What is the recommended use and dosing of Inclisiran (generic name) for patients with primary hypercholesterolemia or mixed dyslipidemia?

Inclisiran for Primary Hypercholesterolemia and Mixed Dyslipidemia

Inclisiran is FDA-approved as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic cardiovascular disease (ASCVD) requiring additional LDL-C lowering, dosed at 284 mg subcutaneously at baseline, 3 months, then every 6 months. 1

FDA-Approved Indications and Dosing

The recommended dosage is 284 mg administered as a single subcutaneous injection initially, again at 3 months, and then every 6 months thereafter, in combination with maximally tolerated statin therapy. 2, 1

• Inclisiran is indicated for adults with primary hypercholesterolemia (including HeFH) or mixed dyslipidemia as an adjunct to diet and maximally tolerated statin therapy who require additional LDL-C lowering. 2, 1
• The drug must be administered by a healthcare provider via subcutaneous injection and is billed under medical benefit rather than pharmacy benefit. 2

Mechanism and Efficacy

• Inclisiran is a small interfering RNA (siRNA) that catalytically silences PCSK9 messenger RNA translation, inhibiting hepatic PCSK9 protein production at the intracellular level, thereby up-regulating LDL receptor density on hepatocytes. 2
• In pooled analysis of 3,660 patients from ORION-9, ORION-10, and ORION-11 trials, inclisiran demonstrated a mean placebo-corrected LDL-C reduction of 50.7% at day 510 and time-adjusted mean reduction of 50.5%. 2
• LDL-C reduction becomes apparent within 14 days post-dose, with mean reductions of 38-51% observed 30-180 days post-dose. 1

Treatment Algorithm and Positioning

The American College of Cardiology positions PCSK9 monoclonal antibodies (evolocumab, alirocumab) as the preferred PCSK9 inhibitor class over inclisiran due to demonstrated cardiovascular outcomes benefits in FOURIER and ODYSSEY Outcomes trials. 3

For Patients with ASCVD at Very High Risk:

1. First-line: Maximize statin therapy (high-intensity or maximally tolerated dose). 2
2. Second-line: Add ezetimibe if LDL-C remains ≥55 mg/dL or <50% reduction achieved. 2
3. Third-line: Add PCSK9 monoclonal antibody (evolocumab or alirocumab) if LDL-C remains ≥55 mg/dL or non-HDL-C ≥85 mg/dL despite statin plus ezetimibe. 2, 3
4. Alternative to PCSK9 mAb: Consider inclisiran in place of (not in addition to) a PCSK9 mAb only in specific circumstances. 2, 3

Specific Circumstances Favoring Inclisiran Over PCSK9 mAbs:

• Demonstrated poor adherence to PCSK9 monoclonal antibodies due to the convenience of twice-yearly dosing. 2, 3
• Adverse effects from both available PCSK9 mAbs (evolocumab and alirocumab). 2, 3
• Inability to self-inject medications, as inclisiran requires healthcare provider administration. 2, 3

Critical Caveats and Limitations

There is no evidence or mechanistic plausibility for combining a PCSK9 monoclonal antibody with inclisiran; if inclisiran is used, it must replace (not supplement) the PCSK9 mAb. 2, 3

• The effect of inclisiran on cardiovascular morbidity and mortality has not been determined; cardiovascular outcomes data will not be available until ORION-4 and VICTORION-2P trials complete in 2026-2027. 2, 3
• When comparing similarly designed trials, LDL-C lowering with inclisiran appears approximately 10% less than that achieved with PCSK9 monoclonal antibodies. 2
• Initial year therapy costs are higher than PCSK9 mAbs, though the cost difference decreases in subsequent years; patient assistance programs and copay support are available for eligible patients. 2

Safety Profile

• Injection site reactions occur more frequently with inclisiran than placebo (5.0% vs 0.7%) but are predominantly mild, with none being severe or persistent. 2
• Overall safety profile is similar to placebo aside from injection site reactions. 2
• No dose adjustments are necessary for patients with mild, moderate, or severe renal impairment or mild to moderate hepatic impairment. 1
• Inclisiran has not been studied in patients with end-stage renal disease or severe hepatic impairment. 1

Special Populations

• No overall differences in safety or effectiveness were observed between patients ≥65 years and younger adults; 54% of clinical trial participants were ≥65 years. 1
• Age, body weight, gender, race, and creatinine clearance do not significantly influence inclisiran pharmacokinetics based on population analysis of 4,328 patients. 1