Inclisiran: The Every-6-Month Injectable Dyslipidemia Medication
Inclisiran (Leqvio®) is the dyslipidemia medication administered via subcutaneous injection every 6 months after an initial loading phase. 1, 2
Dosing Schedule
The FDA-approved dosing regimen consists of: 2
- Initial dose: 284 mg subcutaneous injection at baseline
- Second dose: 284 mg at 3 months
- Maintenance dosing: 284 mg every 6 months thereafter
This twice-yearly maintenance schedule represents a significant adherence advantage over other non-statin lipid-lowering therapies, particularly for patients with adherence concerns. 1
Mechanism and Efficacy
Inclisiran is a small interfering RNA (siRNA) that works differently from PCSK9 monoclonal antibodies: 1
- Mechanism: Interferes with PCSK9 mRNA translation in hepatocytes, producing very long-lasting knockdown of PCSK9 synthesis
- LDL-C reduction: Achieves 44-54% reduction in LDL cholesterol levels 1, 3
- Sustained effect: The 4-year mean LDL-C reduction was 44.2% in ORION-3 study 1
- Time to effect: LDL-lowering can be measured as early as 30 days after initiation 2
In the pivotal ORION-10 and ORION-11 trials, inclisiran demonstrated placebo-corrected LDL-C reductions of 52.3% and 49.9% respectively at day 510, with time-adjusted reductions of 53.8% and 49.2%. 4
FDA-Approved Indications
Inclisiran is indicated as an adjunct to diet and statin therapy for: 2
- Adults with primary hyperlipidemia
- Adults with heterozygous familial hypercholesterolemia (HeFH)
- Patients requiring additional LDL-C lowering beyond maximally tolerated statin therapy
The 2022 ACC Expert Consensus Decision Pathway includes inclisiran as an option for non-statin therapy in patients at very high risk of atherosclerotic cardiovascular disease or those with LDL-C >190 mg/dL. 1, 3
Safety Profile
Inclisiran demonstrates a favorable safety profile comparable to placebo: 2, 4
- Most common adverse reaction: Injection site reactions (2.8% vs 0.9% placebo), predominantly mild and transient 2
- Other common reactions: Arthralgia (4%), bronchitis (3%) 2
- Discontinuation rate: Only 2.5% discontinued due to adverse events (vs 1.9% placebo) 2
- Long-term safety: Analysis of up to 6 years of treatment showed treatment-emergent adverse events occurred at comparable rates to placebo 1
Serious hypersensitivity reactions including angioedema have been reported, making prior serious hypersensitivity to inclisiran a contraindication. 2
Administration Details
The medication must be administered by a healthcare professional via subcutaneous injection into the abdomen, upper arm, or thigh. 2 This requirement means inclisiran is billed under medical benefit rather than pharmacy benefit coverage, which may affect insurance coverage patterns. 1
Clinical Advantages
The VICTORION-Initiate study demonstrated that an "inclisiran first" strategy (adding inclisiran immediately upon failure to reach LDL-C <70 mg/dL despite maximally tolerated statins) led to: 1
- 60% LDL-C reduction versus 7% with usual care at day 330
- 81.8% of patients achieving LDL-C <70 mg/dL versus 22.2% with usual care
- 71.6% achieving LDL-C <55 mg/dL versus 8.9% with usual care
Important Caveats
Cardiovascular outcomes data are pending. The effect of inclisiran on cardiovascular morbidity and mortality has not yet been determined. 1 Two major outcomes trials (ORION-4 and VICTORION-2P) are ongoing with approximately 15,000 participants each, evaluating major adverse cardiac events over 5 years. 1, 5
When comparing to PCSK9 monoclonal antibodies, inclisiran's LDL-C lowering appears approximately 10% less than that achieved with alirocumab or evolocumab in similarly designed trials. 1 However, the convenience of twice-yearly dosing may outweigh this modest difference in efficacy for many patients, particularly those with adherence challenges.