What is the comparison between Inclisiran (Pcsk9 inhibitor) and Evolocumab (Repatha, Pcsk9 inhibitor) for Low-Density Lipoprotein (LDL) cholesterol reduction?

Inclisiran vs Evolocumab for LDL Cholesterol Reduction

Evolocumab demonstrates superior LDL-C reduction (approximately 59-61%) compared to inclisiran (43-55%), and has proven cardiovascular outcome benefits with significant reductions in MI, stroke, and coronary revascularization, making it the preferred choice when maximal LDL lowering and cardiovascular risk reduction are priorities. 1, 2, 3

LDL Cholesterol Lowering Efficacy

Evolocumab Performance

• Reduces LDL-C by 59-64% when added to maximally tolerated statin therapy, achieving median LDL-C levels of 30 mg/dL from baseline of 92 mg/dL 1, 2, 4
• Demonstrates consistent 50-65% LDL-C reduction across multiple trials 1
• Achieves mean LDL-C levels of approximately 35 mg/dL (0.9 mmol/L) on maximal statin therapy, with many patients reaching <25 mg/dL 1

Inclisiran Performance

• Reduces LDL-C by 43-55% depending on dosing (284mg vs 300mg formulations) 3
• The 284mg dose achieves -54.83% LDL-C reduction, while the 300mg dose achieves -43.11% reduction 3
• Represents a less potent LDL-lowering effect compared to evolocumab by approximately 6-18 percentage points 3

Cardiovascular Outcomes: The Critical Difference

Evolocumab's Proven Benefits

Evolocumab has demonstrated significant cardiovascular event reduction in large outcome trials, which inclisiran has not yet proven:

• Reduces composite cardiovascular endpoints by 15% (11.3% vs 9.8%, P<0.001) over median 2.2 years in the FOURIER trial 1
• Reduces MI risk by 28% (OR 0.72,95% CI: 0.64-0.81) 3
• Reduces stroke risk by 21% (OR 0.79,95% CI: 0.66-0.94), including 25% reduction in ischemic stroke 1, 3
• Reduces coronary revascularization by 23% (OR 0.77,95% CI: 0.70-0.84) 3
• Reduces cardiovascular death, MI, or stroke by 20% (from 7.4% to 5.9%) 1

Inclisiran's Uncertain Outcomes

• No completed cardiovascular outcome trials demonstrating MACE reduction 5
• The ORION-4 trial is currently ongoing but results are not yet available 5
• Cannot be recommended based on cardiovascular outcomes at this time

Dosing and Administration Considerations

Evolocumab Regimen

• 140 mg subcutaneously every 2 weeks OR 420 mg monthly 1, 2
• Requires 24-26 injections per year (biweekly dosing) or 12 injections per year (monthly dosing) 1
• Administered in thigh, abdomen, or upper arm 1, 2

Inclisiran Regimen

• 300 mg subcutaneously every 6 months after initial loading doses 5
• Requires only 2 injections per year after loading, representing a significant adherence advantage 5
• This is inclisiran's primary clinical advantage—dosing convenience

Safety and Tolerability

Both agents demonstrate similar safety profiles:

• Injection site reactions are infrequent and mild with both evolocumab and inclisiran 1
• Evolocumab shows slightly increased neurocognitive events compared to placebo, though non-significant 1
• No excess adverse events occur even at very low LDL-C levels (<25 mg/dL or <15 mg/dL) with evolocumab 1
• Both are well-tolerated in statin-intolerant patients 1
• Myalgia rates are comparable to ezetimibe for both agents 1

Clinical Decision Algorithm

Choose Evolocumab when:

• Patient has established ASCVD requiring proven cardiovascular risk reduction 1, 2
• Maximal LDL-C lowering is needed (target <25-30 mg/dL) 1, 2
• Patient has recent ACS or high-risk features requiring aggressive secondary prevention 1
• Patient has familial hypercholesterolemia requiring intensive therapy 1

Consider Inclisiran when:

• Patient adherence to frequent injections is a major concern 5
• Cardiovascular outcomes are less critical than LDL lowering alone 5
• Patient specifically requests less frequent dosing and accepts unproven cardiovascular benefit 5

Critical Pitfall to Avoid

Do not assume equivalent cardiovascular benefit between these agents simply because both inhibit PCSK9. Evolocumab has proven mortality and morbidity benefits in large outcome trials (FOURIER with 27,564 patients), while inclisiran's cardiovascular efficacy remains unproven pending ORION-4 results 1, 5. The 6-month dosing interval of inclisiran is attractive but cannot justify its use over evolocumab when cardiovascular risk reduction is the primary goal 5.

FDA-Approved Indications

Evolocumab is approved for:

• Lowering LDL-C in adults with primary hyperlipidemia (including heterozygous FH) 1, 2
• Reducing risk of MI, stroke, and coronary revascularization in adults with established ASCVD 1, 2
• Lowering LDL-C in adults and pediatric patients (≥10 years) with homozygous FH 1, 2

Inclisiran lacks the cardiovascular risk reduction indication that evolocumab possesses 5.