CLS Familial Hypercholesterolemia Management 3 — Questions and Answers
Question 1: Ezetimibe lowers LDL-C in FH patients primarily through which mechanism?
- Inhibiting HMG-CoA reductase in hepatocytes
- Blocking NPC1L1 transporter in intestinal enterocytes (Correct answer)
- Increasing PCSK9 degradation
- Upregulating LDL receptor expression via LXR pathway
Correct answer: Blocking NPC1L1 transporter in intestinal enterocytes
Ezetimibe inhibits the NPC1L1 transporter at the brush border of intestinal enterocytes, reducing cholesterol absorption by approximately 50%.
Question 2: Which PCSK9 inhibitor was the first FDA-approved monoclonal antibody for reducing LDL-C in heterozygous FH?
- Inclisiran
- Alirocumab (Correct answer)
- Bempedoic acid
- Lomitapide
Correct answer: Alirocumab
Alirocumab (Praluent) was the first PCSK9 inhibitor approved by the FDA in 2015 for heterozygous FH management.
Question 3: Inclisiran differs from monoclonal antibody PCSK9 inhibitors in that it:
- Blocks LDL receptor recycling instead of PCSK9 binding
- Uses siRNA to suppress hepatic PCSK9 synthesis, allowing twice-yearly dosing (Correct answer)
- Is given as a daily oral tablet
- Only reduces Lp(a) without affecting LDL-C
Correct answer: Uses siRNA to suppress hepatic PCSK9 synthesis, allowing twice-yearly dosing
Inclisiran is an siRNA that silences PCSK9 mRNA in hepatocytes, reducing PCSK9 production and enabling dosing only twice per year after initiation.
Question 4: Lomitapide is approved for homozygous FH and works by inhibiting which protein?
- Microsomal triglyceride transfer protein (MTP) (Correct answer)
- PCSK9
- NPC1L1
- ATP citrate lyase
Correct answer: Microsomal triglyceride transfer protein (MTP)
Lomitapide inhibits MTP, which is essential for assembling VLDL and chylomicrons, thereby reducing hepatic and intestinal lipoprotein secretion.
Question 5: Bempedoic acid reduces LDL-C in FH patients by inhibiting ATP citrate lyase. Its key advantage over statins is that it:
- Lowers LDL-C more than high-intensity statins
- Is activated only in the liver, minimizing muscle-related side effects (Correct answer)
- Reduces Lp(a) by more than 50%
- Does not require dose adjustment in renal impairment
Correct answer: Is activated only in the liver, minimizing muscle-related side effects
Bempedoic acid requires hepatic activation by ACSVL1 and is not converted to its active form in muscle, reducing the risk of myopathy seen with statins.
Question 6: A patient with HeFH on maximum-dose rosuvastatin plus ezetimibe still has LDL-C of 185 mg/dL. According to ACC/AHA guidelines, what is the most appropriate next step?
- Switch to atorvastatin and re-check in 12 weeks
- Add a PCSK9 inhibitor (Correct answer)
- Add niacin
- Initiate LDL apheresis immediately
Correct answer: Add a PCSK9 inhibitor
Current guidelines support adding a PCSK9 inhibitor when LDL-C remains above goal despite maximally tolerated statin plus ezetimibe in high-risk FH patients.
Question 7: Which clinical finding distinguishes xanthelasma from tendon xanthomas in FH patients?
- Xanthelasma are found on tendons; tendon xanthomas on eyelids
- Xanthelasma are soft yellowish plaques on eyelid skin; tendon xanthomas are firm nodules within tendon tissue (Correct answer)
- Xanthelasma occur only in homozygous FH; tendon xanthomas in heterozygous FH
- Xanthelasma contain triglycerides; tendon xanthomas contain cholesterol esters
Correct answer: Xanthelasma are soft yellowish plaques on eyelid skin; tendon xanthomas are firm nodules within tendon tissue
Xanthelasma are soft lipid deposits on periorbital skin with lower FH specificity, while tendon xanthomas are firm cholesterol deposits within tendon fibers highly specific for FH.
CLS Familial Hypercholesterolemia Management 3
Ezetimibe lowers LDL-C in FH patients primarily through which mechanism?