Gerald F. Watts

Extreme hypertriglyceridemia, defined as triglyceride (TG) levels ≥1000 mg/dL, is almost always indicative of chylomicronemia. The current diagnostic approach categorizes individuals with chylomicronemia into familial chylomicronemia syndrome (FCS; prevalence 1-10 per million), caused by the biallelic combination of pathogenic variants that impair the lipolytic action of lipoprotein lipase (LPL), or multifactorial chylomicronemia syndrome (MCS, 1 in 500). A pragmatic framework should emphasize the severity of the phenotype and the risk of complications. Therefore, we endorse the term "persistent chylomicronemia" defined as TG ≥1000 mg/dL in more than half of the measurements to encompass patients with the highest risk for pancreatitis, regardless of their genetic predisposition. We suggest classification of PC into four subtypes: 1) genetic FCS, 2) clinical FCS, 3) PC with "alarm" features, and 4) PC without alarm features. Although patients with FCS most likely have PC, the vast majority with PC do not have genetic FCS. Proposed alarm features are: (a) history of recurrent TG-induced acute pancreatitis, (b) recurrent hospitalizations for severe abdominal pain without another identified cause, (c) childhood pancreatitis, (d) family history of TG-induced pancreatitis, and/or (e) post-heparin LPL activity <20 % of normal value. Alarm features constitute the strongest risk factors for future acute pancreatitis risk. Patients with PC and alarm features have very high risk of pancreatitis, comparable to that in patients with FCS. Effective, innovative treatments for PC, like apoC-III inhibitors, have been developed. Combined with lifestyle modifications, these agents markedly lower TG levels and risk of pancreatitis in the very-high-risk groups, irrespective of the monogenic etiology. Pragmatic definitions, education, and focus on patients with PC specifically those with alarm features could help mitigate the risk of acute pancreatitis and other complications.

To the Editor: In the PALISADE trial, Watts et al. (Jan. 9 issue)1 found that plozasiran significantly reduced triglyceride levels and decreased the incidence of pancreatitis among patients with persistent chylomicronemia. After 10 months of treatment, triglyceride levels were reduced from baseline by approximately 80% with both the 25-mg dose and the 50-mg dose of plozasiran. Current guidelines2,3 recommend targeting a triglyceride level of less than 500 mg per deciliter. According to Figure S3 in the Supplementary Appendix of the article (available at NEJM.org), this target was reached in approximately half the patients who had received plozasiran after 10 months. . . .

Treatment of familial hypercholesterolemia is directed toward the moment of the medical encounter. However, risk for heart disease as a consequence of having familial hypercholesterolemia is related to lifelong exposure to elevated low-density lipoprotein cholesterol, rather than low-density lipoprotein cholesterol level at a specific time point. The purpose of this review is to reassess contemporary research on treatment of familial hypercholesterolemia and current evidence-based guidelines, to present an approach that emphasizes treatment across the life course, and to recognize the importance of family experiences to care. To accomplish this, we review the changing treatment needs that emerge across the life course, from birth through childhood, adolescence, young adulthood, peripregnancy, middle age, and late in life. Special attention is paid to improving adherence to treatment, the potential role of monitoring atherosclerosis in a lifelong model of care, and medical issues related to care transitions: from pediatric to internal medicine care, peripregnancy, after a cardiac event, and care after age 70 years in the absence of a cardiac event. Novel considerations related to treatment of homozygous familial hypercholesterolemia are discussed. The summary identifies research gaps that need to be closed to move from the current point-of-care model to one that considers treatment over the life course.

Extreme hypertriglyceridemia, defined as triglyceride (TG) levels ≥1000 mg/dL, is almost always indicative of chylomicronemia. The current diagnostic approach categorizes individuals with chylomicronemia into familial chylomicronemia syndrome (FCS; prevalence 1-10 per million), caused by the biallelic combination of pathogenic variants that impair the lipolytic action of lipoprotein lipase (LPL), or multifactorial chylomicronemia syndrome (MCS, 1 in 500). A pragmatic framework should emphasize the severity of the phenotype and the risk of complications. Therefore, we endorse the term "persistent chylomicronemia (PC)" defined as TG ≥1000 mg/dL in more than half of the measurements to encompass patients with the highest risk for pancreatitis, regardless of their genetic predisposition. We suggest classification of PC into 4 subtypes: (1) genetic FCS, (2) clinical FCS, (3) PC with "alarm" features, and (4) PC without alarm features. Although patients with FCS most likely have PC, the vast majority with PC do not have genetic FCS. Proposed alarm features are: (a) history of recurrent TG-induced acute pancreatitis, (b) recurrent hospitalizations for severe abdominal pain without another identified cause, (c) childhood pancreatitis, (d) family history of TG-induced pancreatitis, and/or (e) postheparin LPL activity <20% of normal value. Alarm features constitute the strongest risk factors for future acute pancreatitis risk. Patients with PC and alarm features have very high risk of pancreatitis, comparable to that in patients with FCS. Effective, innovative treatments for PC, like apolipoprotein C-III inhibitors, have been developed. Combined with lifestyle modifications, these agents markedly lower TG levels and risk of pancreatitis in the very-high-risk groups, irrespective of the monogenic etiology. Pragmatic definitions, education, and focus on patients with PC, specifically those with alarm features, could help mitigate the risk of acute pancreatitis and other complications.

Familial hypercholesterolaemia (FH) is an autosomal dominant condition, marked by elevated plasma concentrations of low-density lipoprotein (LDL)-cholesterol from birth. It confers a substantial risk of premature atherosclerotic cardiovascular disease (ASCVD), posing a major public health burden due to potential lifelong exposure to high LDL-cholesterol concentrations if untreated [1]. Despite growing awareness, FH continues to be underdetected and untreated, particularly in community settings, because of lack in implementation of evidence informed care, sparking several international calls to action [1].

A Phase 3 Study to Evaluate the Efficacy and Safety of ARO-APOC3 in Adults With Familial Chylomicronemia Syndrome

A Phase 2 Open-Label Extension Study to Evaluate the Long-Term Safety and Efficacy of ARO-APOC3 in Adults With Dyslipidemia

A Double-blind, Placebo-controlled Phase 2b Study to Evaluate the Efficacy and Safety of ARO-ANG3 in Adults With Mixed Dyslipidemia

Phase 2 Study to Evaluate the Safety and Efficacy of ARO-ANG3 in Subjects With Homozygous Familial Hypercholesterolemia (HOFH)

A Double-Blind, Placebo-Controlled Phase 2b Study to Evaluate the Efficacy and Safety of ARO-APOC3 in Adults With Severe Hypertriglyceridemia