What is the recommended use and dosing of Leqvio (inclisiran) injection for treating primary hypercholesterolemia or mixed dyslipidemia?

Leqvio (Inclisiran) for Primary Hypercholesterolemia and Mixed Dyslipidemia

Leqvio (inclisiran) is administered as 284 mg subcutaneous injection initially, again at 3 months, then every 6 months thereafter, as an adjunct to diet and maximally tolerated statin therapy for adults with primary hypercholesterolemia (including heterozygous familial hypercholesterolemia) or mixed dyslipidemia who require additional LDL-C reduction. 1

FDA-Approved Indications

Leqvio is indicated as an adjunct to diet and statin therapy for treating adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce LDL cholesterol. 1 The medication is specifically 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. 1, 3

Dosing Regimen and Administration

The recommended dosing schedule consists of:

• Initial dose: 284 mg subcutaneous injection at baseline 1
• Second dose: 284 mg at 3 months 1
• Maintenance dosing: 284 mg every 6 months thereafter 1, 4

Missed Dose Management

• If a planned dose is missed by less than 3 months: Administer Leqvio and maintain the patient's original dosing 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, then every 6 months 1

Administration Details

Leqvio must be administered by a healthcare professional via subcutaneous injection into the abdomen, upper arm, or thigh. 1, 4 Do not inject in areas of active skin disease or injury, such as sunburns, skin rashes, inflammation, or skin infections. 1 The medication should appear clear and colorless to pale yellow; do not use if particulate matter or discoloration is seen. 1

Efficacy

Inclisiran achieves approximately 50% reduction in LDL-C levels with twice-yearly dosing. 5, 4 Specifically:

• Mean placebo-corrected reduction in LDL-C of 50.7% at day 510 in phase 3 trials (ORION-9, ORION-10, ORION-11) 5
• Time-adjusted mean reduction of 50.5%, indicating sustained efficacy 5
• LDL-C reductions ranging from 44-54% across clinical trials 2, 6

The LDL-lowering effect may be measured as early as 30 days after initiation and anytime thereafter without regard to timing of the dose. 1

Mechanism of Action

Inclisiran is a small interfering RNA (siRNA) that interferes with PCSK9 mRNA translation in hepatocytes, producing a very long-lasting knockdown of PCSK9 synthesis. 4 This results in decreased PCSK9 production, which leads to more LDL receptors being available to clear LDL cholesterol from circulation. 6

Safety Profile

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

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

• Injection site reactions: 8% (vs 2% placebo) 1
• Arthralgia: 5% (vs 4% placebo) 1
• Bronchitis: 4% (vs 3% placebo) 1

Injection site reactions are predominantly mild, transient, and not persistent. 5, 2 Adverse reactions led to discontinuation in only 2.5% of patients treated with Leqvio versus 1.9% with placebo. 1

Contraindications

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

Clinical Guideline Support

The 2022 American College of Cardiology Expert Consensus Decision Pathway includes inclisiran as an option for non-statin therapy in patients who cannot tolerate statins or in addition to maximally tolerated statin therapy in those at very high risk of atherosclerotic cardiovascular disease. 5, 6 The American College of Cardiology, American Heart Association, and other major societies include inclisiran among non-statin LDL-lowering therapies that can be added when LDL-C goals are not met with statin therapy alone. 5

Important Caveats

The effect of inclisiran on cardiovascular morbidity and mortality has not yet been determined. 4 Two cardiovascular outcomes trials are currently in progress:

• ORION-4: Following approximately 15,000 participants for a planned median duration of about 5 years 5
• VICTORION-2P: Evaluating major adverse cardiac events over 5 years 4

Until these trials are completed, inclisiran should be used primarily for its proven LDL-C lowering effects in patients who require additional reduction beyond maximally tolerated statin therapy. 5, 1

Practical Advantages

The twice-yearly maintenance dosing regimen after the initial loading phase offers a significant convenience advantage over daily oral medications and other injectable therapies requiring more frequent administration. 5, 4 This infrequent dosing schedule is particularly beneficial for adherence in patients with limited therapeutic options or those who struggle with daily medication regimens. 5