For a patient on maximally tolerated statin, should I use inclisiran (Leqvio) or evolocumab (Repatha) to lower LDL‑cholesterol?

PCSK9 Inhibitor Selection: Evolocumab Over Inclisiran

For patients on maximally tolerated statin therapy requiring additional LDL-cholesterol lowering, evolocumab (Repatha) should be prescribed as first-line PCSK9 inhibitor therapy rather than inclisiran (Leqvio), based on proven cardiovascular outcomes benefit. 1, 2, 3

Evidence-Based Treatment Algorithm

Step 1: Verify Current Therapy Optimization

• Confirm patient has been on maximally tolerated statin therapy for ≥3 months 1
• Add ezetimibe 10 mg daily if not already prescribed 4, 2
• Reassess LDL-C after 4-12 weeks 1, 2

Step 2: Determine Need for PCSK9 Inhibition

• Add PCSK9 inhibitor if LDL-C remains ≥70 mg/dL (or ≥55 mg/dL in patients with multiple ASCVD events) despite statin plus ezetimibe 4, 1
• Target LDL-C <55 mg/dL (<1.4 mmol/L) with >50% reduction from baseline in secondary prevention 4

Step 3: Select Evolocumab as First-Line PCSK9 Inhibitor

Evolocumab should be prescribed first because:

• Proven cardiovascular outcomes: The FOURIER trial (27,564 patients) demonstrated a 15% relative risk reduction in composite cardiovascular events and a 20% reduction in CV death/MI/stroke (7.4% vs 5.9%; P<0.001) 3
• Superior LDL-C lowering: Achieves approximately 59% LDL-C reduction (median LDL-C from 92→30 mg/dL) compared to inclisiran's 50% reduction 3, 5
• Guideline-preferred agent: The American College of Cardiology explicitly recommends PCSK9 monoclonal antibodies as preferred over inclisiran due to proven cardiovascular outcomes benefits 1, 2, 3

Dosing: 140 mg subcutaneously every 2 weeks OR 420 mg once monthly 3

Step 4: Reserve Inclisiran for Specific Circumstances Only

Consider inclisiran ONLY if evolocumab (or alirocumab) fails due to: 1, 2, 3

• Documented poor adherence to twice-monthly or monthly PCSK9 mAb injections (benefit from twice-yearly dosing) 2, 3
• Adverse effects experienced from both available PCSK9 mAbs (evolocumab and alirocumab) 1, 3
• Inability to self-inject medications (inclisiran allows clinic-based administration every 6 months) 2, 3

Dosing: 284 mg subcutaneously on day 1, day 90, then every 6 months 4, 6

Critical Evidence Gaps for Inclisiran

Lack of Cardiovascular Outcomes Data

• Inclisiran has NO completed cardiovascular outcomes trials demonstrating reduction in mortality or major adverse cardiovascular events 1, 2, 7
• Exploratory analyses from ORION-9, ORION-10, and ORION-11 showed suggestive trends (7.4% vs 10.2% non-adjudicated CV events) but these were not primary endpoints and lack adjudication 4
• ORION-4 and VICTORION-2P trials will not report results until 2026-2027 2, 3, 7

Comparative Efficacy

• Network meta-analysis of 21 RCTs (10,835 patients) ranked evolocumab as most effective (87% probability) for LDL-C reduction, followed by alirocumab (71.4%), then inclisiran (47.2%) 5
• Both agents achieve approximately 50-59% LDL-C reduction, but evolocumab has demonstrated this translates to cardiovascular benefit while inclisiran has not 3, 8, 5

Common Pitfalls to Avoid

Do NOT Combine PCSK9 Agents

• Never prescribe inclisiran in addition to evolocumab or alirocumab 2, 3
• There is no evidence or mechanistic plausibility for combining a PCSK9 mAb with inclisiran 2
• If switching to inclisiran, it must replace (not supplement) the PCSK9 mAb 2, 3

Do NOT Prescribe Inclisiran When LDL-C Goals Already Met

• If patient's LDL-C is already <70 mg/dL on current therapy, inclisiran authorization should be denied 1
• Example: A patient with LDL-C of 46 mg/dL does not meet the ≥70 mg/dL threshold required for PCSK9 inhibitor approval 1

Do NOT Skip Ezetimibe

• Ezetimibe must be optimized before adding any PCSK9 inhibitor 4, 2
• The treatment sequence is: maximally tolerated statin → add ezetimibe → reassess → add PCSK9 mAb if needed 1, 2

Safety Considerations

Evolocumab Safety Profile

• Well tolerated over 2.2 years in FOURIER with no increase in cognitive adverse events 3
• Rare hypersensitivity reactions warrant discontinuation 3
• FDA-approved for pediatric patients ≥10 years with familial hypercholesterolemia 3

Inclisiran Safety Profile

• Mild, transient injection-site reactions most common adverse effect 6, 7
• Sustained LDL-C reduction of approximately 45% maintained through 4 years in extension studies 4, 7
• No serious adverse events detected in half a million doses administered worldwide 6

When Either Agent Is Appropriate

Both evolocumab and inclisiran are indicated for: 3

• Adults with clinical ASCVD requiring additional LDL-C lowering beyond maximally tolerated statin ± ezetimibe
• Heterozygous familial hypercholesterolemia
• LDL-C ≥70 mg/dL (or non-HDL-C ≥100 mg/dL) despite optimal statin therapy

However, evolocumab should still be prescribed first due to proven cardiovascular outcomes benefit. 1, 2, 3

Special Populations

Statin-Intolerant Patients

• Both PCSK9 mAbs and inclisiran have demonstrated efficacy with fewer skeletal muscle-related adverse effects in statin-intolerant populations 4
• Inclisiran maintained 45% LDL-C reduction through 4 years in ORION-3 extension trial (though only 33% were not taking statins) 4
• Consider bempedoic acid as alternative, which reduced four-point MACE by 13% in CLEAR Outcomes trial of statin-intolerant patients 4

Very High-Risk ASCVD Patients

• For patients with multiple ASCVD events or very high risk, referral to lipid specialist is advised before selecting inclisiran over proven PCSK9 mAb 3
• Recent acute coronary syndrome patients should receive evolocumab based on FOURIER trial evidence 3