What is the recommended treatment regimen for Repatha (evolocumab) in patients with high cholesterol?

Repatha (Evolocumab) Treatment Regimen for High Cholesterol

Repatha should be administered subcutaneously at either 140 mg every 2 weeks OR 420 mg once monthly, with both regimens providing equivalent LDL-C reduction of approximately 59-64% when added to statin therapy. 1, 2

FDA-Approved Dosing Regimens

Standard Dosing for Adults with Established ASCVD or Primary Hyperlipidemia

• 140 mg every 2 weeks administered subcutaneously 1
• 420 mg once monthly administered subcutaneously 1
• Both regimens provide comparable LDL-C reduction (64% vs 58% respectively) 3
• When switching between regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen 1

Administration Details

• Inject into the abdomen, thigh, or upper arm 1, 2
• Rotate injection sites with each administration 1
• Available as prefilled autoinjectors or prefilled syringes 1
• Consider latex-free presentations for latex-sensitive patients 1

Clinical Indications and Patient Selection

Primary Indication: Established ASCVD

• Strongly recommended for adults with established atherosclerotic cardiovascular disease to reduce risk of myocardial infarction, stroke, and coronary revascularization 4, 2
• Demonstrated 20% reduction in cardiovascular death, myocardial infarction, or stroke in the FOURIER trial 4
• Reduces primary composite endpoint (CV death, MI, stroke, unstable angina, or revascularization) by 15% (HR 0.85,95% CI 0.79-0.92) 5

LDL-C Thresholds for Initiation

Very High-Risk Patients (with established ASCVD):

• Add Repatha when LDL-C remains ≥70 mg/dL despite maximally tolerated statin plus ezetimibe 2
• Target LDL-C goal of <55 mg/dL with ≥50% reduction from baseline 4

Severe Primary Hypercholesterolemia/Familial Hypercholesterolemia:

• Add Repatha when LDL-C remains ≥100 mg/dL despite maximally tolerated statin plus ezetimibe 2
• For patients without clinical ASCVD but with LDL-C >180 mg/dL (4.5 mmol/L) on maximal therapy 2
• Lower threshold of >140 mg/dL (3.6 mmol/L) if additional risk factors present (diabetes with target organ damage, Lp(a) >50 mg/dL, premature family history of ASCVD, marked hypertension) 2

Prerequisite Treatment Requirements

Mandatory Statin Optimization

• Patients must be on maximally tolerated statin therapy for minimum of 4 weeks on stable dose before initiating Repatha 2, 4
• Preferably high-intensity statin therapy 2
• Verify adherence before adding Repatha, as non-adherence is a common cause of failure to reach LDL-C goals 2

Sequential Add-On Therapy Algorithm

1. First: Maximize statin dose and ensure adherence 2
2. Second: Add ezetimibe if LDL-C remains elevated after 4 weeks 2
3. Third: Add Repatha if LDL-C remains above threshold after 4 weeks on statin plus ezetimibe 2

Special Populations

Homozygous Familial Hypercholesterolemia (HoFH)

• Initial dose: 420 mg once monthly 1, 2
• If clinically meaningful response not achieved in 12 weeks, increase to 420 mg every 2 weeks 1, 3
• Patients on lipid apheresis may initiate at 420 mg every 2 weeks to correspond with apheresis schedule 1, 2
• Administer after apheresis session is complete 1
• Not recommended for patients with negative/negative LDLR mutations (LDL receptor activity <2%) as some receptor activity is required for efficacy 2

Pediatric Patients (≥10 years) with HeFH

• Same dosing as adults: 140 mg every 2 weeks OR 420 mg once monthly 1, 2

Statin-Intolerant Patients

• Repatha can be used as monotherapy or with ezetimibe in patients who cannot tolerate statins 2, 6
• Approved by NICE for patients intolerant to statins who fail to meet LDL-C targets 2

Monitoring and Response Assessment

Timing of LDL-C Assessment

• Assess LDL-C as early as 4 weeks after initiation to evaluate response 1, 2
• The LDL-lowering effect can be measured at this early timepoint 1
• Median LDL-C reduction to 30 mg/dL achieved at 48 weeks from baseline of 92 mg/dL 3, 5

Expected Efficacy

• 59-64% additional LDL-C reduction when added to maximally tolerated statin therapy 4, 3
• Sustained efficacy maintained long-term over median 2.2 years of follow-up 5
• Benefits consistent across all baseline LDL-C levels, including lowest quartile (median 74 mg/dL) 5

Safety Profile

Common Adverse Events

• Injection-site reactions (2.1% vs 1.6% with placebo) 5
• Nasopharyngitis, influenza, myalgia, noncardiac chest pain 2
• Most adverse events occur with similar frequency to placebo 5, 7

Important Safety Considerations

• No increase in neurocognitive events despite initial concerns in early trials 2, 7
• Risk of adverse events does not vary by achieved LDL-C level, even with very low levels 7
• Hypersensitivity reactions possible; discontinue if serious reaction occurs 2
• No safety data in pregnancy/lactation; avoid use 2

Drug Interactions

• Potential interactions with cyclosporine, fibrates, and bile acid sequestrants 2

Critical Clinical Pearls

Common Pitfall: Initiating Repatha without first optimizing statin and ezetimibe therapy. The guidelines universally require maximally tolerated statin therapy as the foundation, with ezetimibe as the second-line add-on before considering PCSK9 inhibitors 2.

Cost Consideration: While highly effective, PCSK9 inhibitors are expensive. The 2022 BMJ guideline emphasizes strong recommendations for use only in high and very high-risk patients, with weak recommendations for moderate-risk patients, reflecting the balance between small absolute benefits and significant cost burden 2.

Shared Decision-Making: Given variability in patient values regarding small absolute risk reductions versus injection burden and cost, engage in thorough shared decision-making, particularly for primary prevention 2.