What is the role of inclisiran (PCSK9 inhibitor) for patients who cannot tolerate statins (HMG-CoA reductase inhibitors)?

Role of Inclisiran for Patients Who Cannot Tolerate Statins

Inclisiran is a recommended and effective lipid-lowering therapy for patients who cannot tolerate statins, providing approximately 50% LDL-C reduction with a convenient twice-yearly dosing schedule after initial doses. 1, 2

Mechanism and Efficacy

Inclisiran is a small interfering RNA (siRNA) that targets PCSK9 mRNA, directing catalytic breakdown of PCSK9 mRNA in hepatocytes. This:

• Increases LDL receptor recycling and expression on hepatocyte cell surfaces
• Increases LDL-C uptake from circulation
• Lowers circulating LDL-C levels 3

Key efficacy points:

• Reduces LDL-C by approximately 49-52% 1
• Maintains LDL-C reduction of approximately 45% through 4 years of treatment 2
• Administered subcutaneously on day 1, day 90, and then every 6 months 1
• LDL-C reduction becomes apparent within 14 days of administration 3

Treatment Algorithm for Statin-Intolerant Patients

1. First-line therapy for statin-intolerant patients:

   • Ezetimibe 10 mg daily as monotherapy 2
   • Monitor LDL-C response after 4-12 weeks

2. If LDL-C goal not achieved with ezetimibe:

   • For high/very high-risk patients (including those with established ASCVD): Consider adding inclisiran 1, 2
   • For moderate-risk patients: Consider bempedoic acid 1, 2

3. Specific indications for inclisiran in statin-intolerant patients:

   • Established atherosclerotic cardiovascular disease (ASCVD) 2
   • Heterozygous familial hypercholesterolemia (HeFH) 2, 4
   • Patients requiring significant additional LDL-C lowering 4
   • Patients with adherence concerns (due to twice-yearly dosing) 5

Target LDL-C Levels

Based on risk category:

• Very high risk: <55 mg/dL + ≥50% reduction from baseline 2
• High risk: <70 mg/dL + ≥50% reduction from baseline 2
• Moderate risk: <100 mg/dL 2

Advantages of Inclisiran for Statin-Intolerant Patients

1. Convenient dosing schedule:

   • Initial dose, followed by dose at 3 months, then every 6 months 1
   • May improve adherence compared to other therapies 5

2. Safety profile:

   • No increased risk of muscle or liver adverse events 6
   • Most common adverse effects are mild injection site reactions 5, 7
   • No significant impact on glycemic control (lower risk of new-onset diabetes compared to statins) 6

3. Efficacy in specific populations:

   • Effective regardless of renal function 3
   • Effective in patients with mild to moderate hepatic impairment 3
   • Effective across age groups, with no dose adjustment needed for elderly patients 3

Clinical Evidence in Statin-Intolerant Patients

The ORION-1 trial included individuals with documented statin intolerance, and these patients could continue into the ORION-3 extension trial, where LDL-C reduction of 45% was maintained through 4 years 1. While most patients in inclisiran trials were on statin therapy, evidence suggests similar efficacy in statin-intolerant patients 1.

Comparative Considerations

1. Inclisiran vs. PCSK9 monoclonal antibodies:

   • Both provide significant LDL-C reduction
   • Inclisiran requires less frequent dosing (twice yearly vs. biweekly/monthly)
   • Some data suggest inclisiran may be slightly less potent than PCSK9 monoclonal antibodies 7

2. Inclisiran vs. bempedoic acid:

   • Inclisiran provides greater LDL-C reduction (50% vs. 15-24%) 1
   • Bempedoic acid has demonstrated cardiovascular outcome benefits in statin-intolerant patients (13% reduction in major adverse cardiovascular events) 1
   • Bempedoic acid is administered orally daily, while inclisiran is administered subcutaneously twice yearly 1

Important Caveats and Considerations

1. Cardiovascular outcomes data:

   • Cardiovascular outcome trials for inclisiran are ongoing 1
   • Exploratory analyses suggest reduction in cardiovascular events (7.4% vs. 10.2% in one trial and 7.8% vs. 10.3% in another trial) 1
   • A patient-level pooled analysis suggested cardiovascular events were reduced with inclisiran versus placebo (7.1% vs. 9.4%) 5

2. Real-world efficacy:

   • Some real-world data suggest slightly lower LDL-C reduction (38%) compared to clinical trials (50%) 7
   • Efficacy may be enhanced when combined with statins for patients who can tolerate low doses 7

3. Special populations:

   • Limited data in patients with severe hepatic impairment 3
   • Not studied in patients with end-stage renal disease 3

Inclisiran represents an important therapeutic option for statin-intolerant patients, offering significant LDL-C reduction with a convenient dosing schedule and favorable safety profile. While cardiovascular outcomes data are still pending, its mechanism of action and LDL-C lowering effects suggest it will provide cardiovascular benefit similar to other lipid-lowering therapies.