R3i Editorials

August 2024
New kids on the block for triglyceride lowering
Prof. Jean-Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

Recent times have seen a resurgence of interest in triglycerides (TG), a surrogate for atherogenic TG-rich lipoproteins which are now considered to contribute to residual cardiovascular risk. Such a view is supported by accumulating evidence from epidemiologic, mechanistic, and genetic studies which indicate that elevated levels of TG-rich lipoproteins are strong and independent predictors for atherosclerotic cardiovascular disease (ASCVD) (1). This strengthening evidence-base prompted clinical outcomes studies which aimed to establish TG-rich lipoproteins as causal for ASCVD.
However, the pathway for such trials has been rocky, with only one trial to date, REDUCE-IT (2) demonstrating definitive clinical benefit from lowering TG levels with high-dose icosapent ethyl treatment.
With these persistent questions about TG-lowering and ASCVD, there has been a renewed emphasis on identifying novel agents that act at different sites of TG-rich lipoprotein metabolism. Aided by advances in nucleic acid-based technologies, small interfering RNA (siRNA) therapeutics have gained
in appeal given their specificity and efficiency. As these agents are characterized by low cellular uptake and are susceptible to nuclease-mediated degradation, a carrier is required for efficient delivery into target cells (3). The first approved siRNA, inclisiran, is in clinical use for the treatment of homozygous familial hypercholesterolemia and elevated low-density lipoprotein cholesterol (LDL-C).
This attractive technology has now been used in the search for novel TG-lowering agents (4).
Plozasiran (previously referred to ARO-APOC3) is a first-in-class hepatocyte-targeted apolipoprotein C-III (APOC3) siRNA therapeutic. APOC3 is a cofactor of lipoprotein lipase (LPL), a central regulator of lipid metabolism which has a key role in the hydrolysis of very low-density lipoproteins and chylomicrons. APOC3 inhibits LPL and interferes with the hepatic uptake of TG-rich lipoproteins by an independent LPL pathway (5). Thus, by reducing APOC3 expression, plozasiran reduces TG levels.

An early clinical trial provided proof-of-concept evidence for plozasiran in individuals with hypertriglyceridemia and chylomicronemia (6). Recent trials have investigated plozasiran in the clinical settings of severe hypertriglyceridemia (7), mixed hyperlipidemia as discussed in this month’s
Focus article (8), and most recently, in the PALISADE trial, in patients with familial chylomicronemia syndrome (FCS), a severe, ultra rare genetic disease with an unmet clinical need for new therapies.
Topline results from the PALISADE study showed that plozasiran significantly reduced TG levels (by 80% with 25 mg plozasiran and 78% with 50 mg plozasiran at 10 months), with this response sustained at 12 months (9). On the strength of these results, plozasiran was granted Orphan Drug
Designation and Fast Track Designation by the US Food and Drug Administration and Orphan Drug Designation by the European Medicines Agency (10).
Plozasiran is not the only TG-lowering siRNA therapeutic in development. Another approach targets angiopoietin-like protein 3 (ANGPTL3), a glycoprotein produced by the liver that has a pivotal role in inhibiting LPL and endothelial lipase, as well as hepatic uptake of TG-rich lipoprotein remnants (11). A phase 2 trial with zodasiran, an siRNA therapeutic targeting expression of ANGPTL3 in the liver, has shown efficacy in patients with mixed hyperlipidemia (12), and further trials are ongoing. With these novel therapies in development, the future for TG-lowering therapies appears bright. The
key question – whether lowering levels of TG-rich lipoproteins leads to clinical benefit in terms of reduced residual cardiovascular risk – merits addressing in cardiovascular outcomes studies with these novel agents.

References

  1. Song P, Rudan D, Zhu Y, et al. Global, regional and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis. Lancet Global Health 2019;7:e1020-30.
  2. GBD 2019 Peripheral Artery Disease Collaborators. Global burden of peripheral artery disease and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Global Health 2023;11: E1553-E1565. 
  3. Gornik HL, Aronow HD, Goodney PP, et al. 2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease. J Am Coll Cardiol 2024;doi.org/10.1016/j.jacc.2024.02.013.
  4. Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people. Lancet Diabetes Endocrinol 2015;3:105–13.
  5. Nativel M, Potier L, Alexandre L, et al. Lower extremity arterial disease in patients with diabetes: a contemporary narrative review. Cardiovasc Diabetol 2018;17(1):138.
  6. Das Pradhan A, Glynn RJ, Fruchart JC, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med 2022;387:1923-34.
  7. Marino L, Everett BM, Aday AY, et al. Pemafibrate reduces incidence of lower extremity ischemia ulcer and gangrene: evidence from PROMINENT. Abstract 23102. . Circulation 2023;148:e282–e317.
  8. Rajamani K, Colman PG, Li LP, et al. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet 2009;373:1780-8.
  9. Yuan J, Tan JTM, Rajamani K et al. Fenofibrate rescues diabetes-related impairment of ischemia-mediated angiogenesis by PPARalpha-independent modulation of thioredoxin-interacting protein. Diabetes 2019;68:1040-53.
  10. Deng Y, Han X, Yao Z, et al. PPARalpha agonist stimulated angiogenesis by improving endothelial precursor cell function via a NLRP3 Inflammasome pathway. Cell Physiol Biochem 2017;42:2255-66.
  11. Sharma P, Klarin D, Voight BF, et al. Evaluation of plasma biomarkers for causal association with peripheral artery disease. Arterioscler Thromb Vasc Biol 2024;44:1114–23.