When is Inclisiran used for treating high cholesterol (Hypercholesterolemia)?

When to Use Inclisiran for Hypercholesterolemia

Inclisiran is primarily indicated as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL-C. 1

Primary Indications for Inclisiran

Inclisiran should be considered in the following clinical scenarios:

1. Patients with established ASCVD who have not achieved target LDL-C levels:

   • Patients who have achieved <50% reduction in LDL-C and LDL-C ≥55 mg/dL (or non-HDL-C ≥85 mg/dL) despite maximally tolerated statin therapy plus ezetimibe 2
   • Target LDL-C should be <70 mg/dL for secondary prevention, and <55 mg/dL for very high-risk patients 3

2. Patients with heterozygous familial hypercholesterolemia:

   • When LDL-C remains ≥100 mg/dL despite maximally tolerated statin therapy 2

3. Patients with statin intolerance:

   • When patients cannot tolerate statins or can only tolerate low doses insufficient to achieve LDL-C goals 2

Specific Patient Selection Considerations

Inclisiran may be particularly beneficial for:

• Patients with adherence concerns: The twice-yearly dosing regimen (after initial doses at day 1 and day 90) offers a significant advantage for patients with demonstrated poor adherence to daily medications or PCSK9 monoclonal antibodies that require more frequent administration 2

• Patients unable to self-inject: Since inclisiran must be administered by a healthcare professional, it's suitable for patients who cannot self-administer injectable medications 2

• Patients with adverse effects from PCSK9 monoclonal antibodies: Inclisiran provides an alternative mechanism for PCSK9 inhibition 2

Treatment Algorithm

1. First-line therapy: Maximally tolerated statin therapy + lifestyle modifications
2. Second-line therapy: Add ezetimibe when LDL-C goals not achieved with statins alone
3. Third-line therapy: Consider PCSK9 monoclonal antibodies (evolocumab or alirocumab) or inclisiran when LDL-C goals not achieved with statin + ezetimibe
   • PCSK9 mAbs are currently preferred as initial PCSK9 inhibitors due to demonstrated cardiovascular outcomes benefits 2
   • Inclisiran should be considered when adherence is a concern or PCSK9 mAbs are not tolerated

Dosing and Administration

• Initial dose: 284 mg subcutaneous injection
• Second dose: 284 mg at 3 months
• Maintenance: 284 mg every 6 months thereafter 1
• Must be administered by a healthcare professional 2

Efficacy and Expected Outcomes

• Inclisiran reduces LDL-C by approximately 50% (49-52%) 2, 3
• Maintains LDL-C reduction of approximately 45% through 4 years of treatment 2, 3
• The effect on cardiovascular morbidity and mortality has not yet been determined 2
• Cardiovascular outcomes trials (ORION-4 and VICTORION-2P) are ongoing with results expected in 2026-2027 2

Important Caveats and Considerations

• Insurance coverage: Coverage may vary as inclisiran is billed under medical benefit rather than pharmacy benefit 2
• Cost considerations: Initial year therapy costs are higher than annual costs of PCSK9 mAbs, but subsequent years may be less expensive 2
• Lack of cardiovascular outcomes data: Unlike PCSK9 mAbs, inclisiran does not yet have completed cardiovascular outcomes trials 2, 4
• Injection site reactions: More common with inclisiran than placebo (5.0% vs 0.7%), though predominantly mild 2
• Not for combination therapy: There is no evidence or mechanistic plausibility for additional benefit when combining inclisiran with PCSK9 mAbs 2

Monitoring

• Lipid panel every 3-6 months to assess LDL-C response
• Clinical assessment for cardiovascular symptoms
• Evaluation of injection site reactions

By following this approach to inclisiran therapy, clinicians can appropriately select patients who will benefit most from this novel LDL-C lowering therapy while awaiting definitive cardiovascular outcomes data.