A 48-year-old woman with familial hypercholesterolaemia (FH) is started on a PCSK9 inhibitor (evolocumab) after failing to achieve LDL-C target on high-dose atorvastatin plus ezetimibe. Before initiating the PCSK9 inhibitor, which investigation is most important to establish baseline status and guide therapy?

## Baseline Investigation Before PCSK9 Inhibitor Therapy ### Rationale for LDL-C and Lipoprotein(a) Assessment **Key Point:** Serum LDL-cholesterol and lipoprotein(a) (Lp(a)) are the essential baseline investigations before initiating a PCSK9 inhibitor in familial hypercholesterolaemia. ### Why LDL-C and Lp(a)? 1. **LDL-Cholesterol Baseline** - Establishes the pre-PCSK9 inhibitor LDL-C level to quantify the response to therapy - PCSK9 inhibitors reduce LDL-C by 40–60% from baseline - Determines whether target LDL-C (<55 mg/dL for FH patients with ASCVD) is achieved - Essential for assessing efficacy and deciding on further intensification (addition of bempedoic acid, inclisiran, etc.) 2. **Lipoprotein(a) Measurement** - Lp(a) is an independent cardiovascular risk factor, especially elevated in FH - NOT significantly reduced by PCSK9 inhibitors (unlike LDL-C) - Baseline Lp(a) identifies patients who may benefit from emerging therapies (apo(a)-lowering agents, inclisiran) - Helps stratify residual cardiovascular risk despite LDL-C reduction **High-Yield:** The 2022 ESC/EAS guidelines recommend measuring Lp(a) at least once in all dyslipidaemic patients, especially those with FH or premature ASCVD. This is a game-changer for risk stratification. ### Investigation Timing and Interpretation | Investigation | Timing | Clinical Use | | --- | --- | --- | | LDL-C | Before PCSK9 initiation | Baseline for efficacy assessment; target <55 mg/dL in FH with ASCVD | | Lp(a) | At least once (before PCSK9) | Risk stratification; identifies need for future Lp(a)-lowering agents | | LDLR/APOB/PCSK9 genetics | Optional; not routine | Confirms FH diagnosis; prognostic; family screening | | Carotid ultrasound | Not routine; selective use | Identifies subclinical atherosclerosis; not standard pre-PCSK9 | | Coronary angiography | Only if symptomatic or high-risk | Therapeutic/diagnostic; not routine baseline | **Clinical Pearl:** In FH, Lp(a) is often markedly elevated and contributes to the extreme LDL-C phenotype. Measuring Lp(a) before PCSK9 therapy identifies patients with residual risk who may benefit from inclisiran (an LDL-lowering agent that also reduces Lp(a)) or future apo(a)-targeting therapies. **Mnemonic:** **PCSK9 Baseline = LDL + Lp(a)** - **L**DL-C: quantifies response to PCSK9 inhibitor - **L**ipoprotein(a): identifies residual risk; guides future therapy selection