Inclisiran in ACC/AHA Guidelines
Yes, inclisiran has been included in the 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk, but it does not yet have cardiovascular outcomes data to support its use as a first-line PCSK9 inhibitor. 1
Current Guideline Position on Inclisiran
The 2022 ACC Expert Consensus Decision Pathway recognizes inclisiran as a nonstatin therapy option for LDL-C lowering. Key points from the guidelines include:
Inclisiran is indicated 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 1
The recommended dosage is 284 mg administered subcutaneously initially, again at 3 months, and then every 6 months thereafter 1
Inclisiran demonstrated a mean placebo-corrected LDL-C reduction of approximately 50% in phase 3 trials (ORION-9, ORION-10, and ORION-11) 1
Important Clinical Considerations
Efficacy and Administration
- Inclisiran provides approximately 50% LDL-C reduction, which is about 10% less than that seen with PCSK9 monoclonal antibodies (mAbs) 1
- The twice-yearly maintenance dosing schedule (after initial doses at baseline and 3 months) is particularly advantageous for patients with adherence concerns 1
- Unlike self-administered PCSK9 mAbs, inclisiran must be administered by a healthcare professional 1
Cardiovascular Outcomes
- Critical limitation: The effect of inclisiran on cardiovascular morbidity and mortality has not yet been determined 1, 2
- Two cardiovascular outcomes trials are currently in progress:
Safety Profile
- Injection site reactions are more common with inclisiran than placebo (5.0% vs 0.7%) but are predominantly mild and not persistent 1
- Overall safety profile appears similar to placebo in trials with up to 6 years of follow-up data 1
Practical Considerations
Insurance and Cost
- Health plan coverage may vary for inclisiran as it must be administered by a clinician and is billed under medical benefit rather than pharmacy benefit coverage 1
- Initial year therapy costs for inclisiran are higher than annual costs of PCSK9 mAbs, but the cost difference is less in subsequent years 1
- Patient assistance programs and copay support are available for eligible patients 1
Comparison to PCSK9 mAbs
- PCSK9 mAbs (evolocumab and alirocumab) are currently preferred as initial PCSK9 inhibitors due to their demonstrated cardiovascular outcomes benefits 3
- Inclisiran should be considered when adherence is a concern or when PCSK9 mAbs are not tolerated 3
Recent Developments
The VICTORION-Initiate study (presented at ACC 2024) evaluated an "inclisiran first" strategy in patients not reaching LDL-C goals on maximally tolerated statins, showing:
- 60% LDL-C reduction vs 7% with usual care
- 81.8% of patients achieving LDL-C <70 mg/dL vs 22.2% with usual care
- Lower statin discontinuation rates (6.0% vs 16.7%) 1
Clinical Algorithm for Inclisiran Use
- First-line therapy: Maximally tolerated high-intensity statin
- Second-line therapy: Add ezetimibe if LDL-C remains above target
- Third-line therapy: Consider PCSK9 inhibitor when:
- LDL-C remains ≥55 mg/dL in very high-risk ASCVD patients
- LDL-C remains ≥100 mg/dL in HeFH patients
- PCSK9 inhibitor selection:
- Prefer PCSK9 mAbs (evolocumab or alirocumab) when CV outcomes reduction is the primary goal
- Consider inclisiran when medication adherence is a major concern or PCSK9 mAbs are not tolerated
While inclisiran has been included in the ACC guidelines as a nonstatin therapy option, its place in therapy is currently limited by the lack of cardiovascular outcomes data, which is expected to be available in 2026-2027.