CLS Novel Lipid-Lowering Therapies 3 — Questions and Answers
Question 1: In the ORION-10 trial of inclisiran, what was the approximate mean LDL-C percent reduction from baseline at day 510?
- 20–25%
- 35–40%
- 50–55% (Correct answer)
- 70–75%
Correct answer: 50–55%
ORION-10 demonstrated a sustained time-averaged LDL-C reduction of approximately 52% from baseline with inclisiran in patients with ASCVD.
Question 2: A 58-year-old woman with ASCVD and statin myalgia is started on bempedoic acid/ezetimibe combination tablet. Which statement best describes the additive mechanism?
- Both agents inhibit cholesterol absorption at different intestinal transporters
- Bempedoic acid reduces hepatic synthesis while ezetimibe blocks intestinal cholesterol absorption via NPC1L1 (Correct answer)
- Both agents inhibit HMG-CoA reductase at different binding sites
- Ezetimibe inhibits PCSK9 while bempedoic acid reduces LDL receptor degradation
Correct answer: Bempedoic acid reduces hepatic synthesis while ezetimibe blocks intestinal cholesterol absorption via NPC1L1
The complementary mechanisms—hepatic synthesis inhibition by bempedoic acid and intestinal absorption inhibition by ezetimibe via NPC1L1—produce additive LDL-C lowering.
Question 3: ANGPTL3 inhibition by evinacumab lowers LDL-C through which primary pathway?
- Upregulating LDLR expression on hepatocyte surfaces
- Enhancing lipoprotein lipase (LPL) and endothelial lipase (EL) activity to accelerate lipoprotein catabolism (Correct answer)
- Blocking PCSK9-mediated LDLR degradation
- Reducing intestinal cholesterol absorption via NPC1L1 suppression
Correct answer: Enhancing lipoprotein lipase (LPL) and endothelial lipase (EL) activity to accelerate lipoprotein catabolism
ANGPTL3 normally inhibits both LPL and endothelial lipase; evinacumab removes this inhibition, accelerating catabolism of triglyceride-rich and LDL particles.
Question 4: Which of the following novel therapies specifically targets Lp(a) and is currently in advanced clinical development for cardiovascular risk reduction?
- Obicetrapib (CETP inhibitor)
- Pelacarsen (APOL1 ASO)
- Pelacarsen / olpasiran (anti-Lp(a) ASO or siRNA) (Correct answer)
- Gemcabene (APOC3 ASO)
Correct answer: Pelacarsen / olpasiran (anti-Lp(a) ASO or siRNA)
Pelacarsen (an ASO) and olpasiran (a siRNA) both specifically target Lp(a) synthesis and are in Phase 3 cardiovascular outcomes trials.
Question 5: A patient with HoFH on lomitapide develops elevated transaminases (ALT 4× ULN) after 4 months. What is the recommended management?
- Permanently discontinue lomitapide and initiate PCSK9 inhibitor monotherapy
- Reduce the dose by 50% and recheck liver enzymes in 4 weeks
- Continue current dose and add ursodeoxycholic acid for liver protection
- Suspend lomitapide, recheck LFTs within 1 week, and resume at a lower dose if enzymes normalize (Correct answer)
Correct answer: Suspend lomitapide, recheck LFTs within 1 week, and resume at a lower dose if enzymes normalize
Per lomitapide prescribing information and REMS program guidance, dose modification and monitoring is indicated for ALT/AST ≥3× ULN; suspension with reassessment guides safe resumption.
Question 6: Obicetrapib inhibits CETP (cholesteryl ester transfer protein). What is the expected lipid panel effect?
- Markedly decreased LDL-C with no change in HDL-C
- Increased HDL-C and decreased LDL-C (Correct answer)
- Selectively decreased triglycerides with increased LDL-C
- Decreased Lp(a) with no significant change in LDL-C or HDL-C
Correct answer: Increased HDL-C and decreased LDL-C
CETP inhibition reduces the transfer of cholesterol esters from HDL to LDL/VLDL, resulting in increased HDL-C and decreased LDL-C.
Question 7: Mipomersen is an ASO targeting APOB mRNA. For which patient population was it FDA-approved, and what limits its wider use?
- HeFH patients; limited by injection-site reactions only
- HoFH adults; limited by hepatotoxicity risk and REMS program requirements (Correct answer)
- Severe hypertriglyceridemia; limited by myopathy risk
- ASCVD patients intolerant to statins; limited by cost only
Correct answer: HoFH adults; limited by hepatotoxicity risk and REMS program requirements
Mipomersen is FDA-approved for HoFH in adults but requires a REMS program due to hepatotoxicity risk, restricting its clinical use.
CLS Novel Lipid-Lowering Therapies 3
In the ORION-10 trial of inclisiran, what was the approximate mean LDL-C percent reduction from baseline at day 510?