An update on triglyceride-rich lipoproteins and their remnants in atherosclerotic cardiovascular disease.

Residual cardiovascular risk in patients on optimized LDL-lowering therapy remains a hot topic. While inflammation explains part of the residual risk, triglyceride-rich lipoproteins and their remnants also may play an important role. This Focus Issue on dyslipidaemias contains the Special Article entitled ‘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’ by Henry Ginsberg from Columbia University in New York, NY, USA. The authors point out that recent advances in human genetics, together with a large body of epidemiological, pre-clinical, and clinical trial results, provide strong support for a causal association between triglycerides (TG), TG-rich lipoproteins (TRLs), and TRL remnants, and increased risk of myocardial infarction (MI), ischaemic stroke, and aortic valve stenosis. This consensus statement critically appraises current understanding of the structure, function, and metabolism of TRLs, and their pathophysiological role in atherosclerotic cardiovascular disease (ASCVD). Key points are: (i) a working definition of normoand hypertriglyceridaemic states and their relationship to risk of ASCVD; (ii) a conceptual framework for the generation of remnants due to dysregulation of TRL production, lipolysis, and remodelling, as well as clearance of remnant lipoproteins from the circulation; (iii) the pleiotropic proatherogenic actions of TRLs and remnants at the arterial wall; (iv) challenges in defining, quantifying, and assessing the atherogenic properties of remnant particles; and (v) exploration of the relative atherogenicity of TRLs and remnants compared with LDL. Assessment of these issues provides a foundation for evaluating approaches to effectively reduce levels of TRLs and remnants by targeting either production, lipolysis, or hepatic clearance, or a combination of these mechanisms. This consensus statement updates current understanding in an integrated manner, thereby providing a platform for new therapeutic paradigms targeting TRLs and their remnants, with the aim of reducing the risk of ASCVD. The role of omega-3 fatty acids in the prevention of cardiovascular risk remains controversial. In a Fast Track article entitled ‘A possible explanation for the contrasting results of REDUCE-IT vs. STRENGTH: cohort study mimicking trial designs’, Takahito Doi from the Copenhagen University Hospital in Denmark, and colleagues tested the hypothesis that the contrasting results for the effect of high-dose, purified omega-3 fatty acids on the prevention of ASCVD in two randomized trials, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) vs. Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridaemia (STRENGTH), can be explained by differences in the effect of active and comparator oils on lipid traits and C-reactive protein. In the Copenhagen General Population Study (CGPS) with 106 088 individuals, to mimic trial designs, the authors analysed those who met key inclusion criteria in REDUCE-IT (n = 5684; ASCVD = 852) and STRENGTH (n = 6862; ASCVD = 697). The incidence of ASCVD was followed for the median durations of REDUCE-IT and STRENGTH (4.9 and 3.5 years, respectively). When combining changes in plasma triglycerides, LDL cholesterol, and C-reactive protein observed in the active oil groups of the original studies, estimated hazard ratios (HRs) for ASCVD in the CGPS were 0.96 [95% confidence interval (CI) 0.93–0.99] mimicking REDUCE-IT, and 0.94 (95% CI 0.91–0.98) mimicking STRENGTH. In the comparator oil groups, corresponding HRs were 1.07 (95% CI 1.04–1.10) and 0.99 (95% CI 0.98–0.99). Combining these results, the active oil vs. comparator oil HR was 0.88 (95% CI 0.84–0.93) in the CGPS mimicking REDUCE-