For an adult with atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia who has not reached LDL‑C goals despite maximally tolerated statin therapy (with or without ezetimibe), should I choose evolocumab (monoclonal antibody) or inclisiran (small interfering RNA) for PCSK9 inhibition?

Evolocumab vs Inclisiran for PCSK9 Inhibition

Primary Recommendation

Choose evolocumab (Repatha) as the first-line PCSK9 inhibitor for patients with ASCVD or heterozygous familial hypercholesterolemia who have not reached LDL-C goals despite maximally tolerated statin therapy with or without ezetimibe. 1

The 2022 ACC Expert Consensus Decision Pathway explicitly states that "a PCSK9 mAb is preferred as the initial PCSK9 inhibitor of choice in view of their demonstrated safety, efficacy, and cardiovascular outcomes benefits in FOURIER and ODYSSEY Outcomes." 1 Evolocumab reduced major adverse cardiovascular events by 15% with proven mortality and morbidity benefits in the FOURIER trial, whereas inclisiran currently lacks cardiovascular outcomes data. 2

---

Evidence-Based Treatment Algorithm

Step 1: Confirm Eligibility for PCSK9 Inhibition

• LDL-C remains ≥70 mg/dL despite maximally tolerated statin plus ezetimibe in patients with clinical ASCVD 1, 2
• Target LDL-C <55 mg/dL with ≥50% reduction from baseline for very high-risk patients 1, 2
• Very high-risk criteria include: recent acute coronary syndrome, history of myocardial infarction, ischemic stroke, symptomatic peripheral arterial disease, or multiple high-risk conditions 2

Step 2: Initiate Evolocumab as First-Line PCSK9 Inhibitor

• Dosing: 140 mg subcutaneously every 2 weeks OR 420 mg subcutaneously monthly 3
• LDL-C reduction: Approximately 50-60% additional reduction 2, 4
• Cardiovascular benefit: 15% relative risk reduction in major adverse cardiovascular events, 1.5% absolute risk reduction over 2.2 years 2
• Mechanism: Monoclonal antibody that binds extracellular PCSK9 protein, preventing LDL receptor degradation 3

Step 3: Consider Inclisiran Only in Specific Scenarios

Inclisiran should be reserved for patients who meet all of the following criteria 1, 5:

• Demonstrated poor adherence to PCSK9 monoclonal antibodies (missed doses, inability to maintain every-2-week schedule)
• Adverse effects from both evolocumab and alirocumab
• Inability to self-inject requiring healthcare provider administration

---

Key Differences Between Evolocumab and Inclisiran

Cardiovascular Outcomes Evidence

• Evolocumab: Proven 15% reduction in major adverse cardiovascular events in FOURIER trial with 27,564 patients over 2.2 years 2
• Inclisiran: No cardiovascular outcomes data available; ORION-4 and VICTORION trials ongoing and will not be completed for several years 1, 6

Mechanism of Action

• Evolocumab: Monoclonal antibody that binds circulating PCSK9 protein extracellularly 3, 7
• Inclisiran: Small interfering RNA (siRNA) that silences PCSK9 mRNA translation intracellularly, inhibiting PCSK9 synthesis at the hepatocyte level 1, 8, 7

Dosing Frequency

• Evolocumab: Every 2 weeks (140 mg) or monthly (420 mg) 3
• Inclisiran: Initial dose, repeat at 3 months, then every 6 months thereafter 1, 8

LDL-C Lowering Efficacy

• Evolocumab: 50-60% reduction 2, 4
• Inclisiran: 44-54% reduction (pooled analysis: 50.7% at day 510) 1, 6, 9

Safety Profile

• Evolocumab: Similar adverse events to placebo; injection-site reactions rare 2
• Inclisiran: Injection-site reactions more frequent (5.0% vs 0.7% placebo) but predominantly mild; otherwise similar safety profile 1, 9

---

Clinical Scenarios Favoring Inclisiran

Adherence Concerns

• Patients with documented non-adherence to twice-monthly or monthly injections may benefit from the 6-month dosing interval of inclisiran 1, 5
• The infrequent maintenance dosing confers a convenience advantage for patients who struggle with frequent self-injection 9

Intolerance to Both PCSK9 Monoclonal Antibodies

• If a patient experiences adverse effects from both evolocumab and alirocumab, inclisiran becomes a reasonable alternative 1, 5
• Inclisiran has a similar overall safety profile to placebo aside from injection-site reactions 1, 9

Inability to Self-Inject

• Patients who cannot self-administer injections but can access healthcare provider visits every 6 months may prefer inclisiran 1

---

Critical Pitfalls to Avoid

Do Not Use Inclisiran as First-Line PCSK9 Inhibitor

• The ACC explicitly states there is "currently no evidence for additional efficacy in LDL-C lowering or cardiovascular outcomes benefit" for inclisiran compared to PCSK9 monoclonal antibodies 1
• Inclisiran should replace, not be added to, a PCSK9 monoclonal antibody if used 1

Do Not Skip Ezetimibe Before PCSK9 Inhibition

• Many guidelines and reimbursement policies require ezetimibe use as a precondition for prescribing PCSK9 inhibitor therapy 1
• Ezetimibe provides 15-20% additional LDL-C reduction at lower cost with established long-term safety 2

Verify Current LDL-C Levels Before Initiating Therapy

• Current LDL-C ≥70 mg/dL is required to justify PCSK9 inhibitor therapy in patients with ASCVD 5
• Inadequate documentation of LDL-C levels or ASCVD status may result in denial of coverage 5

Confirm Maximally Tolerated Statin Therapy

• Patients must be on the highest tolerated dose of a high-intensity statin before adding PCSK9 inhibition 1, 2
• Document specific statins trialed, doses used, and reasons for intolerance if applicable 5

---

Monitoring and Follow-Up

LDL-C Assessment Timeline

• Measure LDL-C 4 weeks after initiating evolocumab 2
• Measure LDL-C at day 90 (3 months) after initiating inclisiran, then at 6-month intervals 1

Target Achievement

• Very high-risk patients: LDL-C <55 mg/dL with ≥50% reduction from baseline 1, 2
• High-risk patients: LDL-C <70 mg/dL 1, 2
• Secondary target: Non-HDL-C <85 mg/dL for very high-risk patients 1

Safety Monitoring

• No routine laboratory monitoring required for either agent 3, 9
• Assess for injection-site reactions, particularly with inclisiran (5% incidence) 1, 9
• Monitor for cardiovascular events and medication adherence 2

---

Cost and Access Considerations

Reimbursement Requirements

• Most payers require documentation of maximally tolerated statin plus ezetimibe before approving PCSK9 inhibitors 1, 5
• Some countries restrict PCSK9 inhibitor access to specialists (cardiologists, endocrinologists) 1
• Inclisiran reimbursement varies by country; some require cardiovascular outcomes data not yet available 1

Patient Assistance Programs

• Both evolocumab and inclisiran offer patient assistance programs and copay support for eligible patients 2
• Prior authorization typically required for both agents 5