Abstract

Hypertriglyceridaemia is a common clinical problem. Epidemiologic and genetic studies have established that triglyceride-rich lipoproteins (TRL) and their remnants as important contributors to ASCVD while severe hypertriglyceridaemia raises risk of pancreatitis. While low-density lipoprotein is the primary treatment target for lipid lowering therapy, secondary targets that reflect the contribution of TRL such as apoB and non-HDL-C are recommended in the current guidelines. Reduction of severely elevated triglycerides is important to avert or reduce the risk of pancreatitis. Here we discuss interventions for hypertriglyceridaemia, including diet and lifestyle, established treatments such as fibrates and omega-3 fatty acid preparations and emerging therapies, including various biological agents.

Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for a causal association between triglycerides (TG), TG-rich lipoproteins (TRL), and TRL remnants, and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis. These data also indicate that TRL and their remnants may contribute significantly to residual cardiovascular risk in patients on optimized low-density lipoprotein (LDL)-lowering therapy. This statement critically appraises current understanding of the structure, function, and metabolism of TRL, and their pathophysiological role in atherosclerotic cardiovascular disease (ASCVD). Key points are (i) a working definition of normo- and hypertriglyceridaemic states and their relation 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 TRL and remnants at the arterial wall, (iv) challenges in defining, quantitating, and assessing the atherogenic properties of remnant particles, and (v) exploration of the relative atherogenicity of TRL and remnants compared to LDL. Assessment of these issues provides a foundation for evaluating approaches to effectively reduce levels of TRL 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 TRL and their remnants, with the aim of reducing the risk of ASCVD.

Familial hypercholesterolaemia is the most commonly encountered genetic condition that predisposes individuals to premature cardiovascular disease. Nevertheless, most patients are undiagnosed, and treatment is often suboptimal even when the diagnosis seems certain. Advances in molecular technologies are reshaping our understanding of this condition, including revision upwards of the population prevalence. Furthermore, the underlying pathophysiological complexity has been exposed by the range of causative genetic loci, breadth of types and classes of rare disease-causing variants, and polygenic basis of the phenotype in many patients. Genetic testing is not always helpful or definitive. Familial hypercholesterolaemia can be envisioned as a group of related disorders, of which the classic 'textbook' phenotype is a subset. Features such as clinical stigmata, family history of dyslipidaemia or cardiovascular disease, and presence of a rare pathogenic variant all increase diagnostic certainty. However, even in the absence of these elements, the essential feature remains an elevated level of plasma LDL cholesterol, which alone should prompt a dialogue between the care provider and the patient on lifestyle modification and lipid-lowering therapy as the foundation of a long-term strategy to prevent or delay the onset of cardiovascular disease.

No abstract