What is the indication and dosing regimen for Leqvio (inclisiran) in patients with primary hypercholesterolemia or mixed dyslipidemia?

Leqvio (Inclisiran) for Hypercholesterolemia

Leqvio (inclisiran) is FDA-approved as an adjunct to diet and statin therapy for adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce LDL-C, administered as 284 mg subcutaneously initially, at 3 months, then every 6 months. 1

FDA-Approved Indication

• Primary indication: Adults with primary hyperlipidemia (including HeFH) or mixed dyslipidemia as an adjunct to diet and statin therapy to reduce LDL-C 1
• Intended for patients unable to reach LDL-C goals on maximally tolerated statin therapy, with or without other lipid-lowering therapies 2
• Can be used alone or with other lipid-lowering therapies in patients who are statin-intolerant or for whom statins are contraindicated 2, 3

Dosing Regimen

Standard dosing protocol 1:

• Initial dose: 284 mg subcutaneous injection at baseline
• Second dose: 284 mg at 3 months
• Maintenance: 284 mg every 6 months thereafter

Missed dose management 1:

• If missed by less than 3 months: Administer and continue original schedule
• If missed by more than 3 months: Restart entire dosing sequence (initial dose, 3 months, then every 6 months)

Administration Requirements

• Must be administered by a healthcare professional 1
• Injection sites: Abdomen, upper arm, or thigh 1
• Avoid areas of active skin disease, injury, sunburns, rashes, inflammation, or infections 1
• Appears as clear, colorless to pale yellow solution; do not use if particulate matter or discoloration present 1

Efficacy

• LDL-C reduction: Approximately 44-54% reduction in LDL-C levels 4
• Mean placebo-corrected reduction of 50.7% at day 510 in phase 3 trials (ORION-9, ORION-10, ORION-11) 5
• Time-adjusted mean reduction of 50.5% with sustained efficacy 5
• LDL-lowering effect measurable as early as 30 days after initiation 1

Clinical Positioning per ACC Guidelines

The 2022 ACC Expert Consensus Decision Pathway positions inclisiran as follows 6:

• PCSK9 monoclonal antibodies (alirocumab, evolocumab) are preferred as the initial PCSK9 inhibitor due to demonstrated cardiovascular outcomes benefits in FOURIER and ODYSSEY Outcomes trials 6
• Inclisiran may be considered in specific scenarios 6:
  • Patients with demonstrated poor adherence to PCSK9 mAbs (due to twice-yearly vs. every 2-week dosing)
  • Adverse effects from both PCSK9 mAbs
  • Patients unable to self-inject
• Should replace, not be added to, PCSK9 mAbs: No evidence for additional efficacy or cardiovascular benefit with combination therapy 6
• Referral to lipid specialist recommended if considering inclisiran for patients with persistent LDL-C elevation 6

Safety Profile

Common adverse reactions (≥3%) 1:

• Injection site reactions: 8% (vs. 2% placebo) - predominantly mild, transient, non-persistent 5, 1
• Arthralgia: 5% (vs. 4% placebo) 1
• Bronchitis: 4% (vs. 3% placebo) 1

Contraindication 1:

• Prior serious hypersensitivity reaction to inclisiran or any excipients (including angioedema)

Overall safety: Favorable profile comparable to placebo in clinical trials 5, 7, 4

Critical Caveats

Cardiovascular outcomes data pending 5, 7:

• ORION-4 and VICTORION-2P trials evaluating major adverse cardiac events are ongoing
• Expected completion in 2026 and 2027, respectively
• Unlike PCSK9 mAbs, inclisiran lacks proven cardiovascular morbidity/mortality benefit at this time

Treatment hierarchy for ASCVD patients 6:

1. Ezetimibe as first-line nonstatin agent
2. PCSK9 mAb as second-line (proven CV outcomes benefit)
3. Bempedoic acid may be considered (especially with statin intolerance)
4. Inclisiran reserved for specific adherence/tolerability scenarios

Practical advantage: The twice-yearly maintenance dosing after initial loading provides significant adherence benefit compared to every 2-week PCSK9 mAb injections 5, 7, 2