Antonio Giaimo, MD

This segment looks ahead to remaining challenges in FCS diagnosis and access, and to the broader implications of APOC3 inhibition for hypertriglyceridemia management.

Perspectives on Ongoing Unmet Need and the Future of FCS Care

Despite major therapeutic advances, substantial unmet need remains in the diagnosis and management of familial chylomicronemia syndrome (FCS).

In their closing reflections, Nihar R. Desai, MD, and Anthony Giamo, MD, note that many patients first present to hospital-based internists with acute pancreatitis and markedly elevated triglycerides, where distinguishing FCS from multifactorial chylomicronemia can be challenging. They emphasize the importance of early referral to lipid specialists and point to resources such as the National Lipid Association’s directory of lipidologists to facilitate expert evaluation and confirmatory testing.

The experts also highlight real‑world obstacles related to coverage, access, and cost of newly approved APOC3‑targeted therapies. Transitioning from controlled trial settings and modeling exercises to broad clinical impact requires that patients can reliably obtain and continue treatment. In addition, long‑term data on pancreatitis reduction, quality of life, and potential cardiovascular outcomes are still needed, and there is strong interest in head‑to‑head comparisons and expanded indications.

Looking forward, advances in FCS are expected to inform the management of broader populations with severe or mixed hypertriglyceridemia. The mechanistic insights gained from APOC3 inhibition may spur development of additional agents and rational combination strategies targeting triglyceride‑driven disease. The faculty characterize this moment as an inflection point in preventive cardiology and lipidology, in which a historically refractory condition now has effective targeted therapies, and ongoing education, research, and systems‑level efforts will be critical to fully realizing their potential for patients.

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This segment emphasizes the clinical and quality‑of‑life value of achieving deep triglyceride reductions, particularly below 500 mg/dL, in FCS.

Importance of Reducing Triglycerides in FCS Care

Achieving profound triglyceride reductions is central to optimizing outcomes in familial chylomicronemia syndrome. In their exchange, Anthony Giamo, MD, and Nihar R. Desai, MD, emphasize that the American Heart Association defines severe hypertriglyceridemia as triglycerides ≥500 mg/dL and that lowering levels below this threshold is associated with substantial reduction in acute pancreatitis risk. The ability of APOC3‑targeted agents to bring a large proportion of patients below 500 mg/dL therefore represents a clinically meaningful advance.

Beyond hard clinical endpoints, the faculty highlight the impact of triglyceride control on daily functioning and psychosocial well‑being. Patients with FCS frequently live under strict dietary constraints that can preclude routine social activities, such as attending a restaurant meal or holiday gathering, for fear of precipitating pancreatitis. As triglycerides are better controlled with APOC3 inhibitors, clinicians may cautiously liberalize dietary restrictions, de‑escalate reliance on largely ineffective adjunctive agents (such as fibrates and omega‑3 fatty acids), and thereby improve quality of life while maintaining safety.

Desai notes that the consistent advantage seen for plozasiran in simulations—showing a greater proportion of patients crossing below the 500‑mg/dL threshold compared with olezarsen—may translate over time into fewer pancreatitis episodes, reduced medication burden, and better patient‑reported outcomes. Both experts stress the need for future research to quantify these benefits with rigorous clinical endpoints and validated quality‑of‑life measures. Nonetheless, current evidence supports aggressive triglyceride lowering with targeted therapies as a cornerstone of contemporary FCS management.

This segment addresses practical considerations in choosing between newly approved APOC3 inhibitors for patients with FCS. 

Embracing Newly FDA Approved Therapies for FCS Management

The recent approval of multiple APOC3‑targeted agents has transformed the therapeutic landscape for familial chylomicronemia syndrome. Building on trial evidence, Nihar R. Desai, MD, explains that both olezarsen and plozasiran now have US Food and Drug Administration indications for FCS, offering clinicians unprecedented choice in targeted therapy. Olezarsen is administered monthly, whereas plozasiran is dosed quarterly, and this difference in dosing frequency may influence patient preference, adherence, and clinic workflow.

Desai reviews in more detail the simulation work based on the Balance and Palisade trials, emphasizing that, under multiple modeled scenarios and sensitivity analyses—including those restricted to genetically confirmed FCS—the probability of achieving triglyceride levels less than 500 mg/dL was consistently higher with plozasiran than with olezarsen. These modeled differences mirror the numerically greater triglyceride reductions observed in Palisade and are framed as clinically relevant, particularly given the association of this threshold with reduced pancreatitis risk.

Anthony Giamo, MD, underscores that real‑world treatment decisions should integrate trial data, modeled efficacy, dosing schedules, safety profiles, and individual patient characteristics and preferences. While acknowledging the limitations inherent to simulation studies and the lack of direct head‑to‑head comparisons, both experts view APOC3 inhibitors as transformative for FCS care. Clinicians are encouraged to use all available evidence to tailor therapy in a way that maximizes triglyceride lowering and minimizes pancreatitis risk, while remaining attentive to new data that may further refine agent selection.

This segment explores the mechanisms of APOC3‑targeting agents and compares the triglyceride‑lowering profiles of olezarsen and plozasiran in FCS.

Assessing Therapeutic Options in FCS Management

APOC3 inhibition has emerged as a central therapeutic strategy for familial chylomicronemia syndrome despite the underlying defect in lipoprotein lipase activity. In their discussion, Anthony Giamo, MD, and Nihar R. Desai, MD, outline how olezarsen, an antisense oligonucleotide, and plozasiran, a small interfering RNA, both reduce APOC3 expression, thereby relieving inhibition of lipase pathways. Although FCS patients have severely impaired or absent lipoprotein lipase function, APOC3 inhibition still produces robust triglyceride reductions, likely through enhanced activity of alternative lipases such as hepatic lipase and improved chylomicron clearance.

The faculty review data from pivotal trials—Balance for olezarsen and Palisade for plozasiran—demonstrating dramatic triglyceride lowering in patients with FCS. Giamo notes that, in PALISADE, nearly all plozasiran‑treated patients experienced substantial triglyceride reductions, whereas in BALANCE a large majority, though not all, patients receiving olezarsen responded. These findings support APOC3 inhibition as a foundational pharmacologic approach in FCS, moving beyond purely dietary and symptomatic management toward targeted correction of the chylomicronemia state.

Desai further discusses a Monte Carlo simulation that applied the observed trial‑based triglyceride reductions from olezarsen and plozasiran to simulated FCS populations with varying baseline triglyceride distributions. Across multiple time points and sensitivity analyses, plozasiran‑treated cohorts were more likely to achieve triglyceride levels less than 500 mg/dL—a threshold associated with attenuation of pancreatitis risk—than olezarsen‑treated cohorts. Although the experts acknowledge the absence of head‑to‑head randomized comparisons, they suggest that such simulation data, combined with trial results, can inform therapeutic selection in clinical practice.

Antonio Giaimo, MD

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