Is Inclisiran (Leqvio) subcutaneous injections medically necessary for treating familial heterozygous hypercholesterolemia?

Medical Necessity Assessment for Inclisiran (Leqvio) in Heterozygous Familial Hypercholesterolemia

This authorization request does NOT meet medical necessity criteria and should be DENIED based on failure to document adequate statin therapy trial and current LDL-C levels that do not meet threshold requirements.

Critical Deficiencies in This Authorization Request

1. Inadequate Documentation of Statin Therapy Duration

The patient has not been documented to have received at least 3 months of maximally tolerated statin therapy, which is an absolute requirement before considering inclisiran. 1, 2, 3

• The request states "Previously on [MEDICATION] and [MEDICATION]. Currently on [MEDICATION]" without specifying:

  • Which specific statin was used
  • The dose of statin therapy
  • Whether high-intensity or moderate-intensity statin was attempted
  • The duration of statin therapy at maximally tolerated doses
  • Whether ezetimibe was added to statin therapy 1, 2

• The International Atherosclerosis Society explicitly recommends that PCSK9-targeted therapy (including inclisiran) should only be added if LDL-cholesterol goals are not achieved with diet, maximally tolerated statins, ezetimibe, bempedoic acid and other adjunctive therapies. 1

2. Missing Critical LDL-C Values

The authorization request fails to provide the most essential data point: the patient's current LDL-C level while on maximally tolerated statin therapy. 2, 3

• The CPB criteria require either:

  • Current LDL-C ≥100 mg/dL with untreated baseline LDL-C ≥190 mg/dL, OR
  • Current LDL-C ≥70 mg/dL with history of clinical ASCVD 2

• The request only states "LDL Cholesterol Calculated: [RESULT] High" without providing the actual numerical value

• Without this value, it is impossible to determine if the patient meets threshold criteria 2

3. Absence of ASCVD Documentation

There is no documentation of clinical atherosclerotic cardiovascular disease (ASCVD) in this patient. 1, 2

• The patient has:

  • CAC score <100 (indicating minimal coronary calcification) [@request@]
  • Normal EKG showing sinus rhythm [@request@]
  • No documented history of myocardial infarction, stroke, or coronary revascularization [@request@]

• Without established ASCVD, the patient would need to meet the more stringent criteria of untreated LDL-C ≥190 mg/dL AND current LDL-C ≥100 mg/dL after statin therapy. 2

Proper Treatment Algorithm for Heterozygous Familial Hypercholesterolemia

Step 1: Maximize Statin Therapy (NOT adequately documented)

High-potency statins (atorvastatin 40-80mg or rosuvastatin 20-40mg) should be initiated and titrated to maximally tolerated doses over at least 3 months. 1, 3

• The 2023 International Atherosclerosis Society guidelines specify that maximally tolerated high-potency statins should be used as first-line therapy 1
• For patients without ASCVD, the LDL-C goal is <100 mg/dL (2.5 mmol/L) 1, 2

Step 2: Add Ezetimibe (NOT documented as attempted)

If LDL-C remains elevated after 4-8 weeks of maximally tolerated statin therapy, ezetimibe 10mg daily should be added. 1, 2, 3

• This step is mandatory before considering PCSK9 inhibitor therapy 1, 3
• The request provides no documentation that ezetimibe was tried [@request@]

Step 3: Consider Additional Adjunctive Therapies (NOT documented)

Before advancing to inclisiran, consideration should be given to:

• Bempedoic acid (if available and tolerated) 1, 3
• Plant sterols/stanols 1, 3
• Bile acid sequestrants such as colesevelam 1

Step 4: PCSK9 Inhibitor Therapy (Premature at this stage)

Inclisiran should only be considered after Steps 1-3 have been completed and documented, AND the patient still has LDL-C ≥100 mg/dL. 1, 2, 4

• The FDA-approved indication for inclisiran is "as an adjunct to diet and statin therapy" 4
• The 2023 guidelines state PCSK9-targeted therapy should be added only if LDL-cholesterol goals are not achieved with maximally tolerated statins, ezetimibe, and other adjunctive therapies 1

Common Pitfalls in Inclisiran Authorization Requests

Pitfall #1: Jumping to PCSK9 Inhibitors Without Optimizing Oral Therapy

Many authorization requests fail because providers attempt to use inclisiran before exhausting less expensive, evidence-based oral therapies. 1, 2

• Statins remain the cornerstone of FH treatment with the most robust cardiovascular outcomes data 1
• Ezetimibe adds an additional 15-20% LDL-C reduction and has cardiovascular outcomes data 1
• The sequential approach is cost-effective and supported by all major guidelines 1, 3

Pitfall #2: Inadequate Documentation of Treatment Trials

Authorization requests must include:

• Specific statin names and doses tried 2
• Duration of each therapy (minimum 3 months at maximally tolerated dose) 2
• LDL-C values at baseline (before any therapy) 2
• LDL-C values on each treatment regimen 2
• Documentation of side effects if statin intolerance is claimed 2

Pitfall #3: Misunderstanding "Familial Hypercholesterolemia" Diagnosis

A diagnosis of heterozygous FH alone does not automatically qualify a patient for inclisiran. 1, 2, 4

• The patient must ALSO meet LDL-C thresholds after appropriate oral therapy trials 2
• Risk stratification matters: patients without ASCVD have different (higher) LDL-C thresholds than those with established disease 1, 2

What This Authorization Request Should Include

Required Documentation for Approval:

1. Baseline (untreated) LDL-C level - needed to determine if ≥190 mg/dL threshold is met 2

2. Current LDL-C level on maximally tolerated therapy - needed to determine if ≥100 mg/dL threshold is met 2

3. Detailed statin trial documentation:

   • Specific high-intensity statin used (e.g., atorvastatin 40-80mg or rosuvastatin 20-40mg) 1, 2
   • Duration of therapy (must be ≥3 months) 2
   • LDL-C response to statin therapy 2
   • If not on high-intensity statin, documentation of intolerance or contraindication 2

4. Ezetimibe trial documentation:

   • Confirmation that ezetimibe 10mg daily was added to statin 1, 2
   • Duration of combination therapy (should be ≥4-8 weeks) 1, 2
   • LDL-C response to statin + ezetimibe 2

5. Genetic confirmation of heterozygous FH (if available) or clinical criteria used for diagnosis 1

6. Assessment for ASCVD:

   • While CAC score <100 suggests low burden, document any history of MI, stroke, coronary revascularization, or peripheral arterial disease 1, 2

Evidence Supporting Sequential Therapy Approach

The 2023 International Atherosclerosis Society guidance provides Class 1A evidence that maximally tolerated high-potency statins with or without ezetimibe should initially be used in most patients before considering PCSK9 inhibitors. 1

The American College of Cardiology 2022 Expert Consensus includes inclisiran as an option only after maximally tolerated statin therapy in those at very high risk or with LDL-C >190 mg/dL. 5

Inclisiran demonstrated 44-54% LDL-C reduction in clinical trials, but these trials enrolled patients already on maximally tolerated statin therapy. 6, 7, 5

• In the ORION-9 trial specifically for heterozygous FH, the mean baseline LDL-C was 153 mg/dL in patients already on maximally tolerated statins 6
• The placebo-corrected LDL-C reduction at day 510 was 47.9% 6
• All participants were required to be on maximally tolerated statin therapy before enrollment 6, 7

Recommendation for This Authorization Request

DENY this authorization request and require the following before resubmission:

1. Document at least 3 months of maximally tolerated high-intensity statin therapy with specific drug name and dose 2

2. Document addition of ezetimibe 10mg daily to statin therapy for at least 4-8 weeks 1, 2

3. Provide numerical LDL-C values:

   • Baseline (untreated) LDL-C 2
   • LDL-C on statin monotherapy 2
   • Current LDL-C on statin + ezetimibe combination 2

4. Confirm current LDL-C meets threshold of ≥100 mg/dL (for patient without ASCVD) 2

5. Consider trial of bempedoic acid or other adjunctive therapy before advancing to PCSK9 inhibitor 1, 3

The patient's risk factors (smoking, family history, age) are concerning, but these do not bypass the requirement for appropriate sequential therapy trials before using inclisiran. 1, 2 The CAC score <100 actually suggests relatively low coronary atherosclerotic burden, making aggressive oral therapy optimization even more appropriate as the initial approach. 1