TL;DR
Modulation of the Angiopoietin-like protein 3–4–8–8 axis is a novel strategy to address residual atherosclerotic risk beyond traditional LDL receptor–dependent therapies.
Primary hyperlipoproteinemias represent a heterogeneous group of inherited lipid metabolism disorders characterized by persistent abnormalities in plasma lipoproteins, a markedly increased risk of premature atherosclerotic cardiovascular disease (ASCVD) and, in selected phenotypes, acute pancreatitis. Traditionally classified according to the Fredrickson phenotypic system, these disorders are now increasingly understood through a multidimensional framework integrating molecular genetics, intracellular lipid trafficking, inflammatory signaling, and systemic metabolic regulation. Recent advances have identified both monogenic and polygenic determinants underlying disease expression, including pathogenic variants affecting LDLR, APOB, PCSK9, APOE, and lipoprotein lipase pathways, as well as the cumulative contribution of multiple common lipid-associated variants. Furthermore, emerging evidence highlights the role of endoplasmic reticulum stress, oxidative imbalance, adipose–hepatic crosstalk, intestinal lipid absorption, and inflammatory mediators in modulating lipoprotein metabolism and cardiovascular risk. Novel regulators such as angiopoietin-like proteins (ANGPTLs), microRNAs, and pathways involved in cholesterol efflux and remnant lipoprotein clearance have further refined our understanding of disease heterogeneity and therapeutic responsiveness. Familial hypercholesterolemia and familial combined hyperlipidemia exemplify the complex interplay between genetic susceptibility, metabolic dysfunction, and environmental influences that shape phenotype severity and long-term cardiovascular outcomes. Advances in diagnostic strategies, including genetic testing, polygenic risk scores, apolipoprotein profiling, and vascular imaging, have significantly improved risk stratification and personalized management. Simultaneously, innovative therapies—including PCSK9 inhibitors, ANGPTL3-targeted agents, antisense oligonucleotides, and RNA-silencing technologies—are reshaping treatment paradigms and expanding options for high-risk patients. This chapter synthesizes contemporary insights into the pathogenesis of primary hyperlipoproteinemias, emphasizing the transition from traditional lipid-based classification toward precision medicine approaches focused on lifetime cardiovascular risk, molecular characterization, and individualized therapeutic intervention.
These agents have expanded treatment options for patients with familial dyslipidaemia, severe hypertriglyceridaemia, and persistent residual cardiovascular risk while paving the way for precision medicine.
Hypocholesterolemia is perceived as benign given its association with lower cardiovascular risk. However, genetic and epidemiological evidence indicates that persistently low levels of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB) arise from distinct biological mechanisms with different hepatic implications. Hypocholesterolemia may reflect either impaired hepatic assembly and secretion of ApoB-containing lipoproteins or enhanced peripheral clearance of circulating lipoproteins, with divergent outcomes. Genetic defects disrupting ApoB-dependent lipoprotein secretion, notably variants in apolipoprotein B gene (APOB) and microsomal triglyceride transfer protein gene (MTTP), limit hepatic lipid export and promote intrahepatic triglyceride retention, predisposing to steatosis and progressive liver disease without metabolic risk factors. Hypocholesterolemia driven by increased lipoprotein clearance, as observed with loss-of-function variants in proprotein convertase subtilisin/kexin type 9 (PCSK9) or angiopoietin-like protein 3 (ANGPTL3), produces lifelong LDL-C reduction that is cardioprotective without consistent evidence of adverse hepatic outcomes. Cohort and sequencing studies demonstrate an increased burden of liver disease in secretion-driven hypocholesterolemia but not in clearance-driven phenotypes. These findings indicate that clinical consequences are determined by the underlying biological mechanism rather than the degree of cholesterol lowering. After exclusion of secondary causes, genetic testing may be considered in people with metabolic dysfunction-associated steatotic liver disease (MASLD) and hypocholesterolemia to clarify the mechanism, guide follow-up, and enable family cascade screening. In impaired secretion phenotype forms, lifelong MASLD monitoring may be warranted, with timely consideration of therapy if liver disease progresses. In clearance-mediated phenotypes, management should follow standard MASLD risk stratification and care, without additional surveillance related to the genetic defect.
Dyslipidemia is a major contributor to atherosclerotic cardiovascular disease (ASCVD), the leading cause of morbidity and mortality worldwide. Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes hepatic low-density lipoprotein receptor (LDLR) degradation, elevating plasma low-density lipoprotein cholesterol (LDL-C) and contributing to plaque initiation, progression, and destabilization via lipid-dependent and -independent pathways (e.g., inflammation, endothelial dysfunction, thrombosis). PCSK9 inhibition is a validated target for intensive lipid management Beyond statins, monoclonal antibodies (evolocumab, alirocumab) and siRNA-based therapy (inclisiran) achieve reductions in LDL-C of >50%. Large outcome trials (FOURIER, ODYSSEY OUTCOMES, ORION series) have demonstrated reduced major adverse cardiovascular events (MACE) and favorable safety in high-risk populations including acute coronary syndrome, familial hypercholesterolemia, and statin intolerance. Newer approaches include oral small molecule inhibitors (e.g., MK-0616, AZD0780), therapeutic vaccines (e.g., AT04A), and gene-editing (e.g., VERVE-101) with improved adherence, durability or potential cure. For patients with very-high-risk or high-risk ASCVD who do not achieve LDL-C targets with traditional therapies, clinical guidelines, including China-specific recommendations, support the use of PCSK9 inhibitors to lower LDL-C and further reduce CV risk.
Hypertriglyceridemia is a prevalent lipid disorder associated with residual atherosclerotic cardiovascular disease (ASCVD) risk and increased risk of acute pancreatitis at triglyceride (TG) levels above 1000 mg/dL. Causes of hypertriglyceridemia are multifactorial and may be a result of secondary causes (Western diet, alcohol, medications, uncontrolled diseases/disorders), genetic disorders, or a combination of both. Two novel medications (olezarsen, plozasiran), which inhibit hepatic production of apoC-III mRNA and increase TG clearance, have recently been approved to reduce TG levels in adults with familial chylomicronemia syndrome (FCS). Both olezarsen and plozasiran have been evaluated in randomized, placebo-controlled, clinical trials in patients with varying degrees of hypertriglyceridemia. In this review, we report the lipid-lowering effects and safety of both olezarsen and plozasiran from clinical trials in patients with hypertriglyceridemia. Based on available data, both agents are associated with significant TG-lowering effects via reductions in apoC-III, as well as favorable effects on other lipid parameters. Overall, both agents appear generally well tolerated, although monitoring of liver enzymes and glycemic control is warranted for both agents, and additional monitoring of platelet counts for olezarsen. Future clinical trials are needed to assess whether the TG-lowering effects of each agent are associated with reduced risk of pancreatitis and ASCVD events.
The ongoing CORALreef Outcomes trial will determine whether enlicitide-mediated LDL-C reduction translates into fewer major cardiovascular events and will help define its long-term clinical role.
