Is it medically necessary for a 65-year-old female with hypercholesterolemia, intolerant to statins (HMG-CoA reductase inhibitors), to start treatment with Leqvio (Inclisiran)?

Medical Necessity Determination for Leqvio (Inclisiran) in This Case

This patient does NOT meet medical necessity criteria for Leqvio treatment based on current evidence-based guidelines and the provided clinical information.

Rationale for Denial

Critical Missing Elements

1. No Documented ASCVD (Primary Pathway - NOT MET)

• The patient has no documented cardiac history, which is the primary indication pathway for inclisiran in secondary prevention 1
• AHA/ACC guidelines provide Class IIa recommendations for PCSK9 inhibitors (and by extension, inclisiran as a PCSK9 pathway inhibitor) only in patients with very high-risk ASCVD with LDL-C ≥70 mg/dL on maximally tolerated statin plus ezetimibe 1
• Without established ASCVD (no history of MI, stroke, peripheral arterial disease, or coronary revascularization), this patient cannot qualify through the secondary prevention pathway 1

2. Insufficient Statin Trial (Alternative Pathway - NOT MET)

• The patient was only on pravastatin (a moderate-intensity statin) before discontinuation 2
• Guidelines require documentation of intolerance to high-intensity statin therapy or at minimum, adequate trial of moderate-intensity therapy if high-intensity cannot be tolerated 1
• No documented trial of alternative statins (atorvastatin, rosuvastatin, simvastatin) was attempted before declaring statin intolerance 1

3. CK Elevation Does Not Meet Threshold (NOT MET)

• The patient's creatine kinase was 76 U/L (normal range 30-223), which is within normal limits [@case information@]
• The criteria explicitly require CK elevation >3 times upper limit of normal (ULN) for documented statin-associated muscle symptoms 1
• Upper limit of normal = 223 U/L; 3x ULN = 669 U/L. The patient's CK of 76 is nowhere near this threshold
• Muscle symptoms alone without significant CK elevation do not constitute documented statin intolerance per guideline criteria 1

4. LDL-C Level Considerations for Primary Prevention

• Current LDL-C is 123 mg/dL, which does not meet the severe hypercholesterolemia threshold of ≥190 mg/dL for primary prevention 1
• For patients with baseline LDL-C ≥190 mg/dL (severe primary hypercholesterolemia), inclisiran/PCSK9 inhibitors may be considered only after maximally tolerated statin plus ezetimibe therapy, and only if LDL-C remains ≥100 mg/dL 1
• No documentation of ezetimibe trial in this patient [@case information@]

What Should Have Been Done First

Required Sequential Therapy Before Inclisiran Consideration:

1. Trial of multiple statins at varying intensities 1:

   • High-intensity options: atorvastatin 40-80 mg, rosuvastatin 20-40 mg
   • Moderate-intensity alternatives if high-intensity not tolerated: atorvastatin 10-20 mg, rosuvastatin 5-10 mg, simvastatin 20-40 mg
   • Document specific adverse effects and CK levels with each trial

2. Ezetimibe monotherapy or low-dose statin combination 1:

   • For true statin-intolerant patients, ezetimibe 10 mg daily is the next-line therapy
   • Can be combined with lowest tolerable statin dose
   • This is a Class IIa recommendation and must be attempted before PCSK9 pathway inhibitors 1

3. Bile acid sequestrants as alternative 1:

   • Colesevelam or cholestyramine if ezetimibe insufficient
   • Class IIb recommendation for patients with LDL-C ≥190 mg/dL

4. Risk stratification for primary prevention 1:

   • Calculate 10-year ASCVD risk using Pooled Cohort Equations
   • Consider coronary artery calcium (CAC) scoring if risk assessment uncertain
   • At age 65 without diabetes or ASCVD, risk-based treatment decisions are critical

Guideline-Based Indications for Inclisiran

Inclisiran is indicated as adjunct therapy in adults with 3, 4:

• Primary hypercholesterolemia or mixed dyslipidemia
• Unable to reach LDL-C goals on maximally tolerated statin therapy with or without other lipid-lowering therapies
• For statin-intolerant patients: can be used with or without other LLTs, but only after other options exhausted

The evidence base for inclisiran 5:

• Reduces LDL-C by approximately 51% with twice-yearly dosing
• Associated with 24% lower major adverse cardiovascular events (MACE) rate
• Well-tolerated with primarily injection-site reactions
• However, clinical trials enrolled patients with established ASCVD or very high risk 5

Common Pitfalls in This Case

1. Premature escalation to expensive therapy: Jumping to inclisiran without exhausting standard alternatives (ezetimibe, alternative statins, bile acid sequestrants) 1

2. Misinterpretation of statin intolerance: Muscle symptoms with normal CK do not meet criteria for documented statin-associated muscle symptoms requiring CK >3x ULN 1

3. Acute kidney injury attribution: While AKI was noted, this is not a standard contraindication to all statins and should prompt evaluation of alternative agents rather than complete class avoidance 1

4. Lack of risk stratification: No documented 10-year ASCVD risk calculation or consideration of risk-enhancing factors in primary prevention 1

Determination

DENIED - Does not meet medical necessity criteria

The patient requires:

• Documented trials of at least 2-3 different statins with objective CK measurements during symptomatic periods
• Trial of ezetimibe monotherapy or with low-dose statin
• Calculation of 10-year ASCVD risk
• Consider CAC scoring if risk uncertain
• Documentation that LDL-C remains ≥100 mg/dL (ideally ≥130 mg/dL for primary prevention) despite maximal tolerated therapy

Only after these steps are documented would inclisiran consideration be appropriate per evidence-based guidelines 1.