👤 Robert Hegele

Familial hypercholesterolemia (FH) is a common genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol (LDL-C), leading to a high risk of early onset atherosclerotic cardiovascular disease (ASCVD). This document provides an update to the National Lipid Association's 2011 clinical guidance, summarizing the remarkable progress in the field. With a global prevalence of approximately 1 in 311, FH remains severely underdiagnosed. This guidance reviews current diagnostic criteria, including the expanding role of genetic testing to complement diagnosis and to facilitate cascade screening, and emphasizes a thorough differential diagnosis. It provides recommendations for universal pediatric screening and systematic cascade screening in families to improve detection. Management strategies include intensified LDL-C treatment goals for both primary and secondary prevention of ASCVD. A stepwise approach to optimal therapy is outlined, beginning with lifestyle interventions and pharmacotherapy with maximally tolerated statins and ezetimibe. This update incorporates newer agents, including proprotein convertase subtilisin/kexin type 9 inhibitors and bempedoic acid. Additional therapies, such as lomitapide and evinacumab for homozygous FH and lipoprotein apheresis for heterozygous and homozygous FH, are discussed. Further topics include cardiovascular imaging for risk stratification, management in specific populations and circumstances, such as planning for and during pregnancy and in pediatrics, and recognition of health disparities. This guidance equips clinicians with evidence-based strategies to improve the identification and care of patients with FH, ultimately reducing the high morbidity and mortality associated with this condition. Show less

Despite significant advances in lipid-lowering therapeutics, residual lipid risk persists in patients with or at risk of atherosclerotic cardiovascular disease (ASCVD), even after optimizing low-density lipoprotein (LDL) cholesterol. Emerging evidence highlights the role of non-LDL cholesterol fractions, such as remnant cholesterol, lipoprotein(a) [Lp(a)], apolipoprotein B (apoB), and non-high-density lipoprotein (HDL) cholesterol, as key contributors to residual ASCVD risk. Remnant cholesterol, Lp(a), and LDL cholesterol represent three independent lipoprotein species causing ASCVD, while apolipoprotein B (apoB) and non-HDL cholesterol integrate the other three variables. Thus, clinically interpreting elevated apoB and non-HDL cholesterol is potentially complicated since remnants, Lp(a), and LDL cause ASCVD by different mechanisms and by varying proportions in different patients. Indeed, recent research into the pathophysiology of lipid-driven atherogenesis and development of ASCVD has revealed novel mechanisms that in turn suggest new therapeutic strategies targeting non-LDL lipid components. Elevated remnant cholesterol jointly with elevated LDL cholesterol contributes to arterial wall cholesterol deposition, plaque development, and ASCVD endpoints. Furthermore, the additional triglyceride content in remnant particles may theoretically promote intimal inflammation and possibly plaque rupture and erosion, independently contributing to atherogenesis and ASCVD. The lipid component and pro-inflammatory properties of Lp(a) could similarly contribute directly to atherosclerotic plaque development and ASCVD. In addition, the homology with plasminogen of the defining apolipoprotein(a) moiety of Lp(a) has long been speculated to confer anti-fibrinolytic and pro-thrombotic properties that could produce more severe ASCVD outcomes independent of atherogenesis. This review explores the evolving understanding of residual lipid risk in ASCVD, practical guidance for clinicians today, recent advances in therapeutic interventions, and their implications for clinical practice, aiming to optimize lipid management beyond LDL cholesterol reduction today and in the future. Show less

Dyslipidemia is common in patients with MASLD, but the frequency and significance of inherited disorders of dyslipidemia are unclear. We investigated the prevalence and significance of pathogenic variants associated with selected monogenic disorders of dyslipidemia in 3358 patients with well-characterised MASLD. We identified clinically relevant variants in APOB, MTTP, PCSK9, ANGPTL3, LDLR and LDLRAP1 genes which can cause hypobetalipoproteinemia (HBL) and familial hypercholesterolemia (FH). Using ClinVar annotations as initial variant selection, we identified 2027 variants in those 6 genes which are reported as 'pathogenic' or 'likely pathogenic' (P/LP). We first assessed for the presence of P/LP variants in the study cohort and then investigated the effect of carrying P/LP variants on liver histology, by comparing ~4 matched controls for each APOB and LDLR carrier. As interpretative analyses, we also looked at the difference between liver enzymes, lipid measures and outcomes between the carriers and matched controls. Twenty-two variants among these 2027 P/LP variants were present in 24 out of 3358 patients (12 ApoB, 10 LDLR, 1 ANGPTL3 and 1 MTTP variant carriers). Compared to controls, APOB carriers had higher steatosis grade (2.4 vs. 1.7, p-value 0.0028), higher NAFLD activity score (NAS) (4.9 vs. 3.8, p-value 0.04), and numerically higher but statistically not significant fibrosis stage (1.2 vs. 1.1, p-value 0.75) and ALT (87.4 vs. 58.1 U/L, p-value 0.06). Their LDL-c (51 vs. 147.8 mg/dL, p-value 6.1E-09) and triglycerides (91.5 vs. 160.6 mg/dL, p-value 2.8E-03) were significantly lower. Compared to controls, LDLR carriers had numerically higher steatosis grade, NAS, fibrosis stage and LDL-c levels, but these were not statistically different. Monogenic disorders of dyslipidemia are rarely present in patients with MASLD and are sometimes associated with worse liver histology. Testing for these conditions may be considered on a case-by-case basis. Show less

Hypertriglyceridemia (HTG) is a heterogeneous metabolic disorder driven by both genetic susceptibility and secondary factors. Most cases of severe HTG (triglyceride [TG] >10 mmol/L [>885 mg/dL]) have multifactorial chylomicronemia syndrome (MCS) while only a few have familial chylomicronemia syndrome (FCS), a rare autosomal recessive condition. We summarize the pathophysiology of severe HTG, emphasizing impaired intravascular lipolysis of TG-rich lipoproteins and the regulatory role of apolipoproteins (apo), particularly apo C-III. We outline features that distinguish FCS from MCS and discuss diagnostic strategies, including clinical scoring systems and targeted genetic testing. Current management approaches, including responses to conventional TG-lowering therapies and emerging biologic therapies targeting apo C-III, are examined. We searched PubMed for all English language literature focusing on the search terms 'chylomicronemia,' 'familial chylomicronemia syndrome,' 'multifactorial chylomicronemia syndrome,' 'hypertriglyceridemia,' 'APOC3 inhibition,' 'antisense oligonucleotides,' and 'apolipoprotein C-III.' Differentiating FCS from MCS is critical because RNA-based inhibition of apo C-III has transformed the therapeutic landscape for FCS patients. These agents provide substantial, durable TG lowering and meaningful reductions in pancreatitis risk, although cardiovascular benefit remains uncertain. Future efforts should focus on optimizing diagnostic pathways, assessing cardiovascular outcomes, and determining long-term safety of novel biologic therapies. Show less

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder marked by severe hypertriglyceridemia and characteristic clinical manifestations, particularly acute pancreatitis. Conventional triglyceride-lowering therapy is largely ineffective. Apolipoprotein (apo) C-III has emerged as a key therapeutic target to lower triglycerides in FCS. This review compares FCS with more common multifactorial chylomicronemia. We searched PubMed for all English language literature focusing on the search terms 'chylomicronemia,' 'hypertriglyceridemia,' 'APOC3 inhibition,' 'plozasiran,' 'olezarsen,' and 'volanesorsen.' We outline traditional management strategies and their limited role in FCS and explore non-traditional therapies including orlistat, lomitapide, inhibitors of angiopoietin like protein 3 (ANGPTL3), and analogues of fibroblast growth factor 21 (FGF21). The primary focus is on RNA-based gene silencing therapeutics that target apo C-III, particularly the small interfering RNA plozasiran and the allele specific oligonucleotides volanesorsen and olezarsen, highlighting key differences in efficacy and tolerability. In a phase 3 trial of plozasiran, at 10 months, median placebo-adjusted reductions in apo C-III were approximately -90%, while TG levels were reduced up to -59%. Thus, plozasiran and alternative RNA-based therapeutics directed against APOC3 represent transformational therapies for patients with FCS and related phenotypes characterized by severe recalcitrant hypertriglyceridemia. Show less

Genetic determinants play a central role in the development of dyslipidemias, which are major contributors to atherosclerotic cardiovascular disease (ASCVD), aortic valve disease, and acute pancreatitis. With conventional lipid-lowering therapies, such as statins, many patients with genetic dyslipidemias remain inadequately controlled while other patients are unable to tolerate them, necessitating ongoing research and development of innovative therapies. Several therapeutic lipid targets-including proprotein convertase subtilisin/kexin type 9 (PCSK9), lipoprotein(a) [Lp(a)], apolipoprotein (apo) C-III (APOC3), and angiopoietin-like protein 3 (ANGPTL3)-have been identified and validated through human genetic and epidemiologic studies. Emerging ribonucleic acid (RNA) targeting and gene-editing therapies now offer the potential for durable correction of these metabolic disturbances. Small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) targeting PCSK9, Lp(a), apo C-III and ANGPTL3 have shown marked efficacy in lowering atherogenic lipoproteins and triglycerides, while DNA base-editing approaches including clustered regularly interspaced short palindromic repeats (CRISPR), CRISPR associated protein 9 (Cas9) and related base-editing techniques, aim to provide long-term or even permanent gene silencing to control atherogenic lipids. Together, these innovations mark a paradigm shift toward precision, gene-based lipid management, expanding therapeutic options, improving clinical outcomes, and addressing unmet medical needs in patients with severe or refractory dyslipidemias or in those unable to tolerate standard therapies. Show less

Chylomicronemia, defined by fasting triglycerides ≥10 mmol/L (≥885 mg/dL), has diverse etiologies. When clinical features such as abdominal pain, lipemia retinalis, eruptive xanthomas, hepatosplenomegaly, pancreatitis, or visibly lipemic plasma accompany the biochemical disturbance, the condition is called chylomicronemia syndrome. Subtypes include rare monogenic familial chylomicronemia syndrome (FCS), the more common multifactorial chylomicronemia syndrome (MCS), autoimmune chylomicronemia, and lipodystrophy-associated chylomicronemia. Patients are at risk for acute pancreatitis and sometimes atherosclerotic cardiovascular disease. Accurate diagnosis includes medical history, physical exam, laboratory testing (including plasma apolipoprotein B and the ratio of triglyceride to total cholesterol), clinical scoring systems, as well as selective use of genetic testing when FCS is suspected. In adults, the overwhelming majority of patients with chylomicronemia have MCS and not FCS. Treatment centers on dietary fat restriction, total alcohol avoidance, management of secondary factors, and traditional triglyceride-lowering therapies such as fibrates and omega-3 fatty acids. Acute pancreatitis management requires stabilization, analgesia, supportive care, and preventive management of hypertriglyceridemia. Emerging RNA-based therapies targeting apolipoprotein C-III (eg, volanesorsen, olezarsen, and plozasiran) offer transformative potential for FCS and for some refractory patients with other chylomicronemia subtypes. A multidisciplinary approach-integrating clinical, biochemical, and genetic assessment-guides therapy and reduces pancreatitis risk. Show less

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to analyze the genotype distribution of FCS-causing genes in the United Kingdom. Data were anonymously collated from 2 genetic testing laboratories providing national genetic diagnosis services for severe hypertriglyceridemia in the United Kingdom. As of December 2023, 880 individuals underwent genetic testing for FCS. The mean (SD) age at the time of genetic testing was 42.5 (15.3) years. After genotyping, 12.9% of the individuals ( The genetic architecture of FCS in the United Kingdom is complex, with a substantial proportion affected by non- Show less

A 3-year-old patient presented with severe hypertriglyceridemia and suspected familial chylomicronemia syndrome. Genetic analysis of the patient's DNA revealed the presence of 2 different heterozygous nonsense variants in the APOA5 gene encoding apolipoprotein (apo) A-V, namely p.Q275X and p.L242C fs X54. Our objective was to characterize the structural and functional consequences of the patient's co-occuring compound heterozygous variants in APOA5. Biozentrum's SWISS-MODEL was employed to predict the structure of apo A-V variants. Plasma from the patient and their family was used to determine lipid profiles, quantify apo C-II and apo C-III protein levels, and measure lipoprotein lipase (LPL) activity. High-density lipoprotein (HDL) was isolated from plasma and was used to assess sterol efflux capacity and proteome. Structural characterization of the patient's APOA5 variants indicated premature truncation of the C-terminus of apo A-V that comprises the lipid binding domain. The patient's apo A-V was completely absent from the very-low density lipoprotein (VLDL) plasma fraction, associating almost exclusively with the low-density lipoprotein (LDL) and lipoprotein-free fractions. The patient's plasma also demonstrated reduced LPL activity and elevated apo C-II and C-III compared to other family members. The patient's HDL had the lowest sterol efflux capacity of all family members and a distinct proteome with reduced phospholipid transfer protein. Dietary intervention alone was effective in preventing recurring hypertriglyceridemia. These findings add to the current knowledge of apo A-V's role in plasma lipid homeostasis, pointing to a critical role for apo A-V binding to the lipoprotein particle in normal hydrolysis of triglyceride-rich lipoproteins. Show less

Familial chylomicronemia syndrome (FCS) is diagnosed by genetic or nongenetic criteria. To assess responses to treatment of apolipoprotein (apo)C-III, triglycerides, and pancreatitis events in patients with FCS-based diagnostic methods. APPROACH enrolled 66 patients with FCS randomized to volanesorsen or placebo for 12 months. In 50 participants, genetic confirmation of FCS was based on the presence of pathogenic bi-allelic variants in LPL, APOC2, APOA5, GPIHBP1, or LMF1 genes. In 16 participants without a genetic diagnosis, FCS was diagnosed using clinical criteria and postheparin lipoprotein lipase activity ≤20% of normal. Plasma levels of apoC-III, triglycerides and related variables were measured at 3, 6, and 12 months. No significant differences were present in mean apoC-III reductions with volanesorsen at 3, 6, or 12 months in patients with FCS diagnosed either genetically or nongenetically. In contrast, the triglyceride reductions were statistically less robust in patients with genetic diagnosis at each timepoint, with mean (95% CI) percent reduction in triglycerides of -68.7% (-78.7, -58.6) vs -84.0% (-99.4, -68.6), P = .014 at Month 3; -58.2% (-78.1, -38.2) vs -84.5% (-122.4, -46.7), P = .009 at Month 6; and -35.6% (-57.7, -13.4) vs. -69.0% (-105.0, -33.1), P = .005 at Month 12. Patients with a genetic diagnosis had significantly lower response rates for achieved triglycerides <500 mg/dL, <750 mg/dL, <880 mg/dL and <1000 mg/dL than patients with a nongenetic diagnosis. All 5 episodes of acute pancreatitis occurred in patients with a genetic diagnosis. For a similar reduction in apoC-III in response to volanesorsen, triglyceride reduction is attenuated in patients with genetically vs nongenetically diagnosed FCS. Show less

Heterozygous familial hypercholesterolemia (HeFH) is the most prevalent inherited dyslipidemia, and it predisposes individuals to premature atherosclerotic cardiovascular disease. Genetic testing can provide a definitive diagnosis. The spectrum of causal DNA variants in Ontario patients with hypercholesterolemia is not fully defined. In Southwestern Ontario patients with a clinical diagnosis of HeFH, we performed targeted next-generation DNA sequencing and bioinformatic analysis to determine the qualitative and quantitative spectrum of pathogenic and likely pathogenic (P/LP) variants. We observed 101 unique P/LP variants in 254 patients, of which 6 were novel This study provides a comprehensive overview of the clinical and genetic spectrum of HeFH in Southwestern Ontario. The P/LP variant diversity reflects historical colonization and later migration patterns both from across the world and interprovincially from Quebec. Show less

Plozasiran, an investigational siRNA targeting hepatic apoC-III, reduces triglyceride-rich lipoproteins (TRLs). The impact of plozasiran on lipoprotein particle numbers and sizes is unknown. However, reductions in the number of TRL particles (TRL-P) and a shift to possibly less atherogenic large low-density lipoprotein particles (LDL-P) are expected. This study aimed to determine the impact of plozasiran on lipoprotein particle concentration and subclass distribution using nuclear magnetic resonance (NMR) in 2 phase 2 studies. Patients (N = 403) from SHASTA-2 (severe hypertriglyceridemia) and MUIR (mixed hyperlipidemia) were administered 2 total subcutaneous doses of plozasiran (10, 25, or 50 mg) or placebo at baseline and week 12. Comprehensive lipoprotein profiling was conducted with NMR. In SHASTA-2, there was a dose-dependent reduction in TRL-P, with placebo-adjusted total TRL-P reductions of -46% and reductions across all TRL subclasses with plozasiran. While total LDL-P was unchanged, large LDL-P concentration increased by +53% and medium by +56%; small LDL-P trended lower (-13%). Total HDL-P increased by +8%, primarily driven by a +36% increase in large high-density lipoprotein particles (HDL-Ps). Similarly, in MUIR, there were dose-dependent reductions in TRL-P, with total TRL-P significantly reduced by -48% (pooled plozasiran) and reductions across all TRL subclasses with plozasiran. While total LDL-P was unchanged, large and medium LDL-P levels increased by +88% and +46%, respectively; small LDL-P levels decreased by -28%. Total HDL-P increased by +12%, driven by a +83% increase in large HDL-P. Plozasiran induced reductions in apoC-III and showed potentially favorable quantitative and qualitative changes in lipoproteins as assessed by NMR in patients with hypertriglyceridemia and mixed hyperlipidemia. Plozasiran reduced TRL-P by ∼50%, shifted LDL to larger particles, and modestly increased HDL-P concentration. While high-potency TRL-lowering therapies can lead to an overall LDL-C increase, plozasiran did not increase LDL-P or apoB but shifted LDL particle size distribution from small dense LDL toward larger sizes. The ∼50% reduction in TRL-P with no increase in apoB and possibly beneficial qualitative changes in LDL suggests the potential of plozasiran to lower cardiovascular risk, which may be evaluated in a prospective outcomes trial. Show less

Clinical endpoints caused by hyperlipoproteinemia include atherosclerotic cardiovascular disease and acute pancreatitis. Emerging lipid-lowering therapies targeting proprotein convertase subtilisin/kexin 9 (PCSK9), lipoprotein(a), apolipoprotein C-III, and angiopoietin-like protein 3 represent promising advances in the management of patients with hyperlipoproteinemia. These therapies offer novel approaches for lowering pathogenic lipid and lipoprotein species, particularly in patients with serious perturbations who are not adequately controlled with conventional treatments or who are unable to tolerate them. Molecular targets for these novel therapeutic agents were identified and validated through genetic epidemiology studies. Proprotein convertase subtilisin/kexin 9 inhibitors (e.g., monoclonal antibodies and small interfering RNA) have revolutionized hypercholesterolemia management by significantly reducing both low-density lipoprotein cholesterol levels and major cardiovascular events. Genome editing of PCSK9 promises to provide a potential cure for patients with familial hypercholesterolemia. Several investigational lipoprotein(a)-targeting therapies aim to reduce the risk of atherosclerotic cardiovascular disease and aortic valve disease, although definitive clinical endpoint studies remain to be completed. Inhibition of APOC3 messenger RNA expression by olezarsen and plozasiran significantly lowers plasma triglyceride levels and markedly reduces pancreatitis risk in patients with familial chylomicronemia syndrome. Finally, angiopoietin-like protein 3 inhibition by the monoclonal antibody evinacumab has transformed management of patients with homozygous familial hypercholesterolemia. Together, these novel agents expand the therapeutic cache, offering personalized lipid-lowering strategies for high-risk patients with hyperlipoproteinemia, improving clinical outcomes and addressing previously unmet medical needs. Show less

Elevated plasma lipoprotein(a) [Lp(a)] is a causal and independent risk factor for atherosclerotic cardiovascular disease and an emerging therapeutic target. Over the past 15 years, many medical bodies from around the world have released scientific statements and clinical guidelines regarding Lp(a). This review tracks how recommendations on Lp(a) have evolved over this timeframe. Powerful studies demonstrating the independent association of elevated Lp(a) in large numbers of patients have been published. The data allowed a more precise formulation of risk categories for Lp(a) levels and of models for how a given level of Lp(a) in a moderate-risk to high-risk primary prevention patient might inform management of modifiable risk factors such as LDL cholesterol. Guidelines and statements have increasingly recommended universal screening for elevated Lp(a) and have identified elevated Lp(a) as a risk-enhancing or amplifying factor. However, some gaps and inconsistencies remain. Ongoing cardiovascular outcomes trials of potent Lp(a)-lowering therapies will inform clinical use of Lp(a) in the future. Presently, consensus is building for measurement of Lp(a) in all adults and for incorporation of Lp(a) levels into clinical decision-making for prevention of cardiovascular disease. However, caution is warranted as the evidence base underlying this consensus has several important missing pieces. Show less

Familial chylomicronemia syndrome (FCS) is a rare Mendelian autosomal recessive disorder (MIM 238600) characterized by extreme and sustained hypertriglyceridemia due to profound reduction of lipoprotein lipase (LPL) activity. This expert opinion statement synthesizes current knowledge on the definition, pathophysiology, genetics, prevalence, diagnosis, and management of FCS. FCS typically manifests at a young age with persistent severe hypertriglyceridemia-defined as ≥10 mmol/L (≥885 mg/dL), or ≥1000 mg/dL (≥11.2 mmol/L) depending on region and whether Systeme International (SI) units are utilized-in the absence of secondary factors, resistance to conventional lipid-lowering therapies, and a high lifetime risk of acute pancreatitis. It is caused by biallelic pathogenic variants in the LPL gene encoding LPL, or 1 of 4 other related genes that encode proteins that interact with LPL. Affected individuals require a strict, lifelong very low-fat diet with <15% of energy from fat. Emerging therapies inhibiting apolipoprotein C-III show promise in reducing serum triglycerides and pancreatitis risk in patients with FCS. A multidisciplinary approach, encompassing dietary management, pharmacotherapy, and patient education, is pivotal in mitigating the significant morbidity associated with FCS. Show less

Genetic testing of patients with severe hypertriglyceridemia often identifies a single heterozygous pathogenic variant in the LPL gene. The complex and variable phenotype associated with this genotype is the topic of this review. Previous research showed that heterozygosity for lipoprotein lipase deficiency is associated with reduced but variable post heparin lipolytic activity alongside inconsistent plasma lipid phenotypes ranging from normal to mild-to-moderate to severe hypertriglyceridemia. Recent research confirms and extends these observations, showing that a heterozygous individual can express a highly variable phenotype over time, depending on the presence of secondary factors. About 10% (range 8-20%) of patients with severe hypertriglyceridemia or multifactorial chylomicronemia syndrome are heterozygous for a rare pathogenic LPL variant, and a clinically relevant minority of these has recalcitrant or sustained hypertriglyceridemia. Heterozygosity for lipoprotein lipase deficiency predisposes to hypertriglyceridemia, which is sometimes severe depending on secondary factors, but is typically quite responsive to routine interventions such as diet, lifestyle and existing lipid-lowering therapies. However, many heterozygotes for pathogenic variants in LPL have completely normal plasma lipids. Show less

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive condition. Effective treatment is important as patients are at risk for severe and potentially fatal acute pancreatitis. We review recent developments in pharmacologic treatment for FCS, namely biological inhibitors of apolipoprotein (apo) C-III and angiopoietin-like protein 3 (ANGPTL3). FCS follows a biallelic inheritance pattern in which an individual inherits two pathogenic loss-of-function alleles of one of the five causal genes - Apo C-III inhibitors currently in development are promising treatments for FCS. Show less

This study aims to show the clinical and biochemical features in patients with severe hypertriglyceridemia (HTG) associated with rare variants in the apolipoprotein A-V (APOA5) gene. Demographics, blood lipid levels, body mass index (BMI) and APOA5 mutation subtypes were collected from the endocrinology clinic registry and analyzed for a retrospective cohort study of ten patients with severe HTG and APOA5 gene variants. Of the 10 cases, four were female, and six were male. The median age was 45.0 years (min-max: 21-60 years), the median triglyceride was 2429.5 mg/dL (27.5 mmol/L) (min-max: 1351-4087 mg/dL, 15.3-46.2 mmol/L), and the mean BMI was calculated as 30.4 ± 4.4 kg/m We report a cohort of patients with biallelic and single copy APOA5 variants, who were diagnosed later in life. Most had secondary factors, such as DM or obesity with increased BMI. Most rare APOA5 variants found in our patients were of uncertain significance. Our results add to the growing evidence that rare variants in certain candidate genes may predispose to developing HTG, together with secondary factors such as obesity. The genetic basis of HTG in many other patients is still unknown and remains the subject of further investigation. Show less

While biallelic rare APOA5 pathogenic loss-of-function (LOF) variants cause familial chylomicronemia syndrome, heterozygosity for such variants is associated with highly variable triglyceride phenotypes ranging from normal to severe hypertriglyceridemia, often in the same individual at different time points. Here we provide an updated overview of rare APOA5 variants in hypertriglyceridemia. Currently, most variants in APOA5 that are considered to be pathogenic according to guidelines of the American College of Medical Genetics and Genomics are those resulting in premature termination codons. There are minimal high quality functional data on the impact of most rare APOA5 missense variants; many are considered as variants of unknown or uncertain significance. Furthermore, particular common polymorphisms of APOA5 , such as p.Ser19Trp and p.Gly185Cys in Caucasian and Asian populations, respectively, are statistically overrepresented in hypertriglyceridemia cohorts and are sometimes misattributed as being causal for chylomicronemia, when they are merely risk alleles for hypertriglyceridemia. Both biallelic and monoallelic LOF variants in APOA5 are associated with severe hypertriglyceridemia, although the biochemical phenotype in the monoallelic state is highly variable and is often exacerbated by secondary factors. Currently, with few exceptions, the principal definitive mechanism for APOA5 pathogenicity is through premature truncation. The pathogenic mechanisms of most missense variants in APOA5 remain unclear and require additional functional experiments or family studies. Show less

Multiple agents are being developed that inhibit apolipoprotein (apo) C-III. This state-of-the-art review examines their potential for atherosclerotic cardiovascular disease (ASCVD) risk reduction. Apo C-III, an apolipoprotein on the surface of triglyceride-rich lipoproteins (TRLs), impairs clearance of TRLs through both lipoprotein lipase dependent and independent pathways, thereby resulting in increased concentrations of triglycerides. Apo C-III has also been shown to have pro-atherogenic effects when bound to high-density lipoprotein (HDL) particles. Classical and genetic epidemiology studies provide support for the concept that apo C-III is associated with an increased risk of ASCVD events. Drug efficacy of agents that silence APOC3 mRNA has been studied in populations with varying hypertriglyceridemia severity, including those with familial chylomicronemia syndrome, multifactorial chylomicronemia syndrome/severe hypertriglyceridemia, and mixed hyperlipidemia. Randomized controlled trials have reported significant reductions in TG and non-HDL cholesterol levels among these patients treated with APOC3 inhibitors. Upcoming clinical outcomes trials seek to establish a role for APOC3 inhibitors to reduce risk of ASCVD. Show less

To investigate the relationship between plasma lipoprotein (a) (Lp[a]) and lipid profiles in patients with severe hypertriglyceridaemia (HTG). This case-control study undertook a retrospective chart review of patients from the Lipid Genetics Clinic at London Health Sciences Centre in Ontario, Canada. Plasma Lp(a) was compared between patients with severe HTG and healthy normolipidaemic control subjects. Severe HTG was defined by plasma triglycerides (TG) ≥ 10 mmol/l. Pairwise correlations between Lp(a), TG, apolipoprotein B (apo B) and non-high-density lipoprotein cholesterol (non-HDL-C) were evaluated. This study reviewed 4400 patients and identified 154 patients with severe HTG, which were compared with 272 control subjects. The median Lp(a) was significantly lower in patients with severe HTG compared with control subjects (5.0 versus 10.2 mg/dl, respectively). No correlation was observed between Lp(a) and TG or non-HDL-C. Lp(a) and apo B were modestly correlated in patients with severe HTG ( Patients with severe HTG have lower plasma Lp(a) than normolipidaemic control subjects. The basis for this relationship is not immediately apparent but is hypothesis-generating and warrants further investigation. Show less

Atherosclerotic cardiovascular disease (ASCVD) is a significant health challenge, and apolipoprotein B (ApoB)-containing lipoproteins are increasingly recognized as central to its progression. Initially labelled as the "low-density lipoprotein hypothesis," our understanding of the etiology of ASCVD has evolved into the "ApoB principle," which highlights the causal and consistent role of all ApoB lipoproteins in ASCVD development. We review the large body of data from genetic studies, to epidemiologic studies, to clinical trials that support this foundational principle. We also provide an overview of the recommendations from guideline committees across the globe on dyslipidemia management and compare these with recent Canadian guidelines. With a few key differences, recent guidelines worldwide provide largely concordant recommendations for diagnosing and managing dyslipidemia with general consensus regarding the need for optimal control of low-density lipoprotein cholesterol and ApoB-containing lipoproteins to prevent cardiovascular events and improve patient care. Show less

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to study the genotype distribution of FCS-causing genes in the United Kingdom, genotype-phenotype correlation, and clinical differences between FCS and multifactorial chylomicronemia syndrome (MCS). The study included 154 patients (FCS, 74; MCS, 80) from the UK FCS national registry and the UK arm of the FCS International Quality Improvement and Service Evaluation Project. FCS was relatively common in non-Europeans and those with parental consanguinity ( The frequency of gene variant distribution varies based on the ethnic origin of patients with FCS. Patients with FCS are at a higher risk of pancreatic complications while the prevalence of atherosclerotic cardiovascular disease is lower in FCS compared with MCS. Carriers of heterozygous pathogenic variants have an intermediate phenotype between FCS and variant-negative MCS. Show less

Biallelic pathogenic variants in APOA5 are an infrequent cause of familial chylomicronemia syndrome characterized by severe, refractory hypertriglyceridemia (HTG), and fasting plasma triglyceride (TG) >10 mmol/L (>875 mg/dL). The TG phenotype of heterozygous individuals with one copy of a pathogenic APOA5 variant is less familiar. We evaluated the longitudinal TG phenotype of individuals with a single pathogenic APOA5 variant allele. Medically stable outpatients from Ontario, Canada were selected for study based on having: 1) a rare pathogenic APOA5 variant in a single allele; and 2) at least three serial fasting TG measurements obtained over >1.5 years of follow-up. Seven patients were followed for a mean of 5.3 ± 3.7 years. Fasting TG levels varied widely both within and between patients. Three patients displayed at least one normal TG measurement (<2.0 mmol/L or <175 mg/dL). All patients displayed mild-to-moderate HTG (2 to 9.9 mmol/L or 175 to 875 mg/dL) at multiple time points. Five patients displayed at least one severe HTG measurement. 10%, 54%, and 36% of all TG measurements were in normal, mild-to-moderate, and severe HTG ranges, respectively. Heterozygosity for pathogenic variants in APOA5 is associated with highly variable TG phenotypes both within and between patients. Heterozygosity confers susceptibility to elevated TG levels, with secondary factors likely modulating the phenotypic severity. Show less

High triglyceride (TG) levels are associated with an increased risk for atherosclerotic cardiovascular disease (ASCVD) and pancreatitis. The objectives for this study were to evaluate for the coexistence of severe HTG and pancreatitis in two different geographic regions of Turkey and to identify rare variants that cause monogenic HTG in our country. In our study from 2014 to 2019, patients with severe HTG who presented to the endocrinology outpatient clinics with TG levels >500 mg/dL (5.7 mmol/L) were evaluated. The LPL, APOC2, APOA5, GPIHBP1, LMF1, and APOE genes were sequenced using next generation sequencing to screen for potentially pathogenic variants. Potentially pathogenic variants were identified in 64 (47.1%) of 136 patients. Variants in LPL were seen in 42 (30.9%) cases, APOA5 variants in 10 (7.4%) cases, APOC2 variants in 5 (3.7%) cases, LMF1 variants in 5 (3.7%) cases, and APOE mutations in 2 (1.5%) cases. In the subgroup that experienced pancreatitis (n = 76, 56.3%), LPL variants were seen at higher frequency (P <0.001) than in the subgroup with no history of pancreatitis (n = 60, 43.7%). Patients who developed pancreatitis (56.3%) demonstrated a median TG of 2083 mg/dL (23.5 mmol/L), and patients without pancreatitis (43.7%) demonstrated a median TG of 1244.5 mg/dL (14.1 mmol/L) (P <0.001). Accurate approach to HTG diagnosis is important for the prevention of pancreatitis and ASCVD. Evaluation of variants in primary HTG after excluding secondary causes may help provide a patient-centric precision treatment plan. Show less

BACKGROUND: Apolipoprotein C-III (APOC3) inhibits triglyceride clearance by reducing lipoprotein lipase–mediated hydrolysis and hepatocyte uptake of triglyceride-rich lipoproteins. ARO-APOC3, a hepatocyte-targeting RNA interference therapeutic, inhibits APOC3 messenger ribonucleic acid expression, lowering triglyceride levels. The objective of this trial was to assess the safety, pharmacodynamic variables, and pharmacokinetic variables of ARO-APOC3 treatment. METHODS: Healthy participants and adults with hypertriglyceridemia were randomly assigned to receive escalating single (day 1) or repeat (days 1 and 29) doses, respectively, of subcutaneous injections of ARO-APOC3 10, 25, 50, or 100 mg or placebo; they were followed up until day 113. Additional cohorts of healthy participants and adults with chylomicronemia received repeat doses of open-label ARO-APOC3. The primary objective was to evaluate the safety and side effect profile of ARO-APOC3. Key secondary and exploratory objectives included pharmacokinetic variables and changes in serum APOC3, triglyceride, and cholesterol levels. RESULTS: Eighty-eight participants received ARO-APOC3 and 24 participants received placebo across double-blind and open-label cohorts. Treatment-emergent adverse events (AEs) of transient, mild to moderate liver transaminase changes occurred in 10 participants: 1 patient receiving ARO-APOC3 25 mg, 5 patients receiving ARO-APOC3 50 mg, and 4 participants receiving ARO-APOC3 100 mg (1 healthy participant and 3 patients with hypertriglyceridemia). These events were asymptomatic, and transaminase levels returned to near baseline by the end of the trial. No AEs related to thrombocytopenia or platelet declines were reported. In the hypertriglyceridemia cohorts, the day 113 mean changes from baseline in APOC3 at the 10-, 25-, 50-, and 100-mg doses were −62.0%, −81.7%, −90.1%, and −94.4%, respectively, compared with −1.6% with placebo. This corresponded to median changes in triglyceride levels of −65.6%, −69.9%, −81.2%, and −81.0% compared with −2.8% with placebo. CONCLUSIONS: In this small trial of short duration, ARO-APOC3 was associated with few AEs and reduced serum levels of APOC3 and triglycerides in healthy participants and patients with hypertriglyceridemia. (Funded by Arrowhead Pharmaceuticals, Inc.; ClinicalTrials.gov number, NCT03783377.) Show less

Mild-to-moderate hypertriglyceridemia (HTG) is commonly encountered and is associated with atherosclerotic cardiovascular disease (ASCVD).  Elevated plasma triglyceride (TG) levels reflect high levels of triglyceride-rich lipoproteins, against which lipid-lowering therapies that reduce low-density lipoprotein cholesterol are relatively ineffective.  Apolipoprotein (apo) C-III is a new pharmacological target to reduce triglycerides and potentially also cardiovascular disease risk. Here, we evaluate current lipid-lowering therapies and their effect on TG levels; genetic, pre-clinical, cellular, molecular biology, and translational studies that emphasize the importance of apo C-III in the metabolism of TG-rich lipoproteins and ASCVD risk; and clinical trials of pharmacotherapies that reduce TG levels via apo C-III inhibition. The PubMed database was searched using terms: apolipoprotein C-III, ARO-APOC3, atherosclerotic cardiovascular disease, olezarsen, triglycerides, and volanesorsen; study types: clinical trials, systematic reviews, and meta-analyses; and time criterion 2005 to present. Apo C-III inhibition is a promising treatment approach for adults with mild-to-moderate HTG and either established atherosclerotic cardiovascular disease or its risk factors.  Biologic agents such as volanesorsen, olezarsen, and ARO-APOC3 significantly reduce plasma levels of apo C-III and TG, although data on cardiovascular outcomes are lacking.  Volanesorsen is associated with thrombocytopenia in patients with severe HTG, but other agents appear to be better tolerated.  Clinical trials with long-term follow-up of cardiovascular outcomes will establish the validity of apo C-III inhibition. Show less

Patients with familial chylomicronaemia syndrome (FCS) have severe hypertriglyceridaemia due to genetically absent lipolytic capacity. They have a poor response to conventional therapies. To reduce the risk of potentially fatal pancreatitis, the management of FCS relies principally on a strict low-fat diet, which is difficult to follow and compromises quality of life. Targeted reduction of apolipoprotein C-III using new anti- Show less