2023, Volume 30, Supplement 2: Managing triglyceride levels to reduce residual cardiovascular risk

Cardiovascular disease remains the world’s biggest killer.1 Whilst we have made enormous progress in preventive cardiology, there remains a large residual risk despite optimal current medical therapies.2...

Epidemiological and genetic studies have revealed that plasma triglyceride (TG) levels are strongly and causally related to atherosclerotic cardiovascular disease (ASCVD). The concentration of this lipid in the circulation is a biomarker of the abundance of triglyceride-rich lipoproteins (TRLs) and their cholesterol-enriched remnants which are generated during lipolysis. Furthermore, both clinical trials and registry data have shown that elevated levels of TRLs contribute significantly to the ‘residual’ risk in individuals treated with statins. Addressing this residual risk is an unmet need in strategies to prevent cardiovascular disease in populations and individuals. Plasma TG levels can be lowered using diet and lifestyle interventions through known actions on the production and clearance of chylomicrons and very low-density lipoprotein (VLDL). Novel pharmacotherapy to regulate TG levels is under development; however, clinical trials have already identified agents that can reduce the risk of ASCVD in individuals with elevated plasma TG levels....

There remains residual cardiovascular (CV) risk in some optimally treated patients with low levels of low-density lipoprotein cholesterol (LDL-C), which is associated with elevated triglyceride (TG) levels. Several trials of TG lowering drugs have failed to demonstrate a concomitant reduction in CV events. The Reduction of Cardiovascular Events with Icosapent Ethyl – Intervention Trial (REDUCE-IT) tested icosapent ethyl (IPE) – a purified formulation of the n-3 PUFA (omega-3 polyunsaturated fatty acid), eicosapentaenoic acid (EPA) – in high-risk CV patients with elevated TG levels and reported a significant reduction in a composite of CV events and revascularisations independent of TG reduction. These findings provide mechanistic insights into CV event reduction in patients with controlled LDL-C. The benefits are associated with on-treatment EPA levels and are in keeping with the broad pleiotropic actions previously reported in cellular and clinical studies that favourably modulate atherosclerotic plaque composition and progression. The association of high-dose IPE with atrial fibrillation provides a cautionary footnote and careful consideration of the risk-benefit ratio is required when commencing treatment with IPE....

The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) was a randomised, double-blind, placebo-controlled trial designed to test the hypothesis that patients with hypertriglyceridaemia and a prior history of cardiovascular (CV) disease or diabetes and multiple CV disease risk factors would benefit from icosapent ethyl (IPE), a highly purified (>96%) form of eicosapentaenoic acid (EPA). Participants (n=8,179) were assigned to IPE 2 g twice daily or matching placebo and monitored for a median period of 4.9 years. Overall, there was a 25% relative risk reduction and 4.8% (p<0.0001) absolute risk reduction in the primary composite end point (CV death, non-fatal myocardial infarction [MI], non-fatal stroke, coronary revascularisation or hospitalisation for unstable angina) in the IPE versus placebo group. Similarly, the key secondary composite end points of CV death, non-fatal MI and non-fatal stroke were reduced by 26% (p<0.0001) with an absolute between-group difference of 3.6%. A number of prespecified and/or post-hoc analyses have consistently demonstrated favourable results with IPE use. Considering the reductions in multiple CV events, REDUCE-IT was a landmark CV clinical trial that demonstrated the benefit of IPE in high-risk patients with hypertriglyceridaemia....

Icosapent ethyl has been found to improve cardiovascular (CV) disease risk in high-risk patients when added to statin treatment; it has received regulatory clearance and recently, National Institute of Health and Care Excellence (NICE) approval1 to be used in the UK for selected patients with hypertriglyceridaemia. There are currently limited treatment options available to reduce the risk of CV events in people with controlled levels of low-density lipoprotein-cholesterol (on a statin) and raised triglyceride levels....