**5.3 Reasons for inconsistent data of omega-3 fatty acids for coronary heart disease**

Most of the RCTs with n-3 supplements generally have not shown a significant reduction of CV events so far. **Table 4** shows comparison of previous RCTs [144, 156–163, 169]. Inconsistent data in RCTs as well as observational studies of n-3 supplements could be attributed to statin use, dose of n-3 fatty acid, or TG and HDL values at baseline. The statin use was very low in two positive studies (GISSI-P [144] and GISSI-HF [169]), which mainly recruited subjects two decades ago, before the wide-spread use of stains. One study showed that although among statinusers coronary vascular events were not reduced with n-3 fatty acid supplements, the events significantly decreased in statin nonusers [170]. This suggests that statin treatment modified the effects of n-3 fatty acids on the incidence of major cardiovascular events.

The dosage is another important factor. Findings in two Cochran review manuscripts showed no dose dependency of n-3 fatty acids [155, 166]. It is of note that the absolute amount of fish intake was very small in some studies, which tends to make the correlation between n-3 fatty acids and CV events less clear. In some studies in cultures where eating fish is not common, the participants who belonged to the group with the highest intake of fish consumed just 2–3 servings/week, and one extreme example is a study to compare subjects who consumed no fish to subjects who ate fish once a week [148]. The JPHC study, conducted in Japan, showed clear

**Study**

**88**

GISSI-P GISSI-HF

OMEGA Alpha-OMEGA

SU.FOL.OM3

ORIGIN Risk & Prevention

ASCEND

JELIS REDUCE-IT

*DHA:*  *(MACE +* 

**Table 4.** *Comparison*

 *of RCTs of n-3 PUFA [156–163].*

*docosahexaenoic*

 *acid, EPA:* 

*revascularization).*

 2018

 8179 CVD+ High risk

*eicosapentaenoic*

 *acid, BL: baseline, EOS: end of study, EP: end point, MACE: major CV event (death, myocardial infarction, stroke), eMACE: expanded major CV event*

2007

 18,645

dyslipidemia

100% 100%

4.9 y

4 g EPA

216 mg/dl

 eMACE

 HR = 0.74 (0.68–0.83)

4.6 y

1.8 g EPA

151 mg

 eMACE

 HR = 0.81 (0.69–0.95)

2018

15,480 Dm

 2013

 12,513 High risk + CVD

 2010 2012

 12,536

dyslipidemia

 + CVD

 2501 Post MI

 2010

 4837 Post MI

2010

3851 Post MI

2008

6975 HF

1999

 11,324 Post MI

 BL = 5% EOS = 46%

22% 94% 85% 85% 53% 41% 75%

7.4 y Pure EPA study

 850 mg EPA + DHA

5 y

 850 mg EPA + DHA

6.2 y

 840 mg EPA + DHA

4.7 y

 600 mg EPA + DHA

3.3 y

 400 mg EPA + DHA

1 y

 840 mg EPA + DHA

3.9 y

 850 mg EPA + DHA

 3.5 y

 850 mg EPA + DHA

 162 mg/dl

 126 mg/dl

 121 mg/dl

 144 mg/dl

 115 mg/dl

 140 mg/dl

 150 mg/dl

 NA

 CV death

MACE

 HR = 0.9 (0.87–1.08)

 HR = 0.97 (0.88–1.08)

 CV death

 HR = 0.98 (0.87–1.1)

 MACE

 HR = 1.08 (0.79–1.47)

 eMACE

 HR = 1.01 (0.87–1.17)

 Sudden death

 OR = 0.95 (0.56–1.6)

 Death + Hosp

 HR = 0.91 (0.83–0.99)

 MACE

 HR = 0.85 (0.74–0.98)

**Year**

**Inclusion**

**Statin**

 **Follow up** EPA/DHA study

 **Regimen**

 **Baseline TG**

 **Primary EP**

**Results**

*New Insights into Metabolic Syndrome*

dose-dependency between n-3 fatty acids and CV events even in the primary prevention population [171]. Incidence of myocardial infarction was reduced by 56% in the comparison of highest (8 servings per week, or 180 g/day) vs. lowest quintiles (once a week, or 23 g/day) of fish intake. Generally speaking, a small gradient of fish consumption is associated with negative results in observational studies.

Because consumption of omega-3 fatty acids is evaluated based on self-report or food surveys by questioners, the issue of reliability about how much n-3 fatty acids was consumed has always existed. Furthermore, variability of n-3 fat content among fish species makes estimation of EPA + DHA consumption more difficult. For instance, EPA + DHA ranges from 200 to 300 mg in 3 pounds of wild tuna to more than 1500 mg in the same amount of wild mackerel.

Dose dependency of n-3 fatty acids appears to be clear in results of RCTs. As shown in **Table 4**, whereas doses of EPA/DHA used in recent negative studies were generally less than 1 g, the JELIS [163] and REDUCE-IT [156] studies, which showed significant CV risk reduction, used larger doses of EPA (see Sections 4 and 5 REDUCE-IT study). Finally, baseline TG value was suggested to affect the effects of n-3 supplements. Three positive studies, GISSI-P [144], JELIS [163], and REDUCE-IT [156] studies recruited subjects with higher baseline TG values of more than 150 mg/ dl compared with the levels in other studies with negative results. In the JELIS study, whereas 1.8 g EPA reduced CV events in the whole population by 19%, the CV reduction was 53% in the subgroup with high TG (>150 mg/dl) and low HDL cholesterol (<40 mg/dl) at baseline [172] (**Figure 11**). A similar trend toward greater efficacy in subjects with higher TG and lower HDL-cholesterol at baseline was also observed in the REDUCE-IT study (**Figure 12a** and **b**) [156]. In subjects with high TG (>200 mg/dl) and low HDL cholesterol (<40 mg/dl) in the REDUCE-IT study, the percent reduction of primary endpoint by 4 g EPA was almost double (38%) compared with that in subjects with normal TG and HDL-cholesterol (21%, P for interaction = 0.04). In two fibrate studies, the BIP study (bezafibrate) [173] and the ACCORD study (fenofibrate) [174], no significant reduction of CV events reported despite the greater decrease in TG (21% in BIP and 26% in ACCORD) with higher

increases in HDL cholesterol (18% in BIP and 6% in ACCORD) compared with the REDUCE-IT study (18% decrease in TG and 3% increase in HDL). However, like the JELIS [163] and REDUCE-IT [156] studies, there was a significant reduction in CV events in subjects with higher baseline TG at >200 mg/dl [173, 174]. These data suggest that with greater abnormalities of baseline TG and HDL cholesterol, the two different dyslipidemic drugs, EPA and fibrates, tend to show greater CV events reduction. However, from the comparison of efficacy size on CV events in studies with EPA and fibrates, although at least some of the beneficial effects in the EPA studies could be explained by changing the plasma lipid, effects other than improve-

*revascularization, or unstable angina. (B) The hazard ratios and 95% CI in the subgroup according to the*

*(A) Kaplan-Meier event curves for the primary end point in the entire cohort in the REDUCE-IT study [156].*

*The end point is a composite of CV, nonfatal myocardial infarction, nonfatal stroke, coronary*

*baseline TG and HDL for the primary efficacy end point in REDUCE-IT study [156].*

*Effects and Issues of Diet Fat on Cardiovascular Metabolism*

*DOI: http://dx.doi.org/10.5772/intechopen.93261*

Reduction of CV events by consumption of fish is mostly attributable to beneficial effects of n-3 fatty acids (EPA/DHA). Potential effects include antiplatelet, activity, inhibition of life-threatening arrhythmia, decrease in LDL cholesterol and TG, increase in HDL cholesterol, decrease in blood pressure, stabilization of inflammation in lipid-rich plaque, and antioxidation. Although n-3 fatty acid products are generally approved for TG lowering, this class of drugs has only modest TG lowering. Based on the modest changes in non-HDL cholesterol, reduction of CV events is calculated to be only 6–8% [175]. Therefore, changes in lipid profile alone cannot explain why EPA in the REDUCE-IT study reduced CV events by 25%.

Previous data have indicated that inhibition of platelet aggregation by n-3 fatty acids at pharmaceutical doses is insufficient for reduction of CV events. Compared with the reported value of inhibition of platelet aggregation by aspirin, prasugrel, or ticagrerol, all of which have been proven effective for reduction of CV events, antiplatelet efficacy of omega-3 fatty acids appears to be relatively small [176]. Supplementation with omega-3 fatty acids had no effect on platelet activation in the presence of aspirin [177] or clopidogrel [178]. A high level of dietary EPA + DHA (4.5, 9.5 g) or estimated biologically equivalent amounts of alpha-linolenic acid did not affect coagulation factors, fibrinogen, plasminogen activator inhibitor-1, or tissue plasminogen activator activity compared with the control [179]. All of these data suggest that antithrombotic efficacy via platelets, coagulation, and fibrinolysis does not play a major role in n-3 fatty acid-induced decrease in CV events in the

ment of dyslipidemia are at work in the reduction of CV events by EPA.

**5.4 Antithrombotic effects of n-3 fatty acids**

**Figure 12.**

positive previous studies.

**91**

#### **Figure 11.**

*Kaplan-Meier event curves for the primary end point in the entire cohort (left) and the subgroup with high TG and low HDL (right) in the JELIS study [163]. The primary end point is a composite of sudden cardiac death, nonfatal myocardial infarction, nonfatal stroke, unstable angina, and coronary revascularization.*

*Effects and Issues of Diet Fat on Cardiovascular Metabolism DOI: http://dx.doi.org/10.5772/intechopen.93261*

**Figure 12.**

dose-dependency between n-3 fatty acids and CV events even in the primary prevention population [171]. Incidence of myocardial infarction was reduced by 56% in the comparison of highest (8 servings per week, or 180 g/day) vs. lowest quintiles (once a week, or 23 g/day) of fish intake. Generally speaking, a small gradient of fish consumption is associated with negative results in observational

more than 1500 mg in the same amount of wild mackerel.

Because consumption of omega-3 fatty acids is evaluated based on self-report or food surveys by questioners, the issue of reliability about how much n-3 fatty acids was consumed has always existed. Furthermore, variability of n-3 fat content among fish species makes estimation of EPA + DHA consumption more difficult. For instance, EPA + DHA ranges from 200 to 300 mg in 3 pounds of wild tuna to

Dose dependency of n-3 fatty acids appears to be clear in results of RCTs. As shown in **Table 4**, whereas doses of EPA/DHA used in recent negative studies were generally less than 1 g, the JELIS [163] and REDUCE-IT [156] studies, which showed

REDUCE-IT study). Finally, baseline TG value was suggested to affect the effects of n-3 supplements. Three positive studies, GISSI-P [144], JELIS [163], and REDUCE-IT [156] studies recruited subjects with higher baseline TG values of more than 150 mg/ dl compared with the levels in other studies with negative results. In the JELIS study, whereas 1.8 g EPA reduced CV events in the whole population by 19%, the CV reduction was 53% in the subgroup with high TG (>150 mg/dl) and low HDL cholesterol (<40 mg/dl) at baseline [172] (**Figure 11**). A similar trend toward greater efficacy in subjects with higher TG and lower HDL-cholesterol at baseline was also observed in the REDUCE-IT study (**Figure 12a** and **b**) [156]. In subjects with high TG (>200 mg/dl) and low HDL cholesterol (<40 mg/dl) in the REDUCE-IT study, the percent reduction of primary endpoint by 4 g EPA was almost double (38%) compared with that in subjects with normal TG and HDL-cholesterol (21%, P for interac-

significant CV risk reduction, used larger doses of EPA (see Sections 4 and 5

tion = 0.04). In two fibrate studies, the BIP study (bezafibrate) [173] and the ACCORD study (fenofibrate) [174], no significant reduction of CV events reported despite the greater decrease in TG (21% in BIP and 26% in ACCORD) with higher

*Kaplan-Meier event curves for the primary end point in the entire cohort (left) and the subgroup with high TG and low HDL (right) in the JELIS study [163]. The primary end point is a composite of sudden cardiac death,*

*nonfatal myocardial infarction, nonfatal stroke, unstable angina, and coronary revascularization.*

studies.

*New Insights into Metabolic Syndrome*

**Figure 11.**

**90**

*(A) Kaplan-Meier event curves for the primary end point in the entire cohort in the REDUCE-IT study [156]. The end point is a composite of CV, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. (B) The hazard ratios and 95% CI in the subgroup according to the baseline TG and HDL for the primary efficacy end point in REDUCE-IT study [156].*

increases in HDL cholesterol (18% in BIP and 6% in ACCORD) compared with the REDUCE-IT study (18% decrease in TG and 3% increase in HDL). However, like the JELIS [163] and REDUCE-IT [156] studies, there was a significant reduction in CV events in subjects with higher baseline TG at >200 mg/dl [173, 174]. These data suggest that with greater abnormalities of baseline TG and HDL cholesterol, the two different dyslipidemic drugs, EPA and fibrates, tend to show greater CV events reduction. However, from the comparison of efficacy size on CV events in studies with EPA and fibrates, although at least some of the beneficial effects in the EPA studies could be explained by changing the plasma lipid, effects other than improvement of dyslipidemia are at work in the reduction of CV events by EPA.

#### **5.4 Antithrombotic effects of n-3 fatty acids**

Reduction of CV events by consumption of fish is mostly attributable to beneficial effects of n-3 fatty acids (EPA/DHA). Potential effects include antiplatelet, activity, inhibition of life-threatening arrhythmia, decrease in LDL cholesterol and TG, increase in HDL cholesterol, decrease in blood pressure, stabilization of inflammation in lipid-rich plaque, and antioxidation. Although n-3 fatty acid products are generally approved for TG lowering, this class of drugs has only modest TG lowering. Based on the modest changes in non-HDL cholesterol, reduction of CV events is calculated to be only 6–8% [175]. Therefore, changes in lipid profile alone cannot explain why EPA in the REDUCE-IT study reduced CV events by 25%.

Previous data have indicated that inhibition of platelet aggregation by n-3 fatty acids at pharmaceutical doses is insufficient for reduction of CV events. Compared with the reported value of inhibition of platelet aggregation by aspirin, prasugrel, or ticagrerol, all of which have been proven effective for reduction of CV events, antiplatelet efficacy of omega-3 fatty acids appears to be relatively small [176]. Supplementation with omega-3 fatty acids had no effect on platelet activation in the presence of aspirin [177] or clopidogrel [178]. A high level of dietary EPA + DHA (4.5, 9.5 g) or estimated biologically equivalent amounts of alpha-linolenic acid did not affect coagulation factors, fibrinogen, plasminogen activator inhibitor-1, or tissue plasminogen activator activity compared with the control [179]. All of these data suggest that antithrombotic efficacy via platelets, coagulation, and fibrinolysis does not play a major role in n-3 fatty acid-induced decrease in CV events in the positive previous studies.

## **5.5 REDUCE-IT study**

## *5.5.1 Results of REDUCE-IT study*

The REDUCE-IT trial has shown that use of highly purified icosapent ethyl (EPA) 2 g twice daily reduced CV events by 33% compared with placebo among patients with high TG and either known CV disease or high risk for CV disease (**Figure 12A**) [156]. The absolute reduction of the primary endpoint was 4.8%, and number needed to treat (NNT) was 21 persons/5 years (105 persons/year). This number is very excellent compared to other clinical trials recently conducted. There have been two other positive classes of drugs in addition to statins which showed significant reduction in CV events, ezetimibe and PCSK9 inhibitor. The absolute risk reduction in ezetimibe study was only 2% for 7 years (34.7–32.7%) [180]. NNT was 50 persons/7 years (350 persons/year). In the two PCSK9 inhibitors, evolocumab [181] and alirocumab [182], NNT value was 67 persons/2.2 years (147 persons/year) and 63 persons/2.8 years (176 persons/year), respectively.

#### *5.5.2 Success factors in the REDUCE-IT study*

This study had three distinctive features, compared to the previous n-3 studies that are considered to be responsible for the positive results; dose, formulation, and baseline TG. The daily dose of EPA used in the REDUCE-IT study was 4 g, more than four times higher than the doses used in previous studies. The daily dosage of n-3 supplements is usually 2 capsules containing the combination of 180 mg EPA and 120 mg DHA (=0.6 g/ day of n-3), and no more than 2 g/day as dietary n-3 supplements in the FDA recommendation of 2014 [183]. The rationale of 4 g EPA in REDUCE-IT was that the blood concentration at this dose (183 μg/ml) was similar to that in Japanese subjects in JELIS study who received 1.8 g of EPA (170 μg/ml) [156, 185]. This occurred because Japanese people have much higher background intake of fish and thus have higher EPA and DHA blood concentrations than seen in Western populations. These data suggest that there may be some threshold dose to show reduction of CV events despite abundant in vitro and ex vivo data of various biological effects at smaller doses of n-3 fatty acid.

Recently, a subgroup analysis of REDUCE-IT study was conducted to determine the degree of benefit of EPA in the 3146 patients in the United States [186]. As shown in **Figure 13**, the US subgroup in REDUCE-IT demonstrated more robust risk reduction. The primary endpoint was reduced by 31% in the US cohort compared with 20% in the non-US cohort. Especially, whereas total mortality was numerically increased after 5 years in the non-US cohort, EPA reduced total mortality by 30% from 9.8 to 7.2% in the US cohort. In the current era when many clinical CV event trials have failed to show mortality benefit, this magnitude of the decrease in total

*The hazard ratios and 95% CI in the US and non-US population for the primary efficacy end point in*

Independent analysis showed that this regimen was a very rare case of high costeffectiveness, and that EPA at \$4.16/day offered better outcomes at lower health

Compared with clinical studies on PUFA, fewer studies focusing on MUFA have been published in the literature. Whereas the replacement of SFA in the diet with MUFA increased CV events in some studies [74], other studies showed reduction [190] or no change [56, 191] in CV events. As already described, one plausible

care costs for payer-eligible patients in the REDUCE IT trial [187]. Cost-

performance results in clinical trials are, generally, very persuasive for obtaining regulatory approval for FDA and EMA. In December 2019, EPA became the first FDA approved drug with an indication for reduction of CV risk among patients with elevated TG levels as an add-on to maximally tolerated statin therapy [188]. A recent analysis of the REDUCE-IT study with the measurement of blood concentration of EPA has clarified the more important role of pleiotropic effects of EPA rather than lowering TG as potential mechanisms to reduce CV events [189]. The blood concentration of EPA at baseline was in a relatively narrow range and the administration of 4 g icosapent ethyl raised the blood levels by 400%. Importantly, the reduction in CV events seen in the REDUCE-IT trial was directly related to ontreatment serum levels of EPA [189]. The reduction in TG levels contributed just 2 percentage points to the overall 25 percentage points reduction in CV events in the study. This means that TG-lowering effect by EPA was not a major reason for the

mortality in the US cohort is very amazing.

*Effects and Issues of Diet Fat on Cardiovascular Metabolism*

*DOI: http://dx.doi.org/10.5772/intechopen.93261*

**Figure 13.**

*REDUCE-IT study [186].*

reduction of CV events in the REDUCE-IT study.

**6. Monounsaturated fat**

**93**

The entry criteria for TG initially was 150 mg/ml and later was changed to 200 mg/ ml to increase the enrollment of patients with more significant TG elevations. Therefore, the participants' TG level at baseline was the highest (TG = 216 mg/dl) among all omega-3 studies. The ongoing STRENGTH trial, which aims to assess the efficacy and safety of a 4 g EPA/DHA combination drug, will help to clarify the influence of different formulations and dosages on CV outcomes. In January 2020, following the recommendation from DSMB, the sponsor for this study decided to close the Phase III STRENGTH trial due to its low likelihood of demonstrating a benefit to patients with mixed dyslipidemia [184]. DHA plus EPA raises LDL levels, whereas EPA alone does not raise LDL levels. The inclusion criteria for lipids were different in the two studies. REDUCE-IT had a mineral oil placebo, whereas STRENGTH had a corn oil placebo. An in vitro study has shown that EPA has direct antioxidant benefits in various apoBcontaining particles that are more pronounced than those of DHA and other TGlowering agents [185]. Although all these differences may explain partially the inconsistent results in the two studies, it appears most plausible that EPA may have different biological effects on CV events compared with those of DHA.

#### *5.5.3 Role of EPA in management of CV disease in the future*

The REDUCE-IT study is actually the first study to demonstrate significant reduction of CV events by purified EPA among Caucasians in the strong statin era.

**Figure 13.**

**5.5 REDUCE-IT study**

*5.5.1 Results of REDUCE-IT study*

*New Insights into Metabolic Syndrome*

*5.5.2 Success factors in the REDUCE-IT study*

The REDUCE-IT trial has shown that use of highly purified icosapent ethyl (EPA) 2 g twice daily reduced CV events by 33% compared with placebo among patients with high TG and either known CV disease or high risk for CV disease (**Figure 12A**) [156]. The absolute reduction of the primary endpoint was 4.8%, and number needed to treat (NNT) was 21 persons/5 years (105 persons/year). This number is very excellent compared to other clinical trials recently conducted. There have been two other positive classes of drugs in addition to statins which showed significant reduction in CV events, ezetimibe and PCSK9 inhibitor. The absolute risk reduction in ezetimibe study was only 2% for 7 years (34.7–32.7%) [180]. NNT

was 50 persons/7 years (350 persons/year). In the two PCSK9 inhibitors,

persons/year) and 63 persons/2.8 years (176 persons/year), respectively.

and ex vivo data of various biological effects at smaller doses of n-3 fatty acid.

biological effects on CV events compared with those of DHA.

*5.5.3 Role of EPA in management of CV disease in the future*

**92**

The entry criteria for TG initially was 150 mg/ml and later was changed to 200 mg/ ml to increase the enrollment of patients with more significant TG elevations. Therefore, the participants' TG level at baseline was the highest (TG = 216 mg/dl) among all omega-3 studies. The ongoing STRENGTH trial, which aims to assess the efficacy and safety of a 4 g EPA/DHA combination drug, will help to clarify the influence of different formulations and dosages on CV outcomes. In January 2020, following the recommendation from DSMB, the sponsor for this study decided to close the Phase III STRENGTH trial due to its low likelihood of demonstrating a benefit to patients with mixed dyslipidemia [184]. DHA plus EPA raises LDL levels, whereas EPA alone does not raise LDL levels. The inclusion criteria for lipids were different in the two studies. REDUCE-IT had a mineral oil placebo, whereas STRENGTH had a corn oil placebo. An in vitro study has shown that EPA has direct antioxidant benefits in various apoBcontaining particles that are more pronounced than those of DHA and other TGlowering agents [185]. Although all these differences may explain partially the inconsistent results in the two studies, it appears most plausible that EPA may have different

The REDUCE-IT study is actually the first study to demonstrate significant reduction of CV events by purified EPA among Caucasians in the strong statin era.

evolocumab [181] and alirocumab [182], NNT value was 67 persons/2.2 years (147

This study had three distinctive features, compared to the previous n-3 studies that are considered to be responsible for the positive results; dose, formulation, and baseline TG. The daily dose of EPA used in the REDUCE-IT study was 4 g, more than four times higher than the doses used in previous studies. The daily dosage of n-3 supplements is usually 2 capsules containing the combination of 180 mg EPA and 120 mg DHA (=0.6 g/ day of n-3), and no more than 2 g/day as dietary n-3 supplements in the FDA recommendation of 2014 [183]. The rationale of 4 g EPA in REDUCE-IT was that the blood concentration at this dose (183 μg/ml) was similar to that in Japanese subjects in JELIS study who received 1.8 g of EPA (170 μg/ml) [156, 185]. This occurred because Japanese people have much higher background intake of fish and thus have higher EPA and DHA blood concentrations than seen in Western populations. These data suggest that there may be some threshold dose to show reduction of CV events despite abundant in vitro

*The hazard ratios and 95% CI in the US and non-US population for the primary efficacy end point in REDUCE-IT study [186].*

Recently, a subgroup analysis of REDUCE-IT study was conducted to determine the degree of benefit of EPA in the 3146 patients in the United States [186]. As shown in **Figure 13**, the US subgroup in REDUCE-IT demonstrated more robust risk reduction. The primary endpoint was reduced by 31% in the US cohort compared with 20% in the non-US cohort. Especially, whereas total mortality was numerically increased after 5 years in the non-US cohort, EPA reduced total mortality by 30% from 9.8 to 7.2% in the US cohort. In the current era when many clinical CV event trials have failed to show mortality benefit, this magnitude of the decrease in total mortality in the US cohort is very amazing.

Independent analysis showed that this regimen was a very rare case of high costeffectiveness, and that EPA at \$4.16/day offered better outcomes at lower health care costs for payer-eligible patients in the REDUCE IT trial [187]. Costperformance results in clinical trials are, generally, very persuasive for obtaining regulatory approval for FDA and EMA. In December 2019, EPA became the first FDA approved drug with an indication for reduction of CV risk among patients with elevated TG levels as an add-on to maximally tolerated statin therapy [188].

A recent analysis of the REDUCE-IT study with the measurement of blood concentration of EPA has clarified the more important role of pleiotropic effects of EPA rather than lowering TG as potential mechanisms to reduce CV events [189]. The blood concentration of EPA at baseline was in a relatively narrow range and the administration of 4 g icosapent ethyl raised the blood levels by 400%. Importantly, the reduction in CV events seen in the REDUCE-IT trial was directly related to ontreatment serum levels of EPA [189]. The reduction in TG levels contributed just 2 percentage points to the overall 25 percentage points reduction in CV events in the study. This means that TG-lowering effect by EPA was not a major reason for the reduction of CV events in the REDUCE-IT study.
