Inclisiran Has No Established Role in Reducing Intracerebral Vascular Calcifications
There is currently no evidence that inclisiran reduces intracerebral vascular calcifications, and this is not an indication for its use. Inclisiran is a PCSK9 inhibitor approved specifically for LDL-cholesterol lowering in patients with atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia who require additional lipid reduction beyond maximally tolerated statin therapy 1.
Current Evidence Base for Inclisiran
The available evidence for inclisiran focuses exclusively on lipid-lowering efficacy and cardiovascular outcomes, not vascular calcification:
Lipid Reduction: Inclisiran reduces LDL-C by approximately 50% when administered twice yearly (after initial doses at baseline and 3 months), with sustained reductions demonstrated for up to 4 years 1, 2
Cardiovascular Outcomes: Pooled analysis from ORION 9-11 trials showed inclisiran reduced composite MACE (OR 0.74; 95% CI 0.58-0.94) at 18 months, though individual endpoints for MI and stroke were not significantly reduced 1
Ongoing Trials: Definitive cardiovascular outcomes data from ORION-4 (expected 2026) and VICTORION trials (2027-2029) are still pending 1
Mechanism of Action Does Not Target Calcification
Inclisiran works by silencing PCSK9 mRNA translation through small interfering RNA technology, thereby increasing hepatic LDL receptor density and lowering circulating LDL-C 1, 3. This mechanism:
- Addresses cholesterol metabolism, not calcium deposition in vessel walls
- Has no known direct effect on vascular calcification pathways
- Differs fundamentally from therapies that might influence calcification processes
Current Approved Indications
According to FDA approval and major guidelines, inclisiran is indicated as:
An adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia or ASCVD requiring additional LDL-C lowering 1
An alternative to PCSK9 monoclonal antibodies in patients with poor adherence, adverse effects from PCSK9 mAbs, or inability to self-inject 1, 4
A consideration for patients failing to reach LDL-C targets (<70 mg/dL) despite maximally tolerated statins 1, 5
Clinical Considerations
Important caveats:
- No published studies have evaluated inclisiran's effect on vascular calcification scores or progression
- The cerebrovascular disease subgroup analysis from ORION trials focused on LDL-C reduction and stroke outcomes, not calcification 6
- While LDL-C lowering theoretically may slow atherosclerosis progression, this does not equate to reducing established vascular calcifications
If your clinical question relates to managing a patient with intracerebral vascular calcifications, the focus should remain on:
- Aggressive LDL-C lowering for atherosclerosis prevention (where inclisiran could play a role as part of lipid management) 1
- Blood pressure control
- Antiplatelet therapy when indicated
- Management of other cardiovascular risk factors
The decision to use inclisiran should be based on lipid management goals and cardiovascular risk reduction, not on any expectation of reducing vascular calcifications 1.