What is the efficacy and safety of Leqvio (inclisiran) for lowering Low-Density Lipoprotein Cholesterol (LDL-C)?

Efficacy and Safety of Leqvio (Inclisiran) for LDL-C Lowering

Leqvio (inclisiran) is a highly effective LDL-C lowering therapy that reduces LDL-C by approximately 45-55% with a favorable safety profile and convenient twice-yearly dosing schedule after the initial two doses. 1, 2

Mechanism of Action and Indication

Leqvio is a small interfering RNA (siRNA) that targets PCSK9 synthesis in hepatocytes, leading to:

• Decreased PCSK9 production
• Reduced degradation of LDL receptors
• Increased clearance of LDL-C from circulation 1

The FDA has approved Leqvio as an adjunct to diet and statin therapy for:

• Adults with primary hyperlipidemia
• Patients with heterozygous familial hypercholesterolemia (HeFH)
• The goal of reducing LDL-C levels 3

Efficacy Profile

Leqvio demonstrates consistent and substantial LDL-C reduction:

• 44-54% reduction in LDL-C levels across clinical trials 1
• Up to 58.3% reduction with the 300 mg dose in Chinese patients 4
• Sustained effect for 6 months after each maintenance dose 2
• Potential for >80% LDL-C reduction when combined with other lipid-lowering therapies 2

Dosing Schedule

Leqvio offers a unique and convenient dosing regimen:

• Initial 284 mg subcutaneous injection
• Second dose at 3 months
• Maintenance doses every 6 months thereafter 3
• LDL-lowering effect measurable as early as 30 days after initiation 3

Safety Profile

Leqvio has demonstrated a favorable safety profile:

• Most common adverse reactions (≥3% and more frequent than placebo):
  • Injection site reactions (8% vs 2% with placebo)
  • Arthralgia (5% vs 4% with placebo)
  • Bronchitis (4% vs 3% with placebo) 3
• Low discontinuation rate (2.1%) due to adverse events 3
• No significant differences in liver function tests or creatine kinase levels compared to placebo 5
• Contraindicated in patients with prior serious hypersensitivity reactions to inclisiran or excipients 3

Place in Therapy According to Guidelines

The 2022 ACC Expert Consensus Decision Pathway recommends:

• Inclisiran may be considered in place of PCSK9 monoclonal antibodies (mAbs) in certain patients 6
• Particularly beneficial for patients with demonstrated poor adherence to PCSK9 mAbs 6
• Suitable for patients with adverse effects from PCSK9 mAbs or those unable to self-inject 6
• Should not be used in combination with PCSK9 mAbs 6

For statin-intolerant patients:

• Inclisiran provides sustained LDL-C reduction of approximately 45% with twice-yearly dosing 7
• Can be considered as part of aggressive combination therapy for high-risk patients 7

Clinical Considerations and Caveats

Important considerations when prescribing Leqvio:

• Should be administered by a healthcare professional 3
• Inject subcutaneously into the abdomen, upper arm, or thigh 3
• Avoid injection in areas of active skin disease or injury 3
• Currently lacks cardiovascular outcomes data, unlike PCSK9 mAbs 6
• Cardiovascular outcomes trials (ORION-4 and VICTORION-2P) are ongoing with expected completion in 2026-2027 6, 1

Advantages Over Other PCSK9 Inhibitors

Leqvio offers several advantages over PCSK9 mAbs:

• Twice-yearly dosing (after initial two doses) vs. biweekly/monthly injections 2
• Potentially improved adherence due to less frequent administration 8
• Healthcare professional administration ensures proper technique 3
• Short circulation time (<48 hours) but prolonged effect (>6 months) 2

Monitoring Recommendations

For optimal management:

• Assess LDL-C when clinically indicated 3
• LDL-C reduction can be measured as early as 30 days after initiation 3
• Monitor for injection site reactions, which are generally mild 5