New insights into the biology of triglyceride (TG) metabolism underpin the development of novel therapies for managing hypertriglyceridaemia to reduce the risk of atherosclerotic cardiovascular disease (ASCVD) and, for severely elevated levels, pancreatitis.
Elevated TG levels – a surrogate for TG-rich lipoproteins and their remnants (click for explanation)* – result from increased production of TG-rich particles, altered processing and catabolism, reduced clearance, or a combination of these mechanisms (1). For decades, raised TG levels have been associated with accelerated atherogenesis, especially in the postprandial (non-fasting) state (2,3). However, understanding of the complexity of TG metabolism and its relation to the development of atherosclerosis lagged behind.
*Remnants (or remnant lipoproteins) result from the metabolism of triglyceride-rich lipoproteins by lipoprotein lipase, as well as hepatic lipase, endothelial lipase and cholesteryl ester transfer protein. They have a triglyceride-depleted core, are enriched in cholesteryl esters and become progressively enriched in apolipoprotein (apo)E as they undergone lipolysis The main structural protein is apoB48 in chylomicron remnants and apoB100 in very low-density lipoprotein (VLDL) remnants.
Contrasting results from large observational studies added further confusion. Some reports showed that elevated non-fasting TG levels were associated with an increased risk of myocardial infarction, ischaemic heart disease and death (4), whereas in the Emerging Risk Factors Collaboration study, the increased risk for coronary artery disease with elevated TG was abrogated by adjustment for high-density lipoprotein cholesterol (HDL-C) and non‑HDL‑C (5). It is important to note, however, that non-HDL-C captures all atherogenic, apolipoprotein (apo)B-containing lipoproteins, including TG-rich lipoproteins, and therefore it is not surprising that adjustment for non-HDL-C made this association non-significant. Further adding to controversy surrounding the putative role of TG in atherogenesis is the well-known fact that patients with chylomicronaemia syndrome, who have very high TG levels, do not develop ASCVD.
Past trials of therapeutic approaches to lowering plasma TG have had mixed results in testing whether lowering elevated TG reduces cardiovascular risk (3,6).
However, in the last decade new insights from epidemiology and genetic studies – in particular, Mendelian randomisation studies, a type of ‘natural’ randomised trial – have moved the field forward (6,7). Studies of variants in genes encoding proteins for major pathways in TG metabolism, notably the key regulator, lipoprotein lipase, apoAV and CIII, and the angiopoietin-like proteins 3, 4 and 8 (ANGPTL3, 4 and 8) have been fundamental to elucidating the relationship between TG-rich lipoproteins and cardiovascular risk (7).
These findings have been critical in driving the development of new therapeutic approaches for managing elevated TG to reduce residual cardiovascular risk on a background of statin therapy. Omega-3 fatty acids have also seen renewed interest. In 2007, the Japan EPA Lipid Interventional Study (JELIS) showed a significant reduction in major coronary events with eicosapentaenoic acid (EPA, 1.8 g/day) (8); other trials were less than successful. In 2019, the landmark REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) showed a profound 25% reduction in major cardiovascular events with high-dose (4 g/day) icosapent ethyl, a purified EPA ethyl ester, catalysing new interest (9). Other novel therapies have also emerged, the most advanced including pemafibrate, and treatments targeting ANGPTL3 (evinacumab, vupanorsen) and apoCIII (volanesorsen).
We are therefore on the cusp of a new era in managing elevated TGs. Major outcomes studies with these new therapies are fundamental to answering the much-debated question: Does lowering elevated triglycerides reduce residual cardiovascular risk?
View key references >
1. Packard CJ, Boren J, Taskinen MR. Causes and consequences of hypertriglyceridemia. Front Endocrinol (Lausanne) 2020;11:252. PUBMED https://pubmed.ncbi.nlm.nih.gov/32477261/
2. Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation 1979;60:473–485. PUBMED https://pubmed.ncbi.nlm.nih.gov/222498/
3. Chapman MJ, Ginsberg HN, Amarenco P, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61. PUBMED https://pubmed.ncbi.nlm.nih.gov/21531743/
4. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299-308. PUBMED https://pubmed.ncbi.nlm.nih.gov/17635890/
5. Di Angelantonio E, Sarwar N, Perry P, et al; Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993–2000. PUBMED https://pubmed.ncbi.nlm.nih.gov/19903920/
6. Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides. Eur Heart J 2020;41:99-109c. PUBMED https://pubmed.ncbi.nlm.nih.gov/31764986/
7. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63. PUBMED https://pubmed.ncbi.nlm.nih.gov/26892957/
8. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007; 369:1090-8. PUBMED https://pubmed.ncbi.nlm.nih.gov/17398308/
9. Bhatt DL, Steg PG, Miller M, et al; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22. PUBMED https://pubmed.ncbi.nlm.nih.gov/30415628/
Read more about trials of novel therapies for managing elevated triglycerides:
|Icosapent Ethyl (Vascepa, Vazkepa)||View the trials|
|ANGPTL3 Inhibitors||View the trials|
|ApoCIII Inhibitors||View the trials|
|SPPARM||View the trials|