Is Leqvio (Inclisiran) medically indicated for a patient with Atherosclerotic Heart Disease (ASCVD), intolerance to statins, and elevated Low-Density Lipoprotein Cholesterol (LDL-C) levels?

Is Leqvio (Inclisiran) Medically Indicated for This Patient?

Yes, Leqvio (inclisiran) is medically indicated and should be continued for this 59-year-old female patient with established ASCVD, documented statin intolerance, and LDL-C of 120 mg/dL, as she meets all criteria for PCSK9 inhibitor therapy according to current guidelines. 1, 2

Patient Risk Stratification

This patient qualifies as very high-risk ASCVD based on the following criteria:

• Established clinical ASCVD with history of coronary interventions (PCI and laser atherectomy), which definitively places her in the very high-risk category 1
• Multiple coronary interventions indicating progressive atherosclerotic disease 1
• LDL-C of 120 mg/dL substantially above the recommended target of <70 mg/dL for very high-risk ASCVD patients 1
• Documented statin intolerance, which eliminates first-line therapy options 2

The 2024 International Lipid Expert Panel specifically identifies patients with ASCVD and statin intolerance as requiring immediate non-statin lipid-lowering therapy to minimize ongoing LDL-C exposure 1

Guideline-Based Justification for Inclisiran

Primary Indication Criteria Met

The 2018 ACC/AHA guidelines establish that adding a PCSK9 inhibitor is reasonable (Class IIa) when:

• Patient has clinical ASCVD 1
• LDL-C remains ≥70 mg/dL on maximally tolerated statin therapy 1
• This patient's LDL-C of 120 mg/dL substantially exceeds this threshold 2

The 2024 ILEP guidelines specifically recommend:

• In patients with confirmed complete statin intolerance, treatment should proceed immediately using non-statin LLT, including PCSK9 inhibitors 1
• For statin-intolerant patients with ASCVD, inclisiran has demonstrated maintained LDL-C reductions of approximately 45% through 4 years of treatment 2

FDA-Approved Indication

Inclisiran is FDA-approved as adjunctive therapy for:

• Adults with clinical ASCVD who require additional LDL-C lowering 3
• The FDA label specifically studied patients with ASCVD taking maximally tolerated statin therapy who required additional LDL-C reduction 3
• In the ORION-10 trial, inclisiran demonstrated 52% LDL-C reduction from baseline (mean baseline 105 mg/dL) to Day 510 3

Treatment Plan Appropriateness

Dosing Schedule Validation

The prescribed regimen is correct per FDA labeling:

• Initial dose at Day 1 ✓
• Second dose at Day 90 (3 months) ✓ — this is the current authorization request
• Subsequent doses every 6 months (Day 270,450, etc.) ✓ 3

This twice-yearly dosing after the initial loading phase represents a significant adherence advantage, particularly important given this patient's history of statin intolerance 2, 4, 5

Expected Clinical Benefit

Based on clinical trial data:

• The VICTORION-INITIATE trial demonstrated that an "inclisiran first" strategy (adding inclisiran immediately when LDL-C remains ≥70 mg/dL despite maximally tolerated statins) resulted in 60% LDL-C reduction versus 7% with usual care 4
• 81.8% of patients achieved LDL-C <70 mg/dL with inclisiran versus only 22.2% with usual care 4
• For this patient with baseline LDL-C of 120 mg/dL, a 50-60% reduction would bring LDL-C to approximately 48-60 mg/dL, well below the <70 mg/dL target 2, 3, 4

Cardiovascular risk reduction:

• Exploratory analyses from ORION trials suggest potential cardiovascular benefit with inclisiran, showing reduction in composite major adverse cardiovascular events (OR 0.74; 95% CI 0.58-0.94) 2
• While definitive cardiovascular outcomes trials (ORION-4, VICTORION-2P) are ongoing, the magnitude of LDL-C reduction achieved strongly supports continued use in this very high-risk patient 2, 6, 7

Statin Intolerance Considerations

The 2024 ILEP guidelines specifically address this scenario:

• When complete statin intolerance is confirmed, treatment should proceed immediately with non-statin LLT rather than attempting further statin rechallenge 1
• The ACC recommends alternative non-statin therapies for patients with documented statin intolerance to achieve LDL-C goals, especially in those with established ASCVD 2
• Inclisiran has demonstrated sustained efficacy in statin-intolerant patients, with LDL-C reductions maintained at approximately 45% through 4 years in the ORION-3 extension study 2

Critical pitfall to avoid: Do not delay PCSK9 inhibitor therapy in statin-intolerant ASCVD patients by attempting multiple statin rechallenges, as this prolongs exposure to elevated LDL-C and increases cardiovascular risk 1

Alternative Therapy Consideration

Why not ezetimibe alone?

• While ezetimibe provides 15-25% LDL-C reduction, this patient's LDL-C of 120 mg/dL would only decrease to approximately 90-102 mg/dL with ezetimibe monotherapy, still substantially above the <70 mg/dL target 1
• The 2024 ILEP guidelines recommend that in statin-intolerant patients with ASCVD, combination therapy including PCSK9 inhibitors should be considered upfront rather than sequential addition 1
• Ideally, this patient should be on both ezetimibe AND inclisiran to maximize LDL-C reduction 1

Why not bempedoic acid?

• Bempedoic acid provides approximately 18-25% LDL-C reduction, which would be insufficient as monotherapy for this patient 1
• Could be considered as part of combination therapy if LDL-C targets are not met with inclisiran alone 1

Safety Profile

Inclisiran demonstrates favorable safety:

• In VICTORION-INITIATE, treatment-emergent adverse events were comparable between inclisiran and usual care (62.8% vs 53.7%) 4
• Injection-site reactions occurred in 10.3% with inclisiran versus 0% with usual care, but were generally mild to moderate 4, 6
• Serious adverse events were similar (11.5% vs 13.4%) 4
• No neutralizing antidrug antibodies have been noted with inclisiran, unlike some PCSK9 monoclonal antibodies 6
• Statin discontinuation rates with inclisiran (6.0%) were noninferior to usual care (16.7%), indicating inclisiran does not discourage concurrent statin use if tolerance improves 4

Prior Authorization Justification Summary

This patient meets all criteria for medical necessity:

1. Established clinical ASCVD (previous PCI and laser atherectomy) — Class I indication 1
2. LDL-C 120 mg/dL, substantially above target of <70 mg/dL — exceeds threshold for PCSK9 inhibitor consideration 1
3. Documented statin intolerance — eliminates first-line therapy and necessitates alternative LLT 1, 2
4. FDA-approved indication — clinical ASCVD requiring additional LDL-C lowering 3
5. Appropriate dosing — second injection at 3 months per FDA labeling 3
6. Expected clinical benefit — 50-60% LDL-C reduction will achieve guideline-recommended targets 3, 4
7. Cardiovascular risk reduction — exploratory data suggests MACE reduction 2

The continuation of inclisiran therapy with the second 3-month injection is medically necessary and guideline-concordant for this very high-risk ASCVD patient with statin intolerance. 1, 2, 3