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

Leqvio (Inclisiran) for Hypercholesterolemia

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

FDA-Approved Indication

• Primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), as an adjunct to diet and statin therapy to reduce LDL-C 1
• The European approval extends to mixed dyslipidemia, though the FDA indication is more specific to primary hyperlipidemia 2, 3

Dosing Regimen

The recommended dosing schedule is:

• Initial dose: 284 mg subcutaneous injection on day 1 1
• Second dose: 284 mg at 3 months 1
• Maintenance: 284 mg every 6 months thereafter 1

Missed Dose Management

• If missed by <3 months: Administer and maintain original schedule 1
• If missed by >3 months: Restart the entire dosing sequence (initial dose, 3 months, then every 6 months) 1

Administration Details

• Must be administered by a healthcare professional (not self-administered) 1
• Injection sites: Abdomen, upper arm, or thigh 1
• Avoid areas with active skin disease, injury, sunburns, rashes, inflammation, or infections 1
• Solution should be clear and colorless to pale yellow; do not use if particulate matter or discoloration present 1

Efficacy

• LDL-C reduction of approximately 50% when added to maximally tolerated statin therapy 4, 5
• Specifically, pooled analysis showed 50.7% placebo-corrected reduction at day 510 and 50.5% time-adjusted mean reduction 4
• The ORION-10 trial demonstrated 52.3% reduction at day 510, while ORION-11 showed 49.9% reduction 5
• LDL-C lowering is approximately 10% less than PCSK9 monoclonal antibodies (alirocumab/evolocumab), though no head-to-head trials exist 4

Clinical Positioning

According to the 2022 ACC Expert Consensus, inclisiran should be considered:

• After PCSK9 monoclonal antibodies as the preferred initial PCSK9 inhibitor due to proven cardiovascular outcomes benefits in FOURIER and ODYSSEY Outcomes trials 4
• In place of (not in addition to) PCSK9 mAbs when used, as there is no evidence for additive benefit with combination therapy 4
• Specifically for patients with poor adherence to PCSK9 mAbs, given the twice-yearly dosing advantage 4
• For patients unable to self-inject or those with adverse effects from both PCSK9 mAbs 4
• Referral to a lipid specialist is recommended if considering inclisiran when LDL-C goals remain unmet on maximally tolerated statin with or without ezetimibe and/or bempedoic acid 4

Safety Profile

• Injection site reactions are the most common adverse event (28% vs 8% placebo), though generally mild and none severe or persistent 4, 1
• Arthralgia (4% vs 5%) and bronchitis (3% vs 4%) occurred at similar rates to placebo 1
• Overall safety profile similar to placebo aside from injection site reactions 4, 2
• Contraindicated in patients with prior serious hypersensitivity to inclisiran or excipients, including angioedema 1

Important Caveats

• Cardiovascular outcomes data are pending from ORION-4 and VICTORION-2P trials (expected 2026-2027), unlike PCSK9 mAbs which have proven CV benefit 4, 6
• Billed under medical benefit (not pharmacy benefit) as it must be administered by a healthcare professional, which may affect insurance coverage 4
• LDL-C can be measured as early as 30 days after initiation and anytime thereafter without regard to timing of dose 1