A 48-year-old woman with familial hypercholesterolaemia (heterozygous) presents with LDL cholesterol 165 mg/dL despite atorvastatin 80 mg + ezetimibe 10 mg daily for 8 weeks. Liver enzymes and CK are normal. She has no history of CAD. What is the most appropriate next step?

Explanation

## Management of Familial Hypercholesterolaemia on Dual Therapy **Key Point:** Heterozygous familial hypercholesterolaemia (HeFH) is a very high-risk condition. When LDL remains above goal despite maximal statin + ezetimibe, PCSK9 inhibitors are the next-step therapy, even without established CAD, because HeFH carries high premature CAD risk. ### Risk Stratification and Escalation in HeFH ```mermaid flowchart TD A[Heterozygous FH diagnosed]:::outcome --> B[Start high-intensity statin<br/>+ ezetimibe]:::action B --> C{LDL at goal?}:::decision C -->|Yes| D[Continue, monitor]:::action C -->|No| E[Add PCSK9 inhibitor]:::action E --> F{LDL at goal?}:::decision F -->|Yes| G[Maintain triple therapy]:::action F -->|No| H[Consider bempedoic acid<br/>or inclisiran]:::action ``` **High-Yield:** PCSK9 inhibitors are **first-line add-on** after statin + ezetimibe failure in HeFH, regardless of CAD status. They reduce LDL by 50–60% and are now recommended in major guidelines (ESC, ACC/AHA) for HeFH. ### Comparison of Third-Line Agents | Agent | Mechanism | LDL Reduction | Route | Indication | |-------|-----------|---------------|-------|------------| | PCSK9 inhibitor (evolocumab, alirocumab) | PCSK9 monoclonal antibody | 50–60% | SC q2w or q4w | HeFH, very high-risk CAD | | Bempedoic acid | Urate transporter inhibitor; ↓ uric acid, ↓ LDL 15–20% | 15–20% | Oral daily | Statin-intolerant or add-on | | Inclisiran | PCSK9 siRNA inhibitor | 50–60% | SC q6m | HeFH, very high-risk (newer) | | Fenofibrate | Fibrate; ↓ TG, modest LDL ↓ | 10–15% LDL | Oral daily | Hypertriglyceridaemia (not primary LDL therapy) | **Clinical Pearl:** This patient has HeFH (very high-risk phenotype) and is on maximal dual therapy. PCSK9 inhibitors are guideline-recommended next step. Inclisiran is an alternative but is newer and less widely available; bempedoic acid is weaker. Fenofibrate is for triglyceride-dominant dyslipidaemia, not primary HeFH management. **Warning:** Do not confuse HeFH with secondary dyslipidaemia or mild hypercholesterolaemia. HeFH is a genetic disorder requiring aggressive LDL lowering to prevent premature CAD, even without prior events.