Inclisiran: Recommendation for Use
Inclisiran is a recommended medication for LDL-cholesterol lowering as an adjunct to maximally tolerated statin therapy, but PCSK9 monoclonal antibodies should be preferred as first-line PCSK9 inhibitor therapy due to proven cardiovascular outcomes benefits. 1
Primary Recommendation Framework
PCSK9 monoclonal antibodies (evolocumab, alirocumab) are the preferred initial PCSK9 inhibitor choice because they have demonstrated cardiovascular outcomes benefits in the FOURIER and ODYSSEY Outcomes trials, while inclisiran's cardiovascular outcomes trials (ORION-4 and VICTORION-2P) are not expected to complete until 2026-2027. 1
When Inclisiran Should Be Considered
Inclisiran may be specifically chosen over PCSK9 monoclonal antibodies in the following clinical scenarios:
Poor adherence to PCSK9 monoclonal antibodies - The twice-yearly dosing regimen (after initial dose and 3-month dose) offers a significant adherence advantage over the every 2-4 week injections required for monoclonal antibodies 1
Adverse effects from both PCSK9 monoclonal antibodies - Patients who have experienced side effects from both available monoclonal antibodies 1
Inability to self-inject - Patients who cannot perform self-injections but can receive office-based biannual injections 1
Approved Indications
The American College of Cardiology supports inclisiran as an adjunct to diet and maximally tolerated statin therapy for: 2, 3
- Adults with heterozygous familial hypercholesterolemia requiring additional LDL-C lowering
- Adults with atherosclerotic cardiovascular disease (ASCVD) requiring additional LDL-C lowering
- Patients with baseline LDL-C ≥190 mg/dL not due to secondary causes
Expected Efficacy
- LDL-C reduction of approximately 50% with sustained reductions demonstrated for up to 4 years 2
- Clinical trials showed placebo-corrected LDL-C reductions of 44-54% 4
- Pooled analysis from ORION 9-11 trials showed reduction in composite MACE (OR 0.74; 95% CI 0.58-0.94) at 18 months, though individual endpoints for MI and stroke were not significantly reduced 2
Critical Caveats
Do not combine inclisiran with PCSK9 monoclonal antibodies - There is no evidence or mechanistic plausibility for additional efficacy in LDL-C lowering or cardiovascular outcomes benefit from combination therapy; if inclisiran is used, it should replace (not supplement) a PCSK9 monoclonal antibody. 1
Real-world efficacy may be lower than trials - A real-world study showed LDL-C reduction of 38% in patients newly starting inclisiran (compared to 50% in trials), and patients switching from PCSK9 monoclonal antibodies to inclisiran showed an increase in LDL-C of 38%, suggesting inclisiran may be less potent than monoclonal antibodies. 5
Treatment Sequencing
For patients with ASCVD or high-risk primary prevention requiring additional LDL-C lowering beyond maximally tolerated statin:
- First-line nonstatin agent: Ezetimibe 1
- Second-line agent: PCSK9 monoclonal antibody (preferred) or inclisiran (if adherence concerns or contraindications to monoclonal antibodies exist) 1
- Third-line consideration: Bempedoic acid (though preference should be given to ezetimibe and PCSK9 inhibitors as first- and second-line nonstatin agents) 1
Specialist Referral Triggers
Refer to a lipid specialist if the patient is being considered for inclisiran prescription and has: 1
- Continued <50% reduction in LDL-C or LDL-C ≥70 mg/dL (or non-HDL-C ≥100 mg/dL) on maximally tolerated statin with or without ezetimibe and/or bempedoic acid
- Very high-risk ASCVD with LDL-C ≥55 mg/dL despite maximal therapy
Safety Profile
- Mild injection site reactions are the most common adverse effect 5
- Clinical trials showed acceptable safety profiles with no severe adverse effects or fatalities directly attributable to inclisiran 6
- Pregnancy considerations: Should be discontinued when pregnancy is recognized unless benefits outweigh risks; may cause fetal harm based on mechanism of action 1