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

Leqvio (Inclisiran) for Primary Hypercholesterolemia and Mixed Dyslipidemia

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 subcutaneous injection initially, at 3 months, then every 6 months. 1

FDA-Approved Indication

• Inclisiran is indicated for adults with primary hypercholesterolemia (including HeFH) or mixed dyslipidemia as an adjunct to diet and statin therapy. 1, 2, 3
• The medication is intended for patients unable to reach LDL-C goals on maximally tolerated statin therapy, with or without other lipid-lowering therapies. 2, 3
• In patients who are statin-intolerant or for whom a statin is contraindicated, inclisiran can be used alone or in combination with other lipid-lowering therapies. 2, 3

Dosing Regimen

The recommended dosing schedule is 284 mg administered subcutaneously initially, again at 3 months, and then every 6 months thereafter. 1, 4, 5

Administration Details

• Inclisiran must be administered by a healthcare professional via subcutaneous injection into the abdomen, upper arm, or thigh. 1, 5
• Do not inject in areas of active skin disease or injury, such as sunburns, skin rashes, inflammation, or skin infections. 1
• The solution should appear clear and colorless to pale yellow; do not use if particulate matter or discoloration is seen. 1

Missed Dose Management

• If a planned dose is missed by less than 3 months, administer inclisiran and maintain dosing according to the patient's original schedule. 1
• If a planned dose is missed by more than 3 months, restart with a new dosing schedule—administer initially, again at 3 months, and then every 6 months. 1

Efficacy

Inclisiran achieves approximately 44-54% reduction in LDL-C levels with sustained efficacy. 5, 6

• In phase 3 trials (ORION-9, ORION-10, ORION-11), inclisiran demonstrated a mean placebo-corrected reduction in LDL-C of 50.7% at day 510, with a time-adjusted mean reduction of 50.5%. 4
• The LDL-lowering effect can be measured as early as 30 days after initiation and anytime thereafter without regard to timing of the dose. 1
• Long-term data from the ORION-3 study showed sustained 44.2% mean LDL-C reduction at 4 years. 5

Mechanism of Action

Inclisiran is a small interfering RNA (siRNA) that inhibits hepatic PCSK9 mRNA translation, producing a very long-lasting knockdown of PCSK9 synthesis. 5, 6

• By reducing PCSK9 production, inclisiran increases the number of LDL receptors available to clear circulating LDL-C. 6
• This mechanism provides sustained LDL-C lowering with infrequent dosing. 2

Safety Profile

Inclisiran demonstrates a favorable safety profile comparable to placebo, with the most common adverse reaction being injection site reactions. 4, 5, 1

Common Adverse Reactions (≥3% and more frequent than placebo):

• Injection site reactions: 8% (vs 2% placebo) - predominantly mild, transient, and not persistent 1, 4
• Arthralgia: 5% (vs 4% placebo) 1
• Bronchitis: 4% (vs 3% placebo) 1

Contraindications

Inclisiran is contraindicated in patients with prior serious hypersensitivity reaction to inclisiran or any excipients, including angioedema. 1

Important Safety Considerations

• Treatment-emergent adverse events occurred at comparable rates to placebo in long-term safety analyses. 5
• Adverse reactions led to discontinuation of treatment in only 2% of patients. 1

Guideline-Based Positioning

The 2022 ACC Expert Consensus Decision Pathway positions inclisiran as an alternative to PCSK9 monoclonal antibodies, particularly for patients with adherence issues or injection intolerance. 7

When to Consider Inclisiran:

• PCSK9 monoclonal antibodies (evolocumab, alirocumab) are preferred as the initial PCSK9 inhibitor due to demonstrated cardiovascular outcomes benefits in FOURIER and ODYSSEY Outcomes trials. 7
• Inclisiran may be considered in patients with demonstrated poor adherence to PCSK9 mAbs, given its twice-yearly dosing regimen. 7
• Patients with adverse effects from both PCSK9 mAbs or those unable to self-inject may be considered for inclisiran therapy. 7
• There is no evidence for additional benefit from combining a PCSK9 mAb with inclisiran; if inclisiran is used, it should replace (not add to) a PCSK9 mAb. 7

Treatment Algorithm Position:

• First-line nonstatin: Ezetimibe 7
• Second-line nonstatin: PCSK9 mAb (preferred) or inclisiran (alternative) 7
• Third-line consideration: Bempedoic acid (especially for statin-associated myalgias) 7

Critical Caveats

The effect of inclisiran on cardiovascular morbidity and mortality has not yet been determined. 5, 6

• The ORION-4 and VICTORION-2P cardiovascular outcomes trials are ongoing and anticipated to be completed in 2026 and 2027, respectively. 7, 4
• ORION-4 is following approximately 15,000 participants for a planned median duration of about 5 years. 4
• Until cardiovascular outcomes data are available, PCSK9 monoclonal antibodies with proven CV benefit should be preferred over inclisiran in most patients. 7

Referral Considerations:

If a patient is considered for inclisiran prescription and has continued LDL-C ≥70 mg/dL (or non-HDL-C ≥100 mg/dL) on maximally tolerated statin with or without ezetimibe and/or bempedoic acid, referral should be made to a lipid specialist. 7

Practical Advantages

• The twice-yearly maintenance dosing regimen offers a significant convenience advantage over daily oral medications and biweekly/monthly injectable PCSK9 mAbs. 4, 2
• This dosing schedule may improve long-term adherence in patients with documented poor medication compliance. 7
• Healthcare professional administration ensures proper injection technique and dosing adherence. 5, 1