Novel Lipid-Lowering Therapies Flashcards

A patient with severe hypertriglyceridemia (TG 1,800 mg/dL) and history of pancreatitis is prescribed icosapentaenoic acid (IPE/icosapent ethyl) 4 g/day. Which mechanism best explains its TG-lowering effect?

Answer: Reduction of hepatic VLDL-TG synthesis and secretion via PPAR-alpha activation and other pathways

Icosapent ethyl reduces hepatic VLDL-TG production through PPAR-alpha activation, reduces de novo lipogenesis, and enhances beta-oxidation, collectively lowering triglycerides.

The REDUCE-IT trial demonstrated that icosapent ethyl 4 g/day reduced major adverse cardiovascular events (MACE) by approximately what percent vs. placebo in high-risk patients on statins?

Answer: 25%

REDUCE-IT showed a 25% relative risk reduction in MACE with icosapent ethyl 4 g/day versus mineral oil placebo in statin-treated patients with elevated triglycerides.

A novel FGF21 analog (pegozafermin) is under investigation for lipid disorders. Which lipid parameter is its primary target?

Answer: Severe hypertriglyceridemia including familial chylomicronemia syndrome

FGF21 analogs like pegozafermin target metabolic pathways governing triglyceride clearance and are being studied for severe hypertriglyceridemia and NASH.

Which of the following correctly describes a key pharmacokinetic difference between alirocumab (PCSK9 monoclonal antibody) and inclisiran (PCSK9 siRNA)?

Answer: Alirocumab reduces circulating PCSK9 protein; inclisiran prevents PCSK9 protein synthesis in hepatocytes

Alirocumab binds circulating PCSK9 protein to prevent receptor binding, while inclisiran enters hepatocytes and degrades PCSK9 mRNA, blocking synthesis at the source.

Gemcabene, a dicarboxylic acid compound in development, primarily targets which lipid parameter through APOC3 suppression?

Answer: Triglycerides by reducing APOC3-mediated LPL inhibition

Gemcabene reduces APOC3 expression, thereby relieving APOC3's inhibitory effect on lipoprotein lipase and enhancing triglyceride-rich lipoprotein clearance.

A patient with HeFH and LDL-C 195 mg/dL on high-intensity statin plus ezetimibe is being evaluated for PCSK9 inhibitor therapy. Which additional novel agent, if added, would be least redundant mechanistically?

Answer: Bempedoic acid (ACL inhibitor to reduce hepatic cholesterol synthesis)

Bempedoic acid targets a different step (ACL/hepatic synthesis) complementary to statins and ezetimibe without redundancy with PCSK9 inhibitors, making it the least mechanistically redundant addition.

RNA interference (RNAi) therapies like inclisiran are delivered using lipid nanoparticle (LNP) technology that targets the liver via which receptor?

Answer: Asialoglycoprotein receptor (ASGPR) via GalNAc conjugation

Inclisiran is conjugated to GalNAc (N-acetylgalactosamine), which binds the hepatocyte-specific asialoglycoprotein receptor, enabling selective hepatic delivery.