R3i Editorial

Remnant cholesterol continues to attract attention as a target to reduce residual cardiovascular risk. Conventionally, remnant cholesterol is defined as the cholesterol contained in remnant lipoprotein particles, i.e. metabolized very-low-density lipoprotein and intermediate-density lipoprotein in the fasting state, to which is added the cholesterol in chylomicron remnants in the postprandial state ¹. There is strong evidence from mechanistic, observational and genetic studies to support a causal association between remnant cholesterol and risk for atherosclerotic cardiovascular disease (ASCVD) ^1,2. This month’s Landmark study adds to this evidence. In a Mendelian randomization study in over 900,000 subjects, each 1 standard deviation increase in remnant cholesterol increased the risk of myocardial infarction by more than 50%, independent of low-density lipoprotein cholesterol ³. Additionally, results from a prospective Chinese cohort analysis, discussed in this month’s Focus ⁴, imply that clinicians should focus both on managing remnant cholesterol levels and reducing variability in levels between visits.

The ongoing conundrum is whether lowering remnant cholesterol levels translates to reduction in cardiovascular events in high-risk patients. Clinical trials of different therapeutic approaches have generated mixed results, and also implicate the intensity of background statin therapy as a confounding factor (5-7). Moreover, positive results from REDUCE-IT may relate to factors other than plasma triglycerides (TGs), given the lack of association between baseline TG level (a marker for remnant cholesterol) and ASCVD risk ⁸. With insufficient evidence from clinical trials, current guidelines for managing dyslipidaemia do not recommend treatment targets for TGs in high-risk patients ⁹.

Genetic insights have been critical in identifying new targets for lowering remnant cholesterol. Evinacumab, a first-in-class angiopoietin-like protein (ANGPTL3) monoclonal antibody, is already approved by US and European regulatory agencies for the management of familial hypercholesterolaemia. Trials have also shown clinical benefit in managing patients with hypertriglyceridaemia (10). Other agents in the pipeline include antisense RNA therapeutics targeting apolipoprotein (apo) C-III and ANGPTL3. Olezarsen, an antisense oligonucleotide targeting apoC-III has been shown to more than halve TG levels in phase II/III trials ¹¹. Additionally, the siRNA ARO-APOC3 resulted in maximal mean reduction of TG levels of 74% to 92% in a phase I trial (12 ). Beyond efficacy, however, long-term safety is an important consideration, and further evaluation of these novel agents is clearly needed.

The heterogeneity of remnant lipoprotein particles and their specific function and impact on atherosclerosis is an important consideration ¹. Recent clinical trials have, perhaps, raised more questions than answers, reflecting the fact that the impact of these treatments on remnant cholesterol levels may relate to effects on several different metabolic pathways, less or more associated with atherosclerosis. Ongoing studies with novel agents will be critical to defining how best to manage elevated remnant cholesterol, with the ultimate aim of reducing cardiovascular events in high-risk patients receiving optimal statin therapy.

References
1. Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021; 42:4791–806.
2. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63.
Yang XH, Zhang BL, Cheng Y, Fu SK, Jin HM. Association of remnant cholesterol with risk of cardiovascular disease events, stroke, and mortality: A systemic review and meta-analysis. Atherosclerosis 2023;371:21-31.
3. Navarese EP, Vine D, Proctor S, et al. Independent causal effect of remnant cholesterol on atherosclerotic cardiovascular outcomes: a Mendelian Randomization Study. Arterioscler Thromb Vasc Biol 2023; doi: 10.1161/ATVBAHA.123.319297
4. Wang J, Jin R, Jin X, et al. Separate and joint associations of remnant cholesterol accumulation and variability with carotid atherosclerosis: a prospective cohort study. J Am Heart Assoc 2023;12:e029352.
5. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019; 380: 11–22.
6. Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA 2020; 324: 2268–80.
7. 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.
8. Bhatt DL, Steg PG, Miller M, Brinton EA, et al; REDUCE-IT Investigators. Reduction in first and total ischemic events with icosapent ethyl across baseline triglyceride tertiles. J Am Coll Cardiol 2019;74:1159-61.
9. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88.
10. Rosenson RS, Gaudet D, Ballantyne CM, et al. Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial. Nat Med 2023;29:729-37.
11. Tardif JC, Karwatowska-Prokopczuk E, Amour ES, et al. Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur. Heart J 2022;43:1401–12.
12. Alexander VJ, Xia S, Hurh E, et al. N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. Eur Heart J 2019;40:2785–96.