Concept and practice in the use of high-dose eicosapentaenoic acid for cardiovascular disease prevention in hypertriglyceridaemia

Figures

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  Figure 1. Relationship of plasma triglyceride to atherosclerosis. (A) Association of plasma TG with ASCVD event rate (based on data from 53). Hypertriglyceridaemia is defined as TG above 1.7 mmol/L (150 mg/dL) (2,16). (B) Plasma TG is a biomarker for the abundance of TRL—chylomicrons, VLDL and their remnants. These apolipoprotein B-containing particles transport TG through the bloodstream. During dietary fat absorption, chylomicrons are made in the intestine to carry TG to tissues especially adipose tissue where it is stored. VLDL are secreted by the liver and supply TG to tissues, particularly muscle, in the fasted state. As TG contained in these particles is hydrolysed (lipolysis) smaller ‘remnant’ lipoproteins are formed. TRL also contains cholesterol (Chol) that is enriched in remnants. TRL cholesterol, also termed remnant cholesterol, is an alternative measure of TRL abundance. Plasma TG can be measured with the patient fasting or non-fasting, if non-fasting then TG levels are likely to be higher reflecting the presence of chylomicrons. ASCVD, atherosclerotic cardiovascular disease; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglyceride; TRL, triglyceride-rich…

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  Figure 2. Role of triglyceride-rich lipoproteins in atherosclerosis. Chylomicron remnants and VLDL remnants can, like LDL, penetrate the artery wall. Once in the subendothelial space these particles can bind to extracellular proteoglycans and subsequently be ingested by macrophages leading to the formation of cholesterol-enriched ‘foam’ (lipid-filled) cells. In this way, cholesterol in TRL can contribute to atherosclerotic plaque progression (16). There is also emerging evidence that TRL and remnants may promote atherogenesis by causing inflammation, endothelial dysfunction, and by stimulating thrombosis. Drugs that increase lipoprotein receptor activity in the liver (statins, ezetimibe, PCSK9 inhibitors) can lower TRL by enhancing their clearance from the bloodstream. High dose EPA inhibits TRL synthesis and thereby lowers TRL levels in the circulation. EPA is also thought to have anti-inflammatory and anti-thrombotic effects. EPA, eicosapentaenoic acid; LDL, low-density lipoprotein; PCSK9, proprotein convertase subtilisin/kexin type 9; TRL, triglyceride-rich lipoproteins; VLDL, very low density lipoprotein.

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  Figure 3. Comparison of trials of therapies addressing lipid-associated risk in acute coronary syndrome. Recent ACS cohorts comprised all subjects recruited to PROVE-IT, IMPROVE-IT and ODYSSEY OUTCOMES and 10.3% of subjects recruited to REDUCE-IT. For each trial, the per cent relative risk reduction (RRR for active drug vs placebo) is given along with the number needed to treat (NNT). Note the length of follow-up has to be taken into account when comparing NNTs in different studies. ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; EPA, eicosapentaenoic acid; IMPROVE-IT, Improved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL, low-density lipoprotein; ODYSSEY OUTCOMES, Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; PCSK9i, Proprotein convertase subtilisin/kexin type 9 inhibitor; PROVE-IT, Pravastatin or Atorvastatin Evaluation and Infection Therapy; REDUCE-IT, Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial; TG, triglyceride.

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  Figure 4. Case histories of typical candidates for high-dose EPA treatment. ACS, acute coronary syndrome; BMI, body mass index; BP, blood pressure; EPA, eicosapentaenoic acid; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Lp(a), lipoprotein (a); MI, myocardial infarction; PCSK9, Proprotein convertase subtilisin/kexin type 9; TG, triglyceride.

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  Figure 5. A ‘desk-card’ summary of combination therapeutic strategies in high-risk patients on optimal, tolerated statin therapy. Evaluation of the lipid profile of the individual once established on optimum tolerated statin treatment allows further therapeutic decisions to be made. Further LDL-C lowering is mandated when LDL-C is high. When TG is elevated, this risk can be addressed with high-dose EPA treatment. These are not mutually exclusive as seen in the Case Studies in figure 4; with mixed hyperlipidaemia a combination of approaches may be appropriate. A version with units in mmol/L is included in online supplemental figure 1. ASCVD, atherosclerotic cardiovascular disease; EPA, eicosapentaenoic acid; LDL, low-density lipoprotein; PCSK9i, Proprotein convertase subtilisin/kexin type 9 inhibitor; TG, triglyceride.