Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy
Open accessAbstract
Background: REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl—Intervention Trial) reported a 25% relative risk reduction in major adverse cardiovascular events with use of icosapent ethyl compared with pharmaceutical grade mineral oil. The mechanisms underlying this benefit remain uncertain. We explored whether treatment allocation in REDUCE-IT might affect a series of biomarkers in pathways known to associate with atherosclerosis risk. Methods: Serum levels of interleukin-1β, interleukin-6, high-sensitivity C-reactive protein, oxidized low-density lipoprotein cholesterol, homocysteine, lipoprotein(a), and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured at baseline, at 12 months, at 24 months, and at the end-of-study visit among REDUCE-IT participants with triglyceride levels ≥ 135 mg/dL and <500 mg/dL who were randomly allocated to treatment with either 4 grams daily of icosapent ethyl or mineral oil used as a comparator. Results: At baseline, median levels of each biomarker were similar in the 2 treatment groups. The levels of biomarkers associated with atherosclerosis increased over time among those allocated to mineral oil treatment; in this group at 12 months, the median percent increases from baseline were 1.5% for homocysteine, 2.2% for lipoprotein(a), 10.9% for oxidized low-density lipoprotein cholesterol, 16.2% for interleukin-6, 18.5% for lipoprotein-associated phospholipase A2, 21.9% for high-sensitivity C-reactive protein, and 28.9% for interleukin-1β (all P values <0.001), with similar changes at 24 months. In the icosapent ethyl group, there were minimal changes in these biomarkers at 12 and 24 months. As such, at study conclusion, between-group treatment differences largely reflected increases in the mineral oil group with median percent differences of 2.4% for lipoprotein(a), 3.0% for homocysteine, 4.2% for oxidized low-density lipoprotein cholesterol, 19.8% for interleukin-6, 26.2% for Lp-PLA2, 38.5% for high-sensitivity C-reactive protein, and 48.7% for interleukin-1β (all P values ≤0.007). These data are consistent with previous REDUCE-IT results in which the median percent change for low-density lipoprotein cholesterol at 12 months was −1.2% among those allocated to icosapent ethyl and 10.9% among those allocated to the mineral oil comparator. Conclusions: Among participants in REDUCE-IT, allocation to icosapent ethyl had minimal effects on a series of biomarkers associated with atherosclerotic disease, whereas levels increased among those allocated to mineral oil. The effect of these findings on interpretation of the overall risk reductions in clinical events observed within REDUCE-IT is uncertain. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.
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- Findingown data
In REDUCE-IT participants allocated to icosapent ethyl, there were minimal changes in the measured biomarkers at 12 and 24 months.
“In the icosapent ethyl group, there were minimal changes in these biomarkers at 12 and 24 months.”
Quote in the paperSubstantial claim - Findingown data
At baseline, median levels of each measured biomarker were similar between the icosapent ethyl and mineral oil groups in REDUCE-IT.
“At baseline, median levels of each biomarker were similar in the 2 treatment groups.”
Quote in the paperNot a substantial claim - Interpretationnone given
The effect of these biomarker findings on interpretation of the overall risk reductions in clinical events observed in REDUCE-IT is uncertain.
“The effect of these findings on interpretation of the overall risk reductions in clinical events observed within REDUCE-IT is uncertain.”
Quote in the paperSubstantial claim - Interpretationown data
The biomarker results of this substudy agree with earlier LDL cholesterol data from the same REDUCE-IT cohort.
“findings consistent with previous data in this cohort for LDL cholesterol.”
Quote in the paperNot a substantial claim - Premisecitation
The interleukin-1β to interleukin-6 to C-reactive protein pathway of innate immunity is important for atherosclerosis development.
“particularly inhibition of the central interleukin-1β to interleukin-6 to C-reactive protein pathway of innate immunity that is important for atherosclerosis development 4,5”
Quote in the paperSubstantial claim0 of 2 sources checked
- Premisecitation
REDUCE-IT reported a 25% relative risk reduction in major adverse cardiovascular events with icosapent ethyl compared with pharmaceutical-grade mineral oil.
“REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) reported a 25% relative risk reduction in major adverse cardiovascular events with use of icosapent ethyl compared with pharmaceutical grade mineral oil.”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Icosapent ethyl lowered triglyceride levels by 20% in REDUCE-IT.
“whereas icosapent ethyl lowered triglyceride levels by 20%”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] source
Not checked in the free run.
- Premisecitation
Pharmacologic interventions have established that lowering biomarkers such as LDL cholesterol and high-sensitivity C-reactive protein is associated with reduced risk.
“whereas pharmacologic interventions have proven that lowering of biomarkers such as LDL cholesterol and hsCRP associate with reduced risk”
Quote in the paperNot a substantial claim0 of 3 sources checked - Study design and conductreasoning
The core design of REDUCE-IT does not allow convincing resolution of whether adverse effects from mineral oil use as a comparator affected clinical outcomes.
“The core design of REDUCE-IT does not make it possible to resolve convincingly whether any adverse effects associated with mineral oil use as a comparator may have affected clinical outcomes.”
Quote in the paperSubstantial claim - Interpretationcitation
The current biomarker data are consistent with previous REDUCE-IT results showing a median percent change in LDL cholesterol at 12 months of -1.2% with icosapent ethyl and 10.9% with mineral oil.
“These data are consistent with previous REDUCE-IT results in which the median percent change for lowdensity lipoprotein cholesterol at 12 months was -1.2% among those allocated to icosapent ethyl and 10.9% among those allocated to the mineral oil comparator.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] source
Not checked in the free run.
- Interpretationreasoning
A bias of the estimated magnitude, even if twice as large, would be unlikely to fully remove the overall clinical benefit of icosapent ethyl observed in REDUCE-IT.
“a potential bias of this magnitude, even if doubled in size, would be unlikely to fully attenuate the overall benefit of icosapent ethyl observed.”
Quote in the paperSubstantial claim - Premisecitation
Regulatory agencies reviewing REDUCE-IT estimated that roughly 3% of the net clinical benefit seen with icosapent ethyl could have resulted from adverse mineral-oil effects on LDL cholesterol and high-sensitivity C-reactive protein.
“Regulatory agencies evaluating REDUCE-IT estimated that approximately 3% of the net clinical benefit observed with icosapent ethyl might have been a consequence of adverse biomarker effects on LDL cholesterol and hsCRP attributable to mineral oil.12”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] source
Not checked in the free run.
- Premisecitation
No change in Lp-PLA2 over time was observed in placebo arms of trials of Lp-PLA2 inhibitors or in studies of Lp-PLA2 stability.
“Furthermore, no change in Lp-PLA2 over time was observed in the placebo arms of trials evaluating potential inhibitors of this pathway 18,19 or in studies of stability of circulating Lp-PLA2 levels over time.20”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
The clinical benefits of icosapent ethyl in REDUCE-IT are not closely tied to baseline or achieved triglyceride levels.
“These effects, however, are not tied closely to baseline or achieved triglyceride levels 3”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] source
Not checked in the free run.
- May combine two claims. 13
- The quote only partly states this claim. 1
- Classified as probably not a substantial claim. 10
May combine two claims.
Findingown dataModerately positive pairwise correlations (r 0.32-0.53) were observed between changes in hsCRP and IL-6, Lp-PLA2 and OxLDL, LDL cholesterol and Lp-PLA2, and LDL cholesterol and OxLDL, with similar effect sizes in both treatment groups (all P<0.001).
“As shown, moderately positive pairwise correlations over time (r values between 0.32 and 0.53) were observed between the change in hsCRP and the change in interleukin-6, the change in Lp-PLA2 and the change in OxLDL, the change in LDL cholesterol and the change in Lp-PLA2, and the change in LDL cholesterol and OxLDL (all P values <0.001) with effect sizes similar in the mineral oil comparator and”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAt study conclusion, between-group differences in biomarker changes largely reflected increases in the mineral oil group, with median percent differences of 2.4% for lipoprotein(a), 3.0% for homocysteine, 4.2% for OxLDL, 19.8% for IL-6, 26.2% for Lp-PLA2, 38.5% for hsCRP, and 48.7% for IL-1β, all P≤0.007.
“As such, at study conclusion, between-group treatment differences largely reflected increases in the mineral oil group with median percent differences of 2.4% for lipoprotein(a), 3.0% for homocysteine, 4.2% for OxLDL, 19.8% for interleukin-6, 26.2% for Lp-PLA2, 38.5% for hsCRP, and 48.7% for interleukin-1β (all P values ≤0.007).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAt 12 months, median percent change in triglycerides was -18.3% in the icosapent ethyl group and 2.2% in the mineral oil group.
“As also shown in the Table for completeness, the median percent change in triglycerides at 12 months was -18.3% in the icosapent ethyl group as compared with 2.2% in the mineral oil group.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAmong REDUCE-IT participants, allocation to icosapent ethyl had minimal effects on biomarkers associated with atherosclerotic disease, while levels increased among those allocated to mineral oil.
“Among participants in REDUCE-IT, allocation to icosapent ethyl had minimal effects on a series of biomarkers associated with atherosclerotic disease, whereas levels increased among those allocated to mineral oil.”
Quote in the paperSubstantial claimMay combine two claims. The quote only partly states this claim.
Findingown dataAmong REDUCE-IT participants, allocation to icosapent ethyl had minimal effects on a series of biomarkers associated with atherosclerotic disease, whereas biomarker levels rose over time in those allocated to the mineral-oil comparator.
“In sum, among participants in REDUCE-IT, allocation to icosapent ethyl had minimal effects on a series of biomarkers associated with atherosclerotic disease, whereas levels increased over time among those allocated to placebo, findings consistent with previous data in this cohort for LDL cholesterol.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationThere has been controversy regarding the use of mineral oil as a comparator within REDUCE-IT.
“there has been controversy regarding the use of mineral oil as a comparator within REDUCE-IT, an issue where biomarker and outcome data are limited.[12][13][14]”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Study design and conductown dataThe REDUCE-IT biomarker analyses came from a randomized, double-blind trial with a large sample size.
“Despite our large sample size and randomized double-blind design, there are limitations to our analyses that merit consideration.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationIt is not proven that elevations of these or other biomarkers necessarily raise risk, and the size of any such effect is unknown, even if the mineral-oil comparator's effects are assumed to be causal.
“the contrapositive conclusion that elevations of these or other biomarkers necessarily increase risk is not proven, nor is the magnitude of any such effect known, even if the effects of the mineral oil comparator used in REDUCE-IT are taken to be causal.[12][13][14]”
Quote in the paperNot a substantial claim0 of 3 sources checkedClassified as probably not a substantial claim.
PremisecitationA large outcomes trial of eicosapentaenoic acid combined with docosahexaenoic acid showed neutral effects.
“in light of neutral effects in a large outcomes trial of eicosapentaenoic acid (EPA) combined with docosahexaenoic acid, 10,11”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationIn the open-label JELIS trial, icosapent ethyl was associated with a 19% reduction in risk of major vascular events, with no placebo used.
“The only other data in this arena are a 19% reduction in risk of major vascular events observed in the open-label JELIS (Japan EPA Lipid Intervention Study), using icosapent ethyl, in which no placebo was used.21”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe effects of treatment were evaluated following the trial's prespecified statistical analysis plan.
“Following the trial prespecified statistical analysis plan, the effects of treatment with icosapent ethyl or mineral oil were evaluated as the median percent change from baseline at 12 months, 24 months, and the end-of-study visit.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenREDUCE-IT was approved by institutional review committees and all participants gave informed consent before enrollment.
“REDUCE-IT was approved globally by institutional review committees and all participants gave informed consent before enrollment.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisenone givenIn REDUCE-IT, icosapent ethyl produced an overall 25% relative risk reduction in first events and a 30% reduction in total ischemic events.
“In the context of an overall 25% relative risk reduction in first events and a 30% reduction in total ischemic events observed”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
Interpretationnone givenNo simple or widely accepted method exists to assess without bias the combined magnitude of the multiple biomarker effects observed in this substudy.
“we are not aware of a simple or widely accepted method to assess in an unbiased manner what the potential magnitude might be of a combination of the multiple effects observed here”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationEvent reductions in REDUCE-IT were similar across baseline triglyceride tertiles and across on-treatment triglyceride levels.
“observed event reductions within REDUCE-IT were similar across baseline triglyceride tertiles as well as across on-treatment levels of triglycerides.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationTreatment with a targeted interleukin-1β inhibitor has demonstrated clinical benefit.
“where treatment with a targeted interleukin-1β inhibitor has demonstrated clinical benefit.6”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe Laboratory of Clinical Chemistry at Children's Hospital Medical Center in Boston, which measured IL-1β, IL-6, and OxLDL, has served as a core reference laboratory for multiple inflammation biology trials.
“Levels of interleukin-1β, interleukin-6, and OxLDL were measured in the Laboratory of Clinical Chemistry, Children's Hospital Medical Center in Boston, Massachusetts, a facility that has served as a core reference laboratory for multiple inflammation biology trials.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable).
Interpretationown dataThe biomarker findings may have implications for understanding the biologic pathways associated with clinical outcomes in REDUCE-IT.
“Our findings may have implications for understanding the biologic pathways associated with clinical outcomes observed in REDUCE-IT.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataAlternative inflammatory pathways and other candidate biomarkers, such as specialized pro-resolving mediators, ceramides and glycoprotein acetylation, were not measured in REDUCE-IT.
“None of these, however, has been measured in REDUCE-IT; nor have alternative biomarkers such as ceramides and glycoprotein acetylation.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn prior large trials (JUPITER, CIRT, CANTOS, SPIRE), placebo groups showed no substantive changes in LDL cholesterol, IL-1β, IL-6, or hsCRP over 3-5 years, and in STRENGTH (corn oil placebo) biomarker levels did not increase over time.
“No substantive biomarker changes were observed in the placebo groups over periods of 3 to 5 years for measures of LDL cholesterol, interleukin-1β, interleukin-6, or hsCRP in the large-scale JUPITER (Justification for the Use of Statin in Prevention: An Intervention Trial Evaluating Rosuvastatin), CIRT (Cardiovascular Inflammation Reduction Trial), CANTOS (Canakinumab Anti-Inflammatory Thrombosis”
Quote in the paperNot a substantial claim0 of 6 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAll P values were 2-sided and all confidence intervals were computed at the 95% level without multiplicity adjustment.
“All P values are 2-sided and all CIs computed at the 95% level without multiplicity adjustment.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The mechanisms underlying the clinical benefit of icosapent ethyl in REDUCE-IT remain uncertain.
“The mechanisms underlying this benefit remain uncertain.”
“The mechanisms underlying these clinical benefits remain uncertain.”
The paper relies on this without support.
No other prospective intervention data demonstrate that mineral oil 4g daily compared with corn oil or other placebo affects the biomarkers measured here.
“We are not aware of other prospective intervention data demonstrating that mineral oil at a quantity of 4 grams daily compared with corn oil or other forms of placebo has effects, direct or indirect, on the biomarkers measured here.”
The paper relies on this without support.
Serum samples stored at -70°C from collection to analysis remained stable for the measured biomarkers.
“Samples within REDUCE-IT have been stored in a commercial freezer facility at -70 °C since original collection starting at time of randomization through trial completion (minimum of 2 and maximum of 9 years before analysis).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A recent study found that higher EPA levels were associated with a reduction in the incidence of cardiovascular events, independent of the effects on triglyceride levels.
“This paper found that higher EPA levels were associated with a reduction in the incidence of cardiovascular events, independent of the effects on triglyceride levels.”
From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [94]
The Discussion (page not specified in our copy) reports fewer cardiovascular events with icosapent ethyl treatment and says the benefit was not closely tied to baseline or achieved triglyceride levels. It does not report an association between measured EPA levels and event incidence, and says the mechanism of benefit remains uncertain. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe relationship between EPA levels and cardiovascular outcomes persisted even in patients who had only modest reductions in triglycerides.
“Notably, the study also observed that the relationship between EPA levels and cardiovascular outcomes persisted even in patients who had only modest reductions in triglycerides, highlighting the importance of EPA concentration in achieving therapeutic benefit [94].”
From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [94]
The paper's introductory discussion reports that cardiovascular event reductions were similar across baseline and on-treatment triglyceride levels. Its Discussion also says the benefits were not closely tied to triglyceride levels. Neither passage establishes a relationship between measured EPA concentrations and outcomes in patients with modest triglyceride reductions; the paper says the mechanism of benefit remains uncertain. (LLM, conf=0.85)
Experimental — accuracy not yet measuredOver a median follow-up of 4.9 years, IPE significantly reduced the risk of MACE by 25% (HR 0.75; 95% CI 0.68-0.83; p < 0.001), with consistent reductions across all major components, including cardiovascular death, myocardial infarction, stroke, and coronary revascularization.
“Over a median follow-up of 4.9 years, IPE significantly reduced the risk of MACE by 25% (HR 0.75; 95% CI 0.68–0.83; p < 0.001), with consistent reductions across all major components, including cardiovascular death, myocardial infarction, stroke, and coronary revascularization.”
From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [104]
The Methods report a median follow-up of 4.9 years and list the events included in the composite outcome. The introductory passage reports a 25% reduction in first major adverse ischemic events (HR 0.75, 95% CI 0.68–0.83; P<0.001). Neither passage establishes that reductions were consistent across each listed component. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBiomarker analyses from REDUCE-IT demonstrated that IPE significantly reduced systemic inflammation and oxidative stress, including a 39.9% decrease in hs-CRP, a 13% reduction in oxidized LDL, and an 18% decrease in lipoprotein-associated phospholipase A2 compared with minimal changes in the placebo group.
“Beyond lipid modification, biomarker analyses from REDUCE-IT [104] demonstrated that IPE significantly reduced systemic inflammation and oxidative stress, including a 39.9% decrease in hs-CRP, a 13% reduction in oxidized LDL, and an 18% decrease in lipoprotein-associated phospholipase A₂ compared with minimal changes in the placebo group.”
From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [104]
The biomarker table (Discussion, p. not provided) reports a 39.91% between-group difference in hsCRP at 24 months, but not a 39.9% decrease within the IPE group. It does not report 13% and 18% IPE reductions in oxidized LDL and Lp-PLA2; both changed minimally in the IPE group while increasing in the mineral-oil group. The Discussion explicitly summarizes the pattern as minimal effects with IPE and increases with the comparator, contrary to the claim's account of minimal placebo changes. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe absolute risk reduction in REDUCE-IT was 4.8%, yielding a number needed to treat (NNT) of 21.
“The absolute risk reduction was 4.8%, yielding a number needed to treat (NNT) of 21.”
From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [104]
The Discussion (page unavailable) reports a reduction in cardiovascular events in REDUCE-IT and specifies a 25% relative risk reduction in first events. Our copy does not report a 4.8% absolute risk reduction or an NNT of 21, so it does not support the claimed figures. (LLM, conf=0.82)
Experimental — accuracy not yet measured
The cardiovascular efficacy of IPE was robustly demonstrated in the REDUCE-IT trial, which enrolled 8,179 statin-treated patients with either established cardiovascular disease or diabetes plus additional risk factors, and fasting TG levels between 135 and 499 mg/dL.
“The cardiovascular efficacy of IPE was robustly demonstrated in the REDUCE-IT trial, which enrolled 8,179 statin-treated patients with either established cardiovascular disease or diabetes plus additional risk factors, and fasting TG levels between 135 and 499 mg/dL [104].”
From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [104]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIn REDUCE-IT, purified EPA ethyl-ester led to substantially higher plasma EPA concentrations (~144 μg/mL) than in STRENGTH (~90 μg/mL).
“In REDUCE-IT [104], the use of a purified EPA ethyl-ester formulation led to substantially higher plasma EPA concentrations (~ 144 µg/mL) than those achieved in STRENGTH (~ 90 µg/mL)”
From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [104]
The Discussion identifies icosapent ethyl as the treatment used in REDUCE-IT, and the References describe it as a pure EPA ethyl ester (page not specified). The paper does not report plasma EPA concentrations of approximately 144 µg/mL in REDUCE-IT or 90 µg/mL in STRENGTH, so it does not support the claimed comparison. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe magnitude of benefit observed in REDUCE-IT exceeded that expected from triglyceride lowering alone.
“Notably, the magnitude of benefit observed in REDUCE-IT exceeded that expected from triglyceride lowering alone [104].”
From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [104]
The introductory passage reports a 25% reduction in first major ischemic events despite a 20% reduction in triglycerides, with event reductions similar across triglyceride levels. The Discussion says the benefits were not closely tied to triglyceride levels, but the paper does not quantify the benefit expected from triglyceride lowering alone and says the causal mechanisms remain uncertain. No page number is available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe questions of efficacy and whether differences in study populations, drug formulations, and placebo arms may explain discrepant results of high-profile trials have been debated.
“The questions of efficacy and whether differences in study populations, drug formulations, and placebo arms may explain discrepant results of high-profile trials have been debated.7,8”
From Effects of Eicosapentaenoic Acid vs Eicosapentaenoic/Docosahexaenoic Acids on Cardiovascular Mortality (2025) · cites this paper as [7]
The introduction (page unavailable) notes differing outcomes for REDUCE-IT and a trial of a different EPA-containing formulation. The Discussion (page unavailable) explicitly describes controversy over whether REDUCE-IT’s mineral-oil comparator affected its results. Our copy does not discuss differences in study populations as an explanation for the discrepant trial results. (LLM, conf=0.83)
Experimental — accuracy not yet measuredJELIS was challenged for its selection of patients with a relatively high background of fish consumption, and REDUCE-IT was revisited for the use of mineral oil as a comparator.
“Moreover, JELIS was often challenged for its selection of patients with a relatively high background of fish consumption, 26 and REDUCE‐IT was revisited for the use of mineral oil as a comparator, 27 , 28 , 29 respectively.”
From Association Between Omega-3 Fatty Acid Intake and Dyslipidemia: A Continuous Dose-Response Meta-Analysis of Randomized Controlled Trials (2023) · cites this paper as [27]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Eligibility threshold differs at 135 mg/dL
MinorThe abstract includes participants whose triglyceride level was exactly 135 mg/dL, whereas the Methods section excludes them by specifying a level greater than 135 mg/dL.
“participants with triglyceride levels ≥135 mg/dL and <500 mg/dL”
“patients with triglyceride levels >135 mg/dL and <500 mg/dL”
The citation lists haven’t been fetched yet
References 22 · Cited by 131
- Authors
- Ridker, P. M., Rifai, N., MacFadyen, J., Glynn, R. J., Jiao, L., Steg, P. G., Miller, M., Brinton, E. A., Jacobson, T. A., Tardif, J.-C., Ballantyne, C. M., Mason, R. P., & Bhatt, D. L.
- Affiliations
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Amarin (United States) (US)
- Université de Paris, FACT and INSERM-U1148, F75018 and Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, France (P.G.S.).
- University of Maryland, Baltimore (US)
- Utah Lipid Center, Salt Lake City (E.A.B.).
- Emory University (US)
- Montreal Heart Institute (CA)
- Houston Methodist (US)
- ORCID
- Venue
- Circulation
- Published
- 2022-08-02
- Volume
- 146
- Issue
- 5
- Pages
- 372-379
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W4283711740
- Cited by
- 131
- References
- 22
- Citations by year
- 2026: 17 · 2025: 22 · 2024: 32 · 2023: 37 · 2022: 22 · 2013: 1
- FWCI
- 17.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- icosapent ethyl, REDUCE-IT trial, triglyceride-rich lipoproteins, atherosclerosis biomarkers, IL-1β, interleukin-6, C-reactive protein, oxidized LDL, homocysteine, lipoprotein(a), lipoprotein-associated phospholipase A2, cardiovascular risk
- MeSH terms
- C-Reactive Protein, Cholesterol, Double-Blind Method, Homocysteine, Humans, Cholesterol, LDL, Mineral Oil, Eicosapentaenoic Acid, Hypertriglyceridemia, Biomarkers, Interleukin-6, Lipoprotein(a), Hydroxymethylglutaryl-CoA Reductase Inhibitors, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Atherosclerosis, Interleukin-1beta
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