What are the differences between inclisiran (Leqvio) and evolocumab (Repatha) regarding dosing schedule, efficacy, safety, and patient selection for LDL‑cholesterol reduction?

Inclisiran vs Repatha: Key Differences for Clinical Practice

For most patients requiring PCSK9 inhibition, evolocumab (Repatha) remains the preferred initial choice due to proven cardiovascular outcomes data, while inclisiran offers a compelling alternative specifically for patients with documented poor adherence or inability to self-inject. 1

Dosing Schedule

Inclisiran provides a major adherence advantage with twice-yearly dosing:

• Inclisiran: 284 mg subcutaneous injection initially, at 3 months, then every 6 months 2
• Evolocumab: 140 mg subcutaneous every 2 weeks OR 420 mg monthly 1

The twice-yearly regimen of inclisiran substantially reduces treatment burden and may improve long-term adherence compared to the more frequent injections required with evolocumab 1, 3

LDL-Cholesterol Lowering Efficacy

Both agents achieve robust and comparable LDL-C reductions:

• Evolocumab: 59% reduction from baseline (median 92 to 30 mg/dL in FOURIER trial) 1
• Inclisiran: 50.7% mean placebo-corrected reduction at day 510, with time-adjusted mean of 50.5% 1, 2

A network meta-analysis found evolocumab slightly more effective (87% probability of being most effective) compared to inclisiran (47.2% probability) for LDL-C reduction 4. However, both achieve clinically meaningful reductions of approximately 50% when added to maximally tolerated statin therapy 1, 5

Cardiovascular Outcomes Evidence

This represents the most critical difference between the two agents:

Evolocumab (Proven CV Benefit):

• FOURIER trial (27,564 patients): 15% relative risk reduction in composite CV death/MI/stroke/hospitalization for angina/revascularization over 2.2 years 1
• 20% reduction in CV death/MI/stroke (7.4% to 5.9%, P<0.001) 1
• Significant reductions in all strokes (HR 0.79) and ischemic stroke (HR 0.75) 1

Inclisiran (Outcomes Data Pending):

• Exploratory analyses from ORION 9-11 showed reduced nonadjudicated CV events (7.4% vs 10.2% in one trial, 7.8% vs 10.3% in another) 1
• ORION-4 and VICTORION-2P cardiovascular outcomes trials ongoing, completion anticipated 2026-2027 1, 6
• ORION-4 following approximately 15,000 participants for median 5 years 2

The lack of completed cardiovascular outcomes trials for inclisiran is why current guidelines prioritize PCSK9 monoclonal antibodies as first-line PCSK9 inhibitors 1

Safety Profile

Both agents demonstrate excellent safety with minimal differences:

Evolocumab:

• Well tolerated in FOURIER trial over 2.2 years 1
• No evidence of increased cognitive adverse effects 1
• Hypersensitivity reactions rare; discontinue if serious reaction occurs 1

Inclisiran:

• Safety profile similar to placebo over 4 years in ORION-3 extension study 5
• Injection site reactions most common: 5.0% vs 0.7% placebo (predominantly mild, not persistent) 2, 7
• Treatment-emergent serious adverse events possibly related to drug: 1% over 4 years 5
• Adverse events at injection site: 14% in long-term follow-up 5

Network meta-analysis suggested evinacumab had best safety profile, followed by inclisiran (59.6% probability) and evolocumab (15.2% probability) for lowest adverse events, though clinical significance of this difference is minimal 4

Patient Selection Criteria

Choose Evolocumab (Repatha) for:

• All patients requiring PCSK9 inhibition as initial therapy (current guideline-recommended approach due to proven CV outcomes) 1
• Patients with established ASCVD at very high risk requiring rapid, proven CV risk reduction 1
• Patients with recent acute coronary syndrome 1
• Pediatric patients ≥10 years with HeFH or HoFH (FDA-approved indication) 1

Consider Inclisiran (Leqvio) as Alternative for:

• Patients with documented poor adherence to PCSK9 monoclonal antibodies (twice-yearly dosing advantage) 1
• Patients with adverse effects from both alirocumab AND evolocumab 1
• Patients unable to self-inject (can receive injections at clinic visits every 6 months) 1
• Patients with statin intolerance requiring additional LDL-C lowering (45% reduction maintained through 4 years in ORION-3) 1, 5
• Patients with primary hyperlipidemia or mixed dyslipidemia on maximally tolerated statin therapy not at LDL-C goal 8, 2, 6

Both Agents Appropriate for:

• Adults with clinical ASCVD requiring additional LDL-C lowering beyond maximally tolerated statin ± ezetimibe 1, 7
• Heterozygous familial hypercholesterolemia 1, 6
• LDL-C ≥70 mg/dL (or non-HDL-C ≥100 mg/dL) despite maximally tolerated statin therapy 1

Critical Clinical Caveats

Do NOT combine inclisiran with PCSK9 monoclonal antibodies - no evidence or mechanistic plausibility for additional efficacy; use inclisiran IN PLACE OF (not in addition to) PCSK9 mAbs 1

Inclisiran requires measurable LDL-C values to assess response; has no effect on triglycerides 2

For patients at very high ASCVD risk (<50% LDL-C reduction or LDL-C ≥55 mg/dL despite maximal therapy), referral to lipid specialist should be considered if considering inclisiran over proven PCSK9 mAb 1

Cost and insurance coverage may differ substantially between agents and influence selection 8, 2