R3i Editorial

Despite optimal risk factor control, residual cardiovascular risk remains a persistent challenge for clinicians managing patients with or at high risk of atherosclerotic cardiovascular disease (ASCVD). Attention has therefore focused on targeting other drivers of this risk. Among lipid-related factors, triglyceride (TG)-rich lipoproteins, remnant cholesterol, and lipoprotein(a) [Lp(a)] have been recognised as key determinants of residual risk ^1-3. However, in the case of TG-rich lipoproteins and remnant cholesterol, major outcomes studies have had mixed results ^4-6. Whether this lack of a definitive answer is attributable to the complexity of TG-rich lipoprotein metabolism, necessitating careful selection of therapeutic targets, the need to reduce total atherogenic cholesterol (both mass and particle number), patient selection criteria or other features of study design is contentious and the subject of ongoing debate ^1 7-9. Furthermore, although Lp(a) is established as a casual risk factor for ASCVD ³, there is no evidence as yet that lowering elevated Lp(a) levels reduces cardiovascular events.

In view of these considerations, the search for novel therapeutics that act at these lipid targets continues. This year’s American College of Cardiology Scientific Sessions provided some intriguing insights. First, there were new data for olezarsen, an siRNA apolipoprotein C-III (APOC3) therapeutic. APOC3 is a key regulator of lipoprotein metabolism and has a pivotal role in regulating TG levels ¹. Studies of genetic variants that result in a loss of function and reduced plasma levels of APOC3 are associated with a reduced risk of coronary heart disease ^10,12, providing a strong rationale for investigating the therapeutic potential of this approach. Preliminary studies with olezarsen were encouraging ^13,14, providing a basis for further investigation. The Bridge–TIMI 73a trial was designed to investigate the efficacy and safety of olezarsen in high-risk patients with moderate or severe hypertriglyceridemia, although in practice the majority of patients (128/154, 83%) had moderately elevated TG levels (150 to 499 mg/dL, overall median TG level 241.5 mg/dL) ¹⁵. Treatment with olezarsen reduced plasma TG levels by ~50% at 6 months, as well as other atherogenic targets including apoB (by 18%) and non-high-density lipoprotein cholesterol (up to 25%). With a favourable safety profile to date, the results suggest potential for this agent in addressing residual cardiovascular risk. Olezarsen also showed benefit in patients with familial chylomicronemia syndrome with significant reduction in fasting TG at 6 months in the 80 mg dose group ¹⁶.

Additionally, there were encouraging data with zerlasiran, the latest siRNA targeting hepatic synthesis of apolipoprotein(a), a key determinant of Lp(a) levels. In patients with stable ASCVD and Lp(a) levels >150 nmol/L, administration of zerlasiran (either 200 mg every 4 weeks or 300 or 450 mg every 8 weeks) resulted in almost 100% inhibition of Lp(a) levels (97-98% reduction) after 2 doses ¹⁷. With favourable tolerability to date, further clinical development is indicated. Another novel siRNA targeting Lp(a) – lepodisiran – is also on the horizon, with a phase 1 study completed (https://clinicaltrials.gov/study/NCT04914546) and an ongoing phase 2 trial due to complete later this year (https://clinicaltrials.gov/study/NCT05565742). Despite these innovations, awareness of the need for Lp(a) testing among clinicians remains a major obstacle to better integration of Lp(a) management into clinical practice ¹⁸.

With evidence that ~40% of patients treated with statins continue to experience cardiovascular events over 10 years, residual cardiovascular risk continues to be a major clinical challenge in the 21st century. New strategies targeting other drivers of both lipid- and non-lipid related residual cardiovascular risk are clearly needed. Insights from ACC.2024 suggest new possibilities, although major outcomes studies are mandatory for proof of benefit.

References
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