EPA: Value of high purity EPA (IPE) in risk management of ASCVD

Therapy targeting low low-density lipoprotein cholesterol (LDL-C) has become an important target to intervene in the risk of atherosclerotic heart disease (ASCVD), but the residual relative risk after statin therapy persists and is receiving increasing attention from experts in the field. Multiple evidence-based medical evidence has found that triglycerides (TG) play an important role in the management of residual persistent cardiovascular risk after statin therapy. TG lowering drugs include niacin, bate, omega-3 unsaturated fatty acids, etc. Among them, the study of omega-3 unsaturated fatty acids represented by high purity EPA (IPE) has obtained positive results of cardiovascular clinical benefit.

Experimental Research:

In 2021, the European Society of Cardiology (ESC) and the American Heart Association (AHA) respectively issued two consensus guidelines related to hypertriglyceridemia and triglyceride-rich lipoproteins (TRL), suggesting that the effect of hypertriglyceridemia on residual risk of ASCVD is of wide concern. Previous studies have suggested that triglyceride level is positively correlated with TRL level and TRL cholesterol (TRL-C) concentration, and the role of TRL-C in the pathogenesis of ASCVD has been paid more and more attention. These guidelines recommend fenofibrate and eicosapentaenoic acid (EPA) for patients with elevated triglyceride levels (<500mg/dL) after statin use. EPA and docosahexaenoic acid (DHA) are both omega-3 unsaturated fatty acids, which are only found in fish and shellfish, so they are commonly called "fish oil". The association between fish and omega-3 fatty acids and cardiovascular events began to be explored at the beginning of the last century, and the AHA recently recommended eating fish rich in omega-3 fatty acids at least 2 times a week for health benefits. More than 15 well-known cardiovascular clinical studies related to EPA and DHA have been completed, involving about 140,000 people, among which REDUCE-IT has a greater impact on the prevention and treatment of ASCVD.

The REDUCE-IT study, an RCT study, enrolled 8179 patients with high triglycerides (150-499mg/dL) after statin treatment to observe the effect of 4g/d ethyl eicosapentaenoate (IPE) on cardiovascular risk for 5 years. The primary endpoint was a composite endpoint, including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and unstable angina pectoris. It was found that a 4g/d dose of IPE could further reduce cardiovascular risk by 25% compared to placebo. Although the benefit mechanism of IPE remains to be further explored and studied, However, the American Diabetes Association (ADA), the AHA, the ESC, the National Lipid Association (NLA), and the U.S. Food and Drug Administration (FDA) recommend that 4g/d IPE be added to ASCVD patients with high triglyceride levels (<500mg/dL) after statin use and those at high risk of ASCVD. To further reduce cardiovascular risk. More clinical trial evidence is expected to expand the indications of EPA/IPE.

Analyze the reasons for the benefits of REDUCE-IT research:

First, the average reduction in TG was 40mg/dL, and a 19% reduction could not fully explain the 25% reduction in cardiovascular benefit from the primary endpoint event. A meta-analysis revealed the relationship between TG reduction and cardiovascular benefit. For every 88mg/dL reduction in TG, the major cardiovascular risk was reduced by 16%. Therefore, the reason for the reduction of major cardiovascular risk in REDUCE-IT study was not only the reduction of TG.

Second, in the subgroup analysis, there was no difference in the occurrence of major and minor events between patients with TG < 150mg/dL and ≥150mg/dL, that is, the degree of benefit of patients in the two groups was similar, and the cardiovascular benefit obtained was not dependent on the level of TG.

Third, the increase in EPA concentration is the key to the benefits of REDUCE-IT research. First, the event rate decreased with increasing plasma EPA concentration, that is, the benefit was closely related to the plasma EPA concentration of the patients. Second, in the subgroup analysis of CVD patients and DM patients with risk factors, the benefit was still associated with plasma EPA concentrations.

Fourth, the EPA plasma concentration increased from 26ug/mL to 144ug/mL in the REDUCE-IT study, while the EPA plasma concentration increased from 97ug/mL to 170ug/mL in the JELIS study, which also achieved clinical benefits, proving that a substantial increase in EPA plasma concentration is the key to clinical benefits. The EPA plasma concentration in the STRENGTH study increased from 21 ug/mL to 90ug/mL, but there was no benefit because the EPA plasma concentration in the treatment group was only the level of the baseline control group in the JELIS study. It can be speculated that one of the possible reasons for the failure of STRENGTH study to obtain positive results is that the plasma concentration of EPA has not reached the threshold of benefit. The EPA plasma concentration must exceed a certain threshold to achieve clinical benefit. How to prove this, we can find some evidence through the omega-3 index risk zone. The omega-3 index is the percentage of the total phospholipid EPA+DHA in the erythrocyte membrane to the total fatty acids, the omega-3 index > 8%, the risk of cardiovascular events is reduced, and the index < 4%, the risk of cardiovascular events is increased, assuming that the index is 4% in the population, supplementation to 7% still does not produce a significant cardiovascular benefit.

Fifth, cardiovascular benefits are strongly associated with prostaglandin I3 (PGI3), a bioactive metabolite of EPA. EPA is metabolized by cyclooxygenase and fat oxidase to form an anti-inflammatory mediator as well as PGI3, which has a strong vasodilating effect. In terms of the mechanism of action, both EPA and DHA are important structural components of the phospholipid bilayer of the cell membrane to maintain the liquid property of the membrane. Some studies suggest that the increase of EPA after fish oil supplementation is much greater than that of DHA (299% and 24%).

Sixth, other beneficial effects of EPA. EPA rapidly esterifies and binds to lipoproteins and membrane phospholipids, and biophysical studies have shown that EPA has an expanding direction, maintains membrane fluidity, and inhibits lipid oxidation and the formation of membrane cholesterol domains. In addition, the thickening of the fibrous cap that promotes vulnerable plaque is also one of the key anti-inflammatory mechanisms of EPA.

In summary, the level of EPA is significant, and more studies are expected to verify the relationship between EPA concentration and cardiovascular benefit, so that the use of dosage can be clarified and more patients can receive more effective treatment.