R3i Editorial

2021 was an exciting time in the lipid field, especially with increased recognition of the importance of triglyceride (TG)-rich lipoproteins and their remnants to atherosclerotic cardiovascular disease (ASCVD) risk. Renewed thinking about the contribution of these lipoproteins to residual cardiovascular risk catalysed new expert consensus and clinical guidance ^1,2. These provided pragmatic criteria for hypertriglyceridemia and focused on how best to manage elevated TG in the clinic, highly relevant with the ongoing development of novel therapies targeting different proteins involved in the regulation of TG metabolism. In addition, results from the PESA (Progression of Early Subclinical Atherosclerosis) study prompted reconsideration of the level at which TG should be targeted for therapeutic intervention, given that at TG levels of 100-149 mg/dL there was already evidence of subclinical atherosclerosis in a low-risk cohort with ‘normal’ LDL-C levels, according to guideline-recommended goals ³.

Remnant cholesterol was very much a ‘rising star’ in recent research. From the PREDIMED study, an observational dietary intervention trial in people without ASCVD, we learnt that remnant cholesterol levels were associated with cardiovascular outcomes independent of other risk factors, whereas this was not the case for LDL-C ⁴. Added to this, a pooled analysis of over 17,000 individuals without cardiovascular disease showed that levels of remnant cholesterol associated with incident ASCVD independent of traditional cardiovascular risk factors, including LDL-C, non-high-density lipoprotein cholesterol or apolipoprotein B levels. Moreover, the excess risk due to elevated remnant cholesterol was apparent even at low LDL-C levels ⁵.

Importantly, the focus extended beyond ischemic heart disease. Elevated remnant cholesterol levels promoted atherosclerosis progression, assessed by carotid intima media thickness, by up to 2-fold among patients with ischemic stroke, when compared with those in the highest versus lowest quartiles ⁶. A study by Danish investigators also highlighted the association of remnant cholesterol with risk for peripheral artery disease (PAD) ⁷, for too long a neglected manifestation of ASCVD, but an increasingly important contributor to the global burden of cardiovascular disease ^8,9. In this general population study, remnant cholesterol levels ≥1.5 mmol/L (≥58 mg/dL) were associated with about 5-fold higher risk for PAD events compared with lower levels ⁷.

From the clinical perspective, the question is how best to manage this risk. Of the available options, further analyses from REDUCE-IT have provided novel insights. High-dose icosapent ethyl reduced the residual risk of coronary revascularizations in statin-treated patients with hypertriglyceridemia (10). Preliminary reports also indicated that this treatment reduced the residual risk for ischemic stroke and PAD outcomes ^11,12, highly relevant given the long-term socioeconomic burden that each of these cardiovascular complications poses for healthcare systems. Full publication of these two analyses is eagerly awaited.

2021 has also been an exciting year for the Residual Risk Reduction Initiative (R3i) Foundation as we build on our pillars of education, research, and advocacy. We continue to expand educational resources, free to download on the website. The latest resources include a booklet and accompanying slide set focused on ‘Triglyceride-rich lipoproteins and ASCVD’ [https://www.r3i.org/slidekits-11] which provide critical information on this rapidly evolving area. And on a final note, the R3i , together with the International Atherosclerosis Society, was the recipient of a key award from Cardiovascular Diabetology for the landmark Consensus Statement on Selective Peroxisome Proliferator‑Activated Receptor alpha Modulators (SPPARMα) [https://cardiab.biomedcentral.com/articles/10.1186/s12933-019-0864-7].

The R3i will continue to build on these strengths in 2022.

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. Virani SS, Morris PB, Agarwala A et al. 2021 ACC Expert Consensus Decision Pathway on the Management of ASCVD Risk Reduction in Patients with Persistent Hypertriglyceridemia. A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2021:78:960-93.
3. Raposeiras-Roubin S, Rosselló X, Oliva B et al. Triglycerides and residual atherosclerotic risk. J Am Coll Cardiol 2021;22: 3031-41.
4. Castañer O, Pintó X, Subirana I et al. Remnant cholesterol, not LDL cholesterol, is associated with incident cardiovascular disease. J Am Coll Cardiol 2020;76: 2712-24.
5. Quispe R, Martin S, Michos ED et al. Remnant cholesterol predicts cardiovascular disease beyond LDL and ApoB: a primary prevention study. Eur Heart J 2021;42:4324-32.
6. Qian S, You S, Sun Y, et al. Remnant cholesterol and common carotid artery intima-media thickness in patients with ischemic stroke. Circ Cardiovasc Imaging 2021;14⁴:e010953.
7. Wadström BN, Wulff AB, Pedersen KM, et al. Elevated remnant cholesterol increases the risk of peripheral artery disease, myocardial infarction, and ischaemic stroke: a cohort-based study. Eur Heart J 2021;ehab705. doi: 10.1093/eurheartj/ehab705.
8. 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 Glob Health 2019;7⁸:e1020-30.
9. Fowkes FGR, Aboyans V, Fowkes FJI. Peripheral artery disease: epidemiology and global perspectives. Nat Rev Cardiol 2016;14:156–70.
10. Peterson BE, Bhatt DL, Steg Ph.G, et al. Reduction in revascularization with icosapent ethyl: insights from REDUCE-IT REVASC. Circulation 2020; do 10.1161/CIRCULATIONAHA.120.050276.
11. Bhatt DL, Steg PG, Miller M, et al. Reduction in Ischemic Stroke With Icosapent Ethyl - Insights From REDUCE-IT. Stroke 2021; 52 (Suppl_1). INTERNATIONAL STROKE CONFERENCE 2021 ORAL ABSTRACTS.
12. Bhatt DL, et al. Benefits of icosapent ethyl in patients with prior peripheral artery disease: REDUCE-IT PAD. Rapid Fire Oral Session, American Heart Association Scientific Sessions 13-15 November 2021.