What is the role of inclisiran in secondary prevention for patients with established cardiovascular disease?

Role of Inclisiran in Secondary Prevention for Established Cardiovascular Disease

Inclisiran should be considered as a third-line therapy for secondary prevention in patients with established cardiovascular disease who have not achieved LDL-C goals despite maximally tolerated statin therapy and ezetimibe, or in those with statin intolerance who need additional LDL-C lowering. 1

Mechanism and Efficacy

• Inclisiran is a small interfering RNA (siRNA) that targets PCSK9 by directing catalytic breakdown of mRNA for PCSK9 in hepatocytes, increasing LDL receptor recycling and expression, thereby lowering circulating LDL-C levels 2
• It provides significant LDL-C reductions of 49-52% in patients with established cardiovascular disease or ASCVD risk equivalents 1
• Administered subcutaneously with an initial dose, a second dose at 90 days, and then every 6 months thereafter, offering a less frequent dosing schedule than PCSK9 monoclonal antibodies 1, 3

Position in Treatment Algorithm

First-line therapy:

• High-intensity statin therapy remains the foundation of secondary prevention, aiming for ≥50% LDL-C reduction from baseline and an LDL-C goal of <55 mg/dL 1

Second-line therapy:

• Add ezetimibe to maximally tolerated statin therapy if LDL-C goals are not achieved 1

Third-line therapy options:

1. PCSK9 monoclonal antibodies (evolocumab or alirocumab) are preferred as initial PCSK9 inhibitors due to their demonstrated cardiovascular outcomes benefits in clinical trials 1
2. Inclisiran may be considered in specific situations:
   • For patients with demonstrated poor adherence to PCSK9 monoclonal antibodies 1
   • For those experiencing adverse effects from PCSK9 monoclonal antibodies 1
   • For patients unable to self-inject more frequently 1
3. Bempedoic acid may be considered for additional LDL-C lowering if other options are not tolerated or contraindicated 1

Important Clinical Considerations

• Inclisiran should be used in place of, not in addition to, PCSK9 monoclonal antibodies as there is no evidence for additional benefit with combination therapy 1
• In exploratory analyses from ORION-10 and ORION-11 trials, inclisiran was associated with fewer cardiovascular events compared to placebo (7.4% vs 10.2% in ORION-10 and 7.8% vs 10.3% in ORION-11) 1
• Definitive cardiovascular outcomes data for inclisiran are still pending; the ORION-4 and VICTORION-2P cardiovascular outcomes trials are expected to be completed in 2026-2027 1
• Inclisiran has demonstrated a favorable safety profile in clinical trials with injection site reactions occurring in approximately 5% of patients 4

Special Populations

• For patients with statin intolerance:
  • Inclisiran is a viable option after attempting ezetimibe or other non-statin therapies 1
  • The ORION-1 trial included patients with documented statin intolerance, and the ORION-3 extension showed maintained LDL-C reduction of 45% through year 4 1
  • About 33% of participants in the ORION-3 extension were not taking statin therapy 1

Practical Implementation

• Inclisiran's twice-yearly maintenance dosing schedule (after initial and 3-month doses) may improve medication adherence compared to daily oral medications or more frequent injections 3, 5
• The medication requires subcutaneous administration but does not need refrigeration like some PCSK9 monoclonal antibodies 3
• Peak plasma concentrations occur approximately 4 hours post-dose with a terminal elimination half-life of about 9 hours, but the pharmacodynamic effect persists for months due to its mechanism of action 2

Limitations and Caveats

• Unlike PCSK9 monoclonal antibodies, inclisiran currently lacks definitive cardiovascular outcomes data 1
• Cost considerations and insurance coverage may impact accessibility for some patients 3
• Patients should be monitored for injection site reactions, although these are generally mild 4