When should Leqvio (inclisiran) be preferred over Repatha (evolocumab)?

When to Prefer Leqvio (Inclisiran) Over Repatha (Evolocumab)

Repatha (evolocumab) should be the default first-choice PCSK9 inhibitor in nearly all patients due to proven cardiovascular outcomes benefits, with Leqvio (inclisiran) reserved specifically for patients who demonstrate poor adherence to PCSK9 monoclonal antibodies, experience adverse effects from both available PCSK9 mAbs, or are unable to self-inject medications. 1

Primary Recommendation: Repatha First-Line

The 2022 American College of Cardiology Expert Consensus explicitly states that PCSK9 monoclonal antibodies (like Repatha) are preferred as the initial PCSK9 inhibitor of choice based on demonstrated safety, efficacy, and cardiovascular outcomes benefits in the FOURIER and ODYSSEY Outcomes trials. 1 Inclisiran lacks this critical outcomes data, with cardiovascular outcomes trials (ORION-4 and VICTORION-2P) not expected to complete until 2026-2027. 1, 2

Specific Clinical Scenarios Where Leqvio May Be Preferred

1. Documented Poor Adherence to Injectable Therapy

• Patients with a proven track record of missing Repatha doses (every 2 weeks or monthly) may benefit from Leqvio's twice-yearly dosing schedule after initial loading. 1, 2
• The convenience advantage of biannual dosing (after day 1, day 90, then every 6 months) addresses adherence barriers in real-world practice. 3, 4

2. Adverse Effects from BOTH Available PCSK9 mAbs

• Patients must have documented intolerance to both evolocumab (Repatha) and alirocumab (Praluent) before considering inclisiran. 1
• Single PCSK9 mAb intolerance is insufficient justification—try the alternative mAb first. 1

3. Inability to Self-Inject

• Patients physically unable to self-administer subcutaneous injections who lack caregiver support for frequent dosing. 1
• Leqvio requires healthcare professional administration, which may be logistically easier with biannual visits versus biweekly/monthly self-injection. 3

Critical Caveats and Common Pitfalls

Never Combine Leqvio with Repatha

There is no evidence or mechanistic plausibility for additional LDL-C lowering or cardiovascular benefit when combining a PCSK9 mAb with inclisiran. 1, 2 If inclisiran is used, it must replace (not supplement) the PCSK9 mAb. 1

Lack of Outcomes Data is a Major Limitation

Unlike Repatha's proven mortality and morbidity benefits, Leqvio's impact on cardiovascular events, myocardial infarction, and stroke remains unproven. 1, 2 This represents a trade-off of convenience over evidence-based outcomes. 2

LDL-C Lowering Efficacy is Comparable

Both agents reduce LDL-C by approximately 50-60% when added to statin therapy. 5, 4, 6 The choice is not based on superior lipid-lowering but on adherence, tolerability, and outcomes evidence. 6

Treatment Algorithm for PCSK9 Inhibitor Selection

Step 1: Patient on maximally tolerated statin ± ezetimibe with LDL-C ≥70 mg/dL (or ≥55 mg/dL if very high risk). 1, 7

Step 2: Initiate Repatha (evolocumab) 140 mg every 2 weeks or 420 mg monthly as first-line PCSK9 inhibitor. 1, 5

Step 3: Assess adherence and tolerability at 3 months. 7

Step 4: If documented poor adherence, adverse effects from Repatha, or self-injection barriers → trial alirocumab (Praluent) as alternative PCSK9 mAb. 1

Step 5: Only if both PCSK9 mAbs fail due to adherence/tolerability/injection barriers → switch to Leqvio (inclisiran) 284 mg at day 1, day 90, then every 6 months. 1, 3

Step 6: Consider lipid specialist referral if LDL-C targets remain unmet despite PCSK9 inhibitor therapy. 1

Practical Considerations

Dosing Convenience vs. Proven Benefit

• Repatha: 140 mg subcutaneous every 2 weeks or 420 mg monthly (self-administered). 3, 5
• Leqvio: 284 mg subcutaneous at baseline, 3 months, then every 6 months (healthcare professional-administered). 3, 4

Cost and Access

Both agents are expensive, but insurance authorization criteria typically require documented PCSK9 mAb failure before approving inclisiran. 7 Attempting to bypass this sequence may result in coverage denial. 7

Safety Profiles are Similar

Both agents demonstrate favorable safety with injection site reactions being the most common adverse effect. 3, 5, 4, 6 Leqvio shows 2.8% injection site reactions versus 0.5% with placebo. 3

When NOT to Use Leqvio

• First-line PCSK9 inhibitor therapy: Always start with Repatha or alirocumab. 1, 2
• Patients already adherent to PCSK9 mAbs: No reason to switch if tolerating and responding well. 1
• Expectation of superior cardiovascular outcomes: No evidence exists for this claim. 2
• Combination with PCSK9 mAb: Explicitly contraindicated by guidelines. 1, 2