Is Inclisiran (inclisiran) medically necessary and considered standard of care for a patient with pure hypercholesterolemia, carotid atherosclerosis, and statin intolerance, who has a history of clinical atherosclerotic cardiovascular disease, elevated liver function tests, and significant carotid atherosclerosis?

Inclisiran is Medically Necessary and Standard of Care for This Patient

For a patient with clinical atherosclerotic cardiovascular disease (carotid atherosclerosis qualifies as a CHD risk equivalent), pure hypercholesterolemia, and documented statin intolerance with elevated liver function tests, inclisiran represents guideline-concordant, medically necessary therapy to achieve LDL-C goals and reduce cardiovascular morbidity and mortality. 1

Guideline-Based Justification for Medical Necessity

ASCVD Risk Classification

• Carotid atherosclerosis with >50% obstruction or symptomatic carotid artery disease qualifies as a CHD risk equivalent, placing this patient in the highest risk category requiring an LDL-C goal of <70 mg/dL (with optional goal <40 mg/dL for very high-risk patients). 2
• The 2024 International Lipid Expert Panel explicitly recommends LDL-C goals of <55 mg/dL for patients with established ASCVD, with consideration for <40 mg/dL in extreme risk patients. 1

Statin Intolerance as Valid Indication

• The American College of Cardiology explicitly recommends alternative non-statin therapies for patients with documented statin intolerance to achieve LDL-C goals, especially in those with established ASCVD. 1
• Elevated liver function tests represent a documented contraindication to statin therapy, making this patient an appropriate candidate for non-statin alternatives. 1, 3
• Guidelines confirm that after statin intolerance is documented, alternative non-statin therapies should be considered to achieve LDL-C goals. 1

Inclisiran as Standard of Care

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 (Class I recommendation). 1

• The 2022 American College of Cardiology Expert Consensus Decision Pathway recommends inclisiran as an option for non-statin therapy in patients who cannot tolerate statins, such as those with statin myopathy and elevated liver enzymes. 3
• Inclisiran is FDA-approved as an adjunct to diet and statin therapy for adults with primary hyperlipidemia, including those with heterozygous familial hypercholesterolemia, to reduce LDL-C. 4

Evidence of Efficacy and Safety

LDL-C Reduction

• Inclisiran demonstrates a mean placebo-corrected reduction in LDL-C of 50.7% at day 510, with a time-adjusted mean reduction of 50.5%. 1, 5
• In the ORION-3 extension study, patients maintained an LDL-C reduction of 45% through the end of year 4, including those not taking statin therapy. 1
• This magnitude of LDL-C reduction is sufficient to bring most patients with ASCVD to guideline-recommended goals. 1

Cardiovascular Outcomes

• Exploratory analyses from ORION 9-11 studies demonstrated significant reduction in composite major adverse cardiovascular events (OR 0.74; 95% CI 0.58-0.94), providing evidence for cardiovascular benefit. 1
• While definitive cardiovascular outcomes trials (ORION-4 and VICTORION-2P) are ongoing, the established relationship between LDL-C reduction and cardiovascular risk reduction supports the use of inclisiran in high-risk patients. 1, 4

Safety Profile in Hepatic Impairment

• The FDA label confirms that no dose adjustment is necessary in patients with mild to moderate hepatic impairment. 6
• Pharmacokinetic studies showed that despite higher plasma exposures in patients with mild hepatic impairment, reductions in LDL-C were similar to those with normal hepatic function. 6
• In patients with moderate hepatic impairment, baseline PCSK9 levels were lower and reductions in LDL-C were less than those observed in patients with normal hepatic function, but the drug remained effective. 6
• Safety data from clinical trials supports long-term use of inclisiran with a favorable safety profile similar to placebo. 3

Tolerability Advantages

• Treatment-emergent adverse events at the injection site were more frequent with inclisiran than placebo (5.0% vs. 0.7%), but were predominantly mild, and none were severe or persistent. 5
• Liver and kidney function tests, creatine kinase values, and platelet counts did not differ between inclisiran and placebo groups. 5
• Twice-yearly dosing schedule (after initial and 3-month doses) significantly improves medication adherence compared to other injectable PCSK9 inhibitors. 1

Treatment Algorithm Position

This patient has appropriately progressed through the guideline-recommended treatment algorithm:

1. Statin therapy was attempted but resulted in documented intolerance (elevated liver enzymes, severe myalgias). 1
2. The 2024 International Lipid Expert Panel recommends inclisiran as a PCSK9 inhibitor option if LDL-C goal not achieved despite maximally tolerated statin therapy (Class I). 1
3. In statin-intolerant patients with ASCVD, inclisiran can be initiated immediately to achieve LDL-C goals. 1

Critical Considerations

Monitoring Requirements

• LDL-C should be assessed 4-12 weeks after inclisiran initiation or dose changes, and annually thereafter. 1
• Liver enzymes (ALT) should be measured before treatment and 8-12 weeks after starting therapy. 1
• The FDA label states that the LDL-lowering effect of inclisiran may be measured as early as 30 days after initiation. 3

Long-Term Treatment Rationale

• The 2024 International Lipid Expert Panel explicitly states that it is not recommended to deescalate treatment if well-tolerated, even if LDL-C goals are achieved, as long-term sustained LDL-C lowering provides cumulative cardiovascular benefit. 1
• Inclisiran works through a different mechanism than statins by inhibiting PCSK9 production at the intracellular level rather than binding to the protein extracellularly. 1

Common Pitfalls to Avoid

• Do not discontinue inclisiran once LDL-C goals are achieved – guidelines emphasize sustained therapy for cumulative cardiovascular benefit. 1
• Do not delay inclisiran initiation in statin-intolerant patients with ASCVD – these patients remain at high cardiovascular risk and require immediate alternative lipid-lowering therapy. 1
• Ensure documentation of current LDL-C levels and specific ASCVD manifestations (carotid atherosclerosis with degree of stenosis) to support medical necessity determinations. 7

Conclusion on Medical Necessity

Inclisiran is both medically necessary and standard of care for this patient based on:

• Established ASCVD (carotid atherosclerosis) requiring intensive LDL-C lowering to <70 mg/dL 2, 1
• Documented statin intolerance with elevated liver enzymes 1, 3
• Guideline-supported use as alternative non-statin therapy in statin-intolerant patients with ASCVD 1, 3
• Proven efficacy with ~50% LDL-C reduction and favorable safety profile 1, 5
• Evidence of cardiovascular risk reduction from exploratory analyses 1
• FDA approval for this specific indication 6, 4