Discussion
ASCVD, TG, Vascepa
PILES, EVENTS, RECRUITMENT, PATHOGENESIS, ATHEROSCLEROTIC CARDIOVASCULAR DISEASE, ASCVD, ENDOTHELIAL DYSFUNCTION
Triglyceride-rich lipoproteins (TGRLs) are closely associated with the pathogenesis and progression of atherosclerotic cardiovascular disease (ASCVD) via direct arterial wall deposition, endothelial dysfunction, recruitment of monocytes and subsequent foam cell formation, stimulation of inflammatory cytokines, and activation of platelets [IPE (Vascepa®) is an omega-3 fatty acid medication possessing a highly refined (96%) EPA ethyl ester that is devoid of DHA [For the main effectiveness objective, IPE at 4 g per day lowered TG levels by 28.4% from baseline and substantially decreased TG levels by 19.9% when adjusted for a placebo. Difference in terms of TG level changes between IPE 2 g/day and placebo didn’t reach the significance level, but there was a numerical decrease in TG levels (median 12.0%) from baseline. At 4 g/day, IPE substantially lowered VLDL-C levels by a median of 27.9% when adjusted for placebo and also decreased other TG-related lipid profiles (non-HDL-C and VLDL-TG). At 2 g per day, IPE also exhibited reducing effects, but this was not statistically significant ones. These findings showed that IPE has a dose-dependent impact, with a maximum benefit of 4 g per day.Moreover, compared to placebo, IPE did not substantially elevate LDL-C levels in this investigation, as is often reported with mixed omega-3 fatty acid agents (including both EPA and DHA) in comparable patient populations [While the magnitude of the median placebo-adjusted TG reduction in the current study appears to be slightly lower than that in the MARINE study (-5.0% and -19.9% at 2 g/day, and -19.9% and -33.1% at 4 g/day, respectively), the within-group percent differences from baseline to 12-week endpoint in each IPE group are very similar to the changes in the MARINE study (12.0% vs 19.9% in 2 g/day, and 28.4% vs 33.1% in 4 g/day, respectively). The following are possible explanations for the apparent disparities between these two investigations. To begin, the baseline TG level differed between the two trials. According to the findings of this research, the TG level at baseline was higher than what was seen in the MARINE study (median 9.37 mmol/L vs 7.67 mmol/L, and the proportion of TG > 8.5 mmol/L is 54.2% vs 39.3%, respectively). The greater the TG level, the more difficult it is to lower it. Second, in this trial, TG fell by a median of 6.2% from baseline in the placebo group, but increased by a median of 9.7% in the MARINE placebo group. This might be attributed to improved nutrition management in the Chinese research population. As a result, in the analysis, the placebo-corrected decrease seemed to have been limited. IPE at 4 g/day demonstrated comparable TG-lowering effects in subgroup analyses with varying baseline TG levels, sex, and statin usage to those of the whole mITT sample. As a result, IPE effects were predictable across patient subgroups.The MARINE study showed that treatment with 4 g or 2 g /day of IPE for 12 weeks statistically significantly increased EPA concentration (in both plasma and red blood cells) in a dose-dependent manner compared to placebo. A linear relationship between EPA levels (in plasma and red blood cells) and TG reduction was observed. Patients in the IPE 4 g/day group had a larger mean percent increase in EPA concentration (in plasma and in red blood cells) and a larger median percent decrease in TG from baseline than patients in the IPE 2 g/day group and the placebo group. Mean levels of plasma and red blood cell fatty acid parameters EPA and DPAn-3 (a metabolite of EPA) also increased in a dose-dependent manner.The results of China phase I study and the population pharmacokinetic (PopPK) analysis of IPE phase I studies in China and the United States showed that within the dose range of 2 g/day to 4 g/day, the baseline-corrected plasma total EPA, red blood cell total EPA and plasma unesterified EPA concentration showed dose proportional property. The dose effect of IPE 2 g/day and 4 g/day was linear. There was no significant difference in the plasma EPA exposure level between Chinese and Americans. It indicates that PD/PK study of IPE has consistency, and the TG lowering effect in different ethnic populations are consistent, and there is no significant racial difference.IPE has been commercially used around the world for many years. Piles of clinical data and experience has been accumulated. Based on the results of phase I studies in China and abroad, it showed the linear correlation between IPE, EPA and TG. The phase III results are consistent with PD/PK studies, which predict that there should be a linear relationship between EPA levels (in plasma and red blood cells) and TG reduction after IPE treatment in the Chinese population. And the main purpose of the phase III study in China is to evaluate the effectiveness and safety of reducing TG after 12 weeks of IPE treatment in the Chinese population. At the same time, TG is a routine clinical detection item in China, and patients generally do not detect EPA in Chinese clinical practice. Therefore, this study set the primary endpoint as TG and did not measure EPA. EPA levels were also examined in the REDUCE-IT study, and higher EPA levels were found to confer cardiovascular benefits. The time of this study was short, and the study endpoints did not involve long-term follow-up and reduction of cardiovascular events, which is one of the reasons why this study did not design to detect EPA.Since this study lacking in the detection of EPA level, larger sample studies will continue to carry out in the Chinese population based on the above research data, and further explore the relationship between EPA levels and TG-lowering efficacy and cardiovascular risk reduction. Unfortunately, this study currently unable to additionally detect the level of EPA because of the original study design and locked database.The acceptability and safety profile results of IPE were consistent with those of prior research [Apart from these, other polyunsaturated fatty acids have also been shown to process lipid-modifying effects, such as linolenic acid and dihomo-γ-linolenic acid (DGLA). It is well established LA consumption leads to lower cholesterol level [