipid management therapy. As a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, it offers a novel mechanism for lowering low-density lipoprotein cholesterol (LDL-C) in patients who require additional lipid reduction beyond what can be achieved with maximally tolerated statin therapy.
Mechanism of Action
Evolocumab binds to PCSK9 with high affinity and specificity, preventing its interaction with the low-density lipoprotein receptor (LDLR). Under normal physiological conditions, PCSK9 binds to LDLRs on hepatocyte surfaces, promoting their degradation and reducing the liver's capacity to clear LDL-C from circulation. By inhibiting PCSK9, evolocumab increases the number of LDLRs available on hepatocytes, enhancing LDL-C uptake and catabolism, thereby significantly reducing circulating LDL-C levels.
Indications
- Primary hyperlipidemia (including heterozygous familial hypercholesterolemia [HeFH]) as an adjunct to diet and maximally tolerated statin therapy
- Homozygous familial hypercholesterolemia (HoFH) in combination with other lipid-lowering therapies
- Established cardiovascular disease to reduce risk of myocardial infarction, stroke, and coronary revascularization
Dosage and Administration
- Standard dosing: 140 mg subcutaneously every 2 weeks OR 420 mg subcutaneously once monthly
- Administration: Subcutaneous injection in the abdomen, thigh, or upper arm
- Special populations: No dosage adjustment required for renal impairment or mild-to-moderate hepatic impairment
- Preparation: Allow prefilled syringe or autoinjector to reach room temperature for 30 minutes before administration
Pharmacokinetics
- Absorption: Bioavailability approximately 72-80% following subcutaneous administration
- Distribution: Volume of distribution ~3.3 L; primarily in vascular space
- Metabolism: Degraded via proteolytic enzymes throughout the body; not metabolized by cytochrome P450 enzymes
- Elimination: Half-life ~11-17 days; clearance occurs via linear and nonlinear pathways
- Steady-state: Reached after 2-3 months of regular dosing
Contraindications
- History of serious hypersensitivity reaction to evolocumab or any component of the formulation
- Active hepatic disease (in patients with HoFH)
Warnings and Precautions
- Hypersensitivity reactions: May occur, including rash, urticaria, and rarely anaphylaxis
- Adverse cardiovascular events: Although evolocumab reduces cardiovascular risk, monitor patients for new cardiovascular symptoms
- Hepatic effects: Monitor liver function tests periodically
- Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity
Drug Interactions
- No clinically significant pharmacokinetic interactions identified with commonly co-administered drugs
- Does not inhibit or induce cytochrome P450 enzymes
- Additive LDL-C lowering effects when used with statins, ezetimibe, or other lipid-lowering therapies
Adverse Effects
Common (≥2% incidence):- Injection site reactions (pain, erythema, bruising)
- Nasopharyngitis
- Upper respiratory tract infections
- Influenza
- Back pain
- Hypersensitivity reactions
- Neurocognitive events (reported in clinical trials but causal relationship not established)
Monitoring Parameters
- Baseline: Lipid panel (LDL-C, HDL-C, triglycerides, total cholesterol), liver function tests
- Therapeutic monitoring: Lipid panel 4-8 weeks after initiation or dosage change, then every 3-12 months
- Periodic monitoring: Liver function tests annually or as clinically indicated
- Clinical assessment: Cardiovascular status, injection site reactions, hypersensitivity symptoms
Patient Education
- Proper injection technique and rotation of injection sites
- Importance of continuing other prescribed lipid-lowering therapies unless instructed otherwise
- Recognition and reporting of injection site reactions
- Signs of hypersensitivity reactions (rash, itching, swelling)
- Storage requirements (refrigerate at 2°C to 8°C; do not freeze)
- Importance of adherence to prescribed dosing schedule
- Continue lifestyle modifications including heart-healthy diet and physical activity
References
1. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722. 2. Repatha® (evolocumab) prescribing information. Amgen Inc.; 2021. 3. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489-1499. 4. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36(17):1012-1022. 5. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation. 2019;139(25):e1082-e1143.