For an adult with coronary risk factors, which PCSK9 inhibitor—inclisiran or evolocumab—has superior proven cardiovascular outcome data?

Evolocumab Has Superior Proven Cardiovascular Outcome Data Compared to Inclisiran

Evolocumab is the clear choice for patients requiring proven cardiovascular risk reduction, as it has robust outcome trial data demonstrating significant reductions in major adverse cardiovascular events, cardiovascular mortality, and total cardiovascular events, while inclisiran currently lacks any completed cardiovascular outcomes trials. 1, 2

Evidence for Cardiovascular Outcomes

Evolocumab: Proven Mortality and Morbidity Benefits

• The FOURIER trial (27,564 patients, 2.2 years follow-up) demonstrated that evolocumab reduced the primary composite endpoint (cardiovascular death, MI, stroke, hospitalization for angina, or revascularization) by 15% (HR 0.85; 95% CI 0.79-0.92; P<0.001) and the key secondary endpoint (cardiovascular death, MI, or stroke) by 20% (HR 0.80; 95% CI 0.73-0.88; P<0.001). 1

• Evolocumab prevented 22 first cardiovascular events and 52 total cardiovascular events per 1000 patients treated for 3 years, with the total event reduction being more than double that of first events alone. 2

• Specific reductions included: myocardial infarction (OR 0.72; 95% CI 0.64-0.81), stroke (OR 0.79; 95% CI 0.66-0.94), and coronary revascularization (OR 0.77; 95% CI 0.70-0.84). 3, 2

• In the diabetes subgroup (40% of FOURIER participants), evolocumab demonstrated consistent cardiovascular benefit. 1

Inclisiran: No Cardiovascular Outcomes Data

• The ORION-10 and ORION-11 trials evaluated inclisiran's LDL-C lowering efficacy but were NOT designed to assess cardiovascular outcomes. 1

• No completed cardiovascular outcomes trial exists for inclisiran demonstrating reductions in MI, stroke, cardiovascular death, or all-cause mortality. 1, 4

• Guidelines consistently note the absence of cardiovascular outcomes data for inclisiran, restricting recommendations to LDL-C reduction only. 5, 6

LDL-C Lowering Efficacy Comparison

While both agents effectively lower LDL-C, this does not translate to equivalent cardiovascular benefit without outcome trial data:

• Evolocumab reduces LDL-C by 59-61% when added to maximally tolerated statin therapy, achieving mean levels of approximately 30-35 mg/dL. 1, 3

• Inclisiran reduces LDL-C by 43-55% depending on dose (284mg vs 300mg), with placebo-corrected reductions of 49.9-52.3%. 1, 5, 3

• Both agents reduce lipoprotein(a) by 18-25%. 1, 7

Clinical Decision Algorithm

For adults with coronary risk factors requiring PCSK9 inhibition:

1. If the goal is proven cardiovascular risk reduction (mortality/morbidity): Choose evolocumab 140mg every 2 weeks or 420mg monthly, as it has demonstrated reductions in cardiovascular death, MI, stroke, and total cardiovascular events in the FOURIER trial. 1, 2

2. If the patient has established ASCVD on maximally tolerated statin therapy: Evolocumab is the evidence-based choice with proven 15-20% relative risk reductions in cardiovascular events. 1, 6

3. If the patient prioritizes dosing convenience over proven outcomes: Inclisiran (every 6 months after loading) may be considered, but counsel the patient that cardiovascular outcomes data are pending and not yet established. 1, 5

4. If the patient has familial hypercholesterolemia: Both agents effectively lower LDL-C, but evolocumab has demonstrated cardiovascular benefit in this population. 1, 5

Critical Caveats

• The absence of cardiovascular outcomes data for inclisiran is not merely a gap in evidence—it represents unknown clinical benefit for the outcomes that matter most: preventing heart attacks, strokes, and death. 6

• LDL-C reduction alone does not guarantee cardiovascular benefit, as demonstrated by failed trials of other lipid-lowering agents (CETP inhibitors, niacin). 1

• Until the VESALIUS-CV trial results are published, inclisiran should not be assumed equivalent to evolocumab for cardiovascular risk reduction. 6

• Both agents are well-tolerated with similar safety profiles (injection site reactions, no excess myalgia or neurocognitive events), so safety does not differentiate them. 1, 3

• For patients requiring proven cardiovascular protection, evolocumab's demonstrated 18% reduction in total cardiovascular events and mortality benefits make it the superior choice over inclisiran's unproven cardiovascular efficacy. 8, 3, 2