CLS Novel Lipid-Lowering Therapies 2 — Questions and Answers
Question 1: Inclisiran is a small interfering RNA (siRNA) therapy that targets PCSK9. What is its primary mechanism of action?
- Blocks PCSK9 from binding to LDL receptors extracellularly
- Degrades PCSK9 mRNA in hepatocytes to reduce PCSK9 synthesis (Correct answer)
- Upregulates LDL receptor expression via SREBP pathway activation
- Inhibits HMG-CoA reductase to decrease hepatic cholesterol production
Correct answer: Degrades PCSK9 mRNA in hepatocytes to reduce PCSK9 synthesis
Inclisiran uses siRNA to degrade PCSK9 mRNA within hepatocytes, thereby reducing PCSK9 protein synthesis and increasing LDL receptor recycling.
Question 2: A patient on inclisiran 284 mg subcutaneous injection experiences LDL-C reduction of approximately 50% after the initial doses. What is the standard maintenance dosing interval?
- Every 2 weeks
- Every month
- Every 3 months
- Every 6 months (Correct answer)
Correct answer: Every 6 months
After the initial dose and a second dose at 3 months, inclisiran is administered every 6 months, offering a major adherence advantage over monoclonal antibodies.
Question 3: Which lipoprotein parameter is primarily reduced by bempedoic acid, and through what mechanism?
- LDL-C, by inhibiting ATP citrate lyase upstream of HMG-CoA reductase in the liver (Correct answer)
- Triglycerides, by activating PPAR-alpha in hepatic tissue
- Lp(a), by reducing apolipoprotein(a) synthesis in the liver
- HDL-C, by inhibiting CETP-mediated cholesterol ester transfer
Correct answer: LDL-C, by inhibiting ATP citrate lyase upstream of HMG-CoA reductase in the liver
Bempedoic acid inhibits ATP citrate lyase (ACL), an enzyme upstream of HMG-CoA reductase in hepatic cholesterol synthesis, primarily lowering LDL-C.
Question 4: A statin-intolerant patient with heterozygous FH is prescribed bempedoic acid. Which adverse effect unique to this drug class requires monitoring?
- Elevated serum creatinine and hyperkalemia
- Hyperuricemia and gout flares (Correct answer)
- QTc prolongation and arrhythmias
- Hepatotoxicity with ALT elevation > 3× ULN
Correct answer: Hyperuricemia and gout flares
Bempedoic acid inhibits urate transporter activity, leading to elevated serum uric acid levels and increased risk of gout flares.
Question 5: Evinacumab, an angiopoietin-like protein 3 (ANGPTL3) inhibitor, is approved for which patient population?
- Adults with statin intolerance and LDL-C > 130 mg/dL
- Homozygous familial hypercholesterolemia (HoFH) regardless of LDL receptor function (Correct answer)
- Patients with hypertriglyceridemia > 500 mg/dL refractory to fibrates
- Adults with atherosclerotic cardiovascular disease and LDL-C > 70 mg/dL on maximally tolerated therapy
Correct answer: Homozygous familial hypercholesterolemia (HoFH) regardless of LDL receptor function
Evinacumab is FDA-approved for adults and pediatric patients ≥12 years with HoFH, notably effective even in those with non-functional LDL receptors.
Question 6: Volanesorsen is an antisense oligonucleotide (ASO) approved for which specific lipid disorder?
- Familial hypercholesterolemia with LDL-C > 190 mg/dL
- Familial chylomicronemia syndrome (FCS) due to lipoprotein lipase deficiency (Correct answer)
- Familial combined hyperlipidemia with mixed dyslipidemia
- Primary prevention in patients with metabolic syndrome
Correct answer: Familial chylomicronemia syndrome (FCS) due to lipoprotein lipase deficiency
Volanesorsen targets APOC3 mRNA to reduce apolipoprotein C-III levels, thereby enhancing triglyceride clearance in patients with FCS.
Question 7: Lomitapide's mechanism involves inhibiting microsomal triglyceride transfer protein (MTP). Which lipoprotein assembly step does this primarily disrupt?
- Conversion of IDL to LDL in the bloodstream
- Assembly and secretion of VLDL in the liver and chylomicrons in the intestine (Correct answer)
- Maturation of HDL particles in peripheral tissues
- Receptor-mediated LDL uptake by hepatocytes
Correct answer: Assembly and secretion of VLDL in the liver and chylomicrons in the intestine
MTP transfers triglycerides and phospholipids onto apolipoprotein B, which is essential for VLDL assembly in the liver and chylomicron assembly in the intestine; lomitapide blocks this step.
CLS Novel Lipid-Lowering Therapies 2
Inclisiran is a small interfering RNA (siRNA) therapy that targets PCSK9.
What is its primary mechanism of action?