What is the indication and dosing for Inclisiran (generic name) in patients with primary hypercholesterolemia or mixed dyslipidemia?

Inclisiran Indication and Dosing for Primary Hypercholesterolemia or Mixed Dyslipidemia

Inclisiran (Leqvio) is indicated as an adjunct to diet in adults with primary hypercholesterolemia or mixed dyslipidemia who are unable to reach LDL-C goals on maximally tolerated statin therapy, with or without other lipid-lowering therapies, or in patients who are statin intolerant or for whom a statin is contraindicated. 1, 2

Dosing Regimen

• Initial dose: 284 mg administered subcutaneously
• Second dose: 284 mg at 3 months (Day 90)
• Maintenance dosing: 284 mg every 6 months thereafter 1, 3

Patient Selection Algorithm

1. First-line approach: Maximize statin therapy 4
2. Second-line approach: Add ezetimibe if LDL-C targets not achieved 4
3. Third-line approach: Consider inclisiran for patients who:
   • Have very high risk of ASCVD or LDL-C levels above target threshold 4
   • Demonstrate poor adherence to PCSK9 monoclonal antibodies 4
   • Experience adverse effects from PCSK9 monoclonal antibodies 4
   • Have difficulty with self-injection 4

Efficacy Profile

• Provides sustained LDL-C reduction of approximately 45-50% with twice-yearly dosing 4, 5
• LDL-C reduction becomes apparent within 14 days of administration 1
• Mean reductions of 38-51% for LDL-C observed 30-180 days post-dose 1
• At Day 180, LDL-C levels remain reduced by approximately 53% 1
• Reduces serum PCSK9 levels by approximately 75% at Day 120 and 69% at Day 180 following initial and 3-month doses 1

Special Populations

• Geriatric use: No dose adjustments required; no differences in safety or efficacy observed between patients ≥65 years and younger adults 1
• Renal impairment: No dose adjustments necessary for mild, moderate, or severe renal impairment; not studied in end-stage renal disease 1
• Hepatic impairment: No dose adjustment needed for mild to moderate hepatic impairment; not studied in severe hepatic impairment 1

Important Clinical Considerations

• Inclisiran is a double-stranded small interfering RNA (siRNA) that suppresses PCSK9 translation in the liver 1, 5
• Unlike PCSK9 monoclonal antibodies that require more frequent administration, inclisiran's twice-yearly maintenance dosing may improve adherence 2, 3
• Inclisiran has been shown to be effective both in combination with statins and as monotherapy 6
• Recent evidence shows inclisiran monotherapy is superior to both placebo and ezetimibe in reducing LDL-C levels in primary prevention patients not receiving lipid-lowering therapy 6

Safety Profile

• Generally well-tolerated with a safety profile similar to placebo 5
• Most common adverse events are mild to moderate, transient injection-site reactions 2, 5
• No significant differences in liver function tests, kidney function tests, creatine kinase values, or platelet counts compared to placebo 5
• Does not prolong QT interval at clinically relevant doses 1

Clinical Pearls and Caveats

• Inclisiran is not effective in homozygous familial hypercholesterolemia despite lowering PCSK9 levels 7
• No drug-drug interactions expected as inclisiran is not a substrate, inhibitor, or inducer of cytochrome P450 enzymes or transporters 1
• The American College of Cardiology recommends targeting LDL-C reduction of ≥50% from baseline for high-risk patients and LDL-C <55 mg/dL for very high-risk patients 4
• Cardiovascular outcomes data for inclisiran are still pending; ORION-4, VICTORION-1 PREVENT, and VICTORION-2 PREVENT trials are ongoing 3