What is the benefit of adding Inclisiran (inclisiran) to standard statin (HMG-CoA reductase inhibitors) plus Ezetimibe (ezetimibe) therapy in reducing cardiovascular events?

Inclisiran Added to Statin Plus Ezetimibe: Limited Survival Benefit Evidence

Inclisiran currently offers no proven survival advantage when added to statin plus ezetimibe therapy, as cardiovascular outcomes trials demonstrating mortality or morbidity benefits are not expected until 2026-2027. 1, 2

Current Evidence Status

The critical limitation is the absence of completed cardiovascular outcomes data:

• PCSK9 monoclonal antibodies (evolocumab, alirocumab) remain the preferred PCSK9 inhibitor class because they have demonstrated cardiovascular outcomes benefits in the FOURIER and ODYSSEY Outcomes trials, unlike inclisiran which lacks this evidence. 1

• The ORION-4 and VICTORION-2P cardiovascular outcomes trials for inclisiran will not be completed until 2026 and 2027, respectively. 1, 2

• A pooled patient-level analysis of Phase III trials (ORION-9, -10, -11) showed inclisiran reduced composite major cardiovascular events (MACE) with an odds ratio of 0.74 (95% CI: 0.58-0.94), but this was a prespecified exploratory endpoint using non-adjudicated events, not a definitive outcomes trial. 3, 4

• This exploratory analysis did not show significant reductions in fatal and non-fatal myocardial infarction (OR 0.80,95% CI: 0.50-1.27) or stroke (OR 0.86,95% CI: 0.41-1.81). 3

Guideline-Recommended Treatment Algorithm

The American College of Cardiology positions inclisiran as a second-line alternative to PCSK9 mAbs, not as an addition to them:

1. First-line nonstatin therapy: Add ezetimibe to maximally tolerated statin therapy if LDL-C targets are not met (≥50% reduction and LDL-C <70 mg/dL for very high-risk patients). 1, 5

2. Second-line therapy: If targets remain unmet after statin plus ezetimibe, add a PCSK9 mAb (evolocumab or alirocumab) as the preferred option due to proven cardiovascular outcomes benefits. 1, 5

3. Inclisiran as an alternative: Consider inclisiran in place of (not in addition to) a PCSK9 mAb only in specific circumstances:

   • Demonstrated poor adherence to PCSK9 mAbs 1, 6, 5
   • Adverse effects from both available PCSK9 mAbs 1, 6
   • Inability to self-inject medications 1, 6

4. Third-line therapy: If LDL-C remains elevated despite statin, ezetimibe, and PCSK9 inhibitor, consider adding bempedoic acid. 1

Critical Caveats

There is no evidence or mechanistic plausibility for combining a PCSK9 mAb with inclisiran — if inclisiran is used, it must replace (not supplement) the PCSK9 mAb. 1, 6

The advantage of inclisiran lies in its twice-yearly subcutaneous dosing schedule administered by healthcare professionals, which may improve adherence compared to self-administered PCSK9 mAbs requiring injections every 2-4 weeks. 7, 4

LDL-C Lowering Efficacy

While not a survival endpoint, inclisiran consistently reduces LDL-C by approximately 50% (44-54% range) when added to maximally tolerated statin therapy, with sustained reductions for up to 4 years. 2, 3, 4, 8

This LDL-C reduction is comparable to PCSK9 mAbs, but without the proven cardiovascular outcomes data that those agents possess. 1, 2

Safety Profile

Inclisiran demonstrates a favorable safety profile with injection-site reactions being the most common adverse effect (10.1% vs 0.7% with placebo), all mild or moderate in nature with none persistent. 8

No significant or serious adverse events have been demonstrated compared to placebo across Phase III trials. 2, 8

Bottom Line for Clinical Practice

Do not add inclisiran to patients already on statin plus ezetimibe expecting survival benefits — the evidence does not exist yet. If additional LDL-C lowering is needed after maximally tolerated statin plus ezetimibe, prescribe a PCSK9 mAb (evolocumab or alirocumab) first due to proven cardiovascular outcomes benefits. 1 Reserve inclisiran for patients who cannot tolerate or adhere to PCSK9 mAbs, recognizing you are choosing convenience over proven outcomes data. 1, 6, 5