Is continued treatment with Leqvio (Inclisiran) medically necessary for a patient with Atherosclerotic Heart Disease and elevated LDL-C levels, intolerant to Repatha and without insurance coverage for Praluent?

Medical Necessity and Appropriateness of Continued Inclisiran (Leqvio) Therapy

Direct Recommendation

Continued treatment with Leqvio (inclisiran) 284 mg subcutaneously at week 0, again at 3 months, then every 6 months thereafter is medically necessary and appropriate for this patient with atherosclerotic heart disease who is intolerant to PCSK9 monoclonal antibody therapy (Repatha). 1, 2

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Medical Necessity Justification

Established Atherosclerotic Cardiovascular Disease (ASCVD)

• This 59-year-old female has documented atherosclerotic heart disease, which qualifies her as having clinical ASCVD and places her at very high cardiovascular risk requiring intensive lipid-lowering therapy 2
• The 2024 International Lipid Expert Panel guidelines recommend LDL-C goals of <55 mg/dL for patients with established ASCVD, with consideration for <40 mg/dL in extreme risk patients 2
• Her most recent LDL-C of 84 mg/dL (from the documented date) remains above the recommended target of <55 mg/dL, demonstrating inadequate lipid control despite current therapy 2, 3

Documented PCSK9 Inhibitor Intolerance

• The patient experienced viral symptoms and severe fatigue following Repatha (evolocumab) injections, representing documented intolerance to PCSK9 monoclonal antibody therapy 3
• The 2025 American Diabetes Association guidelines explicitly state: "For people with diabetes and ASCVD intolerant to statin therapy, PCSK9 inhibitor therapy with monoclonal antibody treatment, bempedoic acid therapy, or PCSK9 inhibitor therapy with inclisiran siRNA should be considered as an alternative cholesterol-lowering therapy" 2
• While this guideline references statin intolerance specifically, the principle of offering alternative PCSK9 inhibition mechanisms applies to patients intolerant to PCSK9 monoclonal antibodies 3

Insurance Coverage Barriers

• Praluent (alirocumab) is not covered by the patient's insurance, eliminating the alternative PCSK9 monoclonal antibody option 3
• This leaves inclisiran as the only available PCSK9 inhibition therapy for this patient 2, 3

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Standard of Care Assessment

FDA-Approved Indication

• Inclisiran is FDA-approved "as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce low-density lipoprotein cholesterol (LDL-C)" 1
• The patient meets this indication with atherosclerotic heart disease (a form of primary hyperlipidemia consequence) and is on concurrent statin therapy (rosuvastatin 20 mg nightly) 1

Guideline-Supported Use

• The 2024 International Lipid Expert Panel position paper includes inclisiran in the treatment algorithm for patients with ASCVD requiring additional LDL-C lowering beyond maximally tolerated statin therapy 2
• The American College of Cardiology recommends inclisiran as an option for non-statin therapy in patients at very high risk of ASCVD who require additional LDL-C lowering 3, 4
• The 2024 guidelines explicitly recommend upfront combined lipid-lowering therapy for high-risk ASCVD patients, with inclisiran listed as an appropriate component of triple or quadruple therapy 2

Evidence of Efficacy

• Phase III clinical trials (ORION-10 and ORION-11) demonstrated that inclisiran reduces LDL-C by approximately 50% when added to maximally tolerated statin therapy 1, 5
• In the ORION trials, the mean LDL-C reduction from baseline to day 510 was -52% (95% CI: -56%, -49%; p < 0.0001) compared to placebo 1
• The ORION-3 extension study showed sustained LDL-C reduction of 45% through 4 years of treatment, including in patients not taking statin therapy 3
• Exploratory analyses from ORION trials suggest potential cardiovascular benefit with inclisiran, showing a reduction in composite major adverse cardiovascular events (odds ratio 0.74; 95% CI 0.58-0.94) 3

Safety Profile

• Inclisiran demonstrated a safety profile similar to placebo in clinical trials, with the primary adverse events being mild to moderate injection site reactions (28% vs 2% for placebo) 1, 5
• Treatment discontinuation due to adverse events occurred in only 2.5% of inclisiran-treated patients versus 1.9% with placebo 1
• The drug has been well-tolerated with no significant safety concerns identified in trials extending up to 4 years 3, 5

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Treatment Algorithm Rationale

Sequential Therapy Approach

• The patient has appropriately progressed through the guideline-recommended treatment algorithm: 2
  • Step 1: Maximally tolerated statin therapy (rosuvastatin 20 mg) - achieved
  • Step 2: PCSK9 monoclonal antibody therapy (Repatha) - attempted but not tolerated
  • Step 3: Alternative PCSK9 inhibition with inclisiran - current appropriate step

Advantages of Inclisiran Over Alternatives

• Dosing convenience: Twice-yearly administration (after initial and 3-month doses) significantly improves medication adherence compared to biweekly PCSK9 monoclonal antibodies 2, 5, 6
• Different mechanism: Inclisiran works by inhibiting PCSK9 production at the intracellular level through RNA interference, rather than binding extracellular PCSK9 protein like monoclonal antibodies, potentially explaining better tolerability in this patient 3, 5
• Sustained effect: The siRNA mechanism provides durable LDL-C lowering between doses without requiring daily or biweekly injections 5, 4

Guideline Recommendation Against De-escalation

• The 2024 International Lipid Expert Panel explicitly states: "In the case where low or even very low LDL-C levels are obtained with LLT, it is not recommended to deescalate the treatment (if well-tolerated)" 2
• This principle supports continuing inclisiran even if LDL-C goals are achieved, as long-term sustained LDL-C lowering provides cumulative cardiovascular benefit 2, 7

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Critical Considerations and Pitfalls

Cardiovascular Outcomes Data

• Important caveat: Unlike PCSK9 monoclonal antibodies (evolocumab and alirocumab), inclisiran does not yet have completed cardiovascular outcomes trials demonstrating reduction in major adverse cardiovascular events 3, 4
• The ORION-4 and VICTORION-2P trials are ongoing to assess cardiovascular outcomes, with results expected in the coming years 4, 6
• However, the well-established principle that each 1% reduction in LDL-C provides approximately 1% reduction in ASCVD risk supports the use of inclisiran based on its proven LDL-C lowering efficacy 8, 7

Monitoring Requirements

• LDL-C should be assessed 4-12 weeks after inclisiran initiation or dose changes, and annually thereafter 2
• The LDL-lowering effect can be measured as early as 30 days after initiation and anytime thereafter without regard to timing of the dose 1
• Liver enzymes (ALT) should be measured before treatment and 8-12 weeks after starting therapy 2

Administration Requirements

• Inclisiran must be administered by a healthcare professional via subcutaneous injection 1
• The patient has already received the first injection and requires continuation at 3 months, then every 6 months 1
• Missing the 3-month dose by less than 3 months allows maintaining the original schedule; missing by more than 3 months requires restarting the dosing schedule 1

Statin Continuation

• The FDA label indicates inclisiran should be used "in combination with statin therapy" 1
• The patient is appropriately maintained on rosuvastatin 20 mg nightly, which should be continued 1
• The 2025 diabetes guidelines emphasize that maximum tolerated statin dose should be used in conjunction with additional lipid-lowering therapies 2

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Documentation Supporting Medical Necessity

Patient Meets All Criteria

1. Established ASCVD: Documented atherosclerotic heart disease 2, 3
2. Inadequate LDL-C control: LDL-C 84 mg/dL, above target of <55 mg/dL for ASCVD patients 2, 3
3. On maximally tolerated statin: Rosuvastatin 20 mg nightly 1
4. PCSK9 mAb intolerance: Documented viral symptoms and severe fatigue with Repatha 3
5. Insurance barrier to alternative: Praluent not covered 3
6. FDA-approved indication: Primary hyperlipidemia with ASCVD requiring additional LDL-C lowering 1

Treatment Is Not Experimental or Investigational

• Inclisiran received FDA approval in 2021 for this specific indication 1, 4
• The drug is included in major society guidelines as standard therapy for patients with ASCVD requiring additional LDL-C lowering 2, 3
• Phase III trials have established efficacy and safety, with the drug now in routine clinical use 1, 5

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Conclusion on Appropriateness

This patient represents an ideal candidate for continued inclisiran therapy based on:

• Established high-risk ASCVD requiring intensive lipid-lowering 2
• LDL-C above guideline-recommended targets despite statin therapy 2, 3
• Documented intolerance to alternative PCSK9 inhibition (Repatha) 3
• Insurance coverage barriers to the only other PCSK9 mAb option (Praluent) 3
• FDA-approved indication and guideline-supported use 1, 2
• Proven efficacy in reducing LDL-C by approximately 50% 1, 5
• Favorable safety profile with minimal adverse events 1, 5
• Convenient twice-yearly dosing that improves adherence 2, 5

The treatment plan is medically necessary, represents standard of care, and should be continued as prescribed. 2, 3, 1