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Cited by 488Fatty Acid Research and HealthLipid metabolism and disordersDiabetes, Cardiovascular Risks, and Lipoproteins

Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association

Open access
Skulas-Ray, Ann C., Wilson, Peter W.F., Harris, William S., Brinton, Eliot A., Kris-Etherton, Penny M., Richter, Chesney K., Jacobson, Terry A., Engler, Mary B. +7 more·2019·Circulation
DOI 10.1161/cir.0000000000000709
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Abstract

Hypertriglyceridemia (triglycerides 200-499 mg/dL) is relatively common in the United States, whereas more severe triglyceride elevations (very high triglycerides, ≥500 mg/dL) are far less frequently observed. Both are becoming increasingly prevalent in the United States and elsewhere, likely driven in large part by growing rates of obesity and diabetes mellitus. In a 2002 American Heart Association scientific statement, the omega-3 fatty acids (n-3 FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were recommended (at a dose of 2-4 g/d) for reducing triglycerides in patients with elevated triglycerides. Since 2002, prescription agents containing EPA+DHA or EPA alone have been approved by the US Food and Drug Administration for treating very high triglycerides; these agents are also widely used for hypertriglyceridemia. The purpose of this advisory is to summarize the lipid and lipoprotein effects resulting from pharmacological doses of n-3 FAs (>3 g/d total EPA+DHA) on the basis of new scientific data and availability of n-3 FA agents. In treatment of very high triglycerides with 4 g/d, EPA+DHA agents reduce triglycerides by ≥30% with concurrent increases in low-density lipoprotein cholesterol, whereas EPA-only did not raise low-density lipoprotein cholesterol in very high triglycerides. When used to treat hypertriglyceridemia, n-3 FAs with EPA+DHA or with EPA-only appear roughly comparable for triglyceride lowering and do not increase low-density lipoprotein cholesterol when used as monotherapy or in combination with a statin. In the largest trials of 4 g/d prescription n-3 FA, non-high-density lipoprotein cholesterol and apolipoprotein B were modestly decreased, indicating reductions in total atherogenic lipoproteins. The use of n-3 FA (4 g/d) for improving atherosclerotic cardiovascular disease risk in patients with hypertriglyceridemia is supported by a 25% reduction in major adverse cardiovascular events in REDUCE-IT (Reduction of Cardiovascular Events With EPA Intervention Trial), a randomized placebo-controlled trial of EPA-only in high-risk patients treated with a statin. The results of a trial of 4 g/d prescription EPA+DHA in hypertriglyceridemia are anticipated in 2020. We conclude that prescription n-3 FAs (EPA+DHA or EPA-only) at a dose of 4 g/d (>3 g/d total EPA+DHA) are an effective and safe option for reducing triglycerides as monotherapy or as an adjunct to other lipid-lowering agents.

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Registry

Crossref · 10.1161/cir.0000000000000709

Cites

122 of 125 references verified0 citation errors · 3 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

46 of 155 cited sources checked · 12 supported · 6 flagged · accuracy not yet measured

  • Findingcitation

    In that trial, non-HDL-C decreased by 4% to 6% in all three groups at 12 and 52 weeks.

    “Non-HDL-C decreased by 4% to 6% in all 3 groups at 12 and 52 weeks”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [52] 52. Shearer GC, Pottala JV, Hansen SN, Brandenburg V, Harris WS. Effects of prescription niacin and omega-3 fatty acids on lipids and vascular func- tion in metabolic syndrome: a randomized controlled trial. J Lipid Res. 2012;53:2429-2435. doi: 10.1194/jlr.P022392 source

      The Methods (Study design; page unavailable) describe four groups treated for 16 weeks, not three groups assessed at 12 and 52 weeks. Results (Table 3; page unavailable) report non-HDL-C decreases in all four groups, but as changes in mg/dL (−5.9, −23, −11, and −7.3), not a 4%–6% decrease in three groups at those time points. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

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  • Findingcitation

    Non-HDL-C decreased by 5% to 7% in the three largest studies of 4 g/d O3AEE.

    “Non-HDL-C decreased by 5% to 7% in the 3 largest studies of 4 g/d O3AEE, 22,33,34”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [22] 22. Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN. Eicosapentaenoic acid ethyl ester (AMR101) therapy in pa- tients with very high triglyceride levels (from the Multi-center, plAcebo- controlled, Randomized, double-blINd, 12-week study with an open- label Extension [MARINE] trial). Am J Cardiol. 2011;108:682-690. doi: 10.1016/j.amjcard.2011.04.015 source
    • cites [33] 33. Bays HE, McKenney J, Maki KC, Doyle RT, Carter RN, Stein E. Effects of prescription omega-3-acid ethyl esters on non-high-density lipoprotein cholesterol when coadministered with escalating doses of atorvastatin. Mayo Clin Proc. 2010;85:122-128. doi: 10.4065/mcp.2009.0397 source
    • cites [34] 34. Skulas-Ray AC, Kris-Etherton PM, Harris WS, Vanden Heuvel JP, Wagner PR, West SG. Dose-response effects of omega-3 fatty acids on triglycerides, inflammation, and endothelial function in healthy persons with moderate hypertriglyceridemia. Am J Clin Nutr. 2011;93:243-252. doi: 10.3945/ajcn.110.003871 source

      The study used four 1-g omega-3 fatty acid ethyl ester capsules per day at its higher dose (Design and interventions). Its lipid table (DISCUSSION; page not provided) reports non-HDL-C of 166.4 mg/dL with placebo and 164.7 mg/dL at the higher dose—about a 1% decrease, not 5% to 7%. The table also reports no significant treatment effect (P = 0.54). (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Findingcitation

    The placebo-corrected LDL-C effect of 4 g/d IPE was -6% (control 8.8%; active 2%).

    “The placebo-corrected LDL-C effect of 4 g/d IPE was -6% (control, 8.8%; active, 2%).36”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] 36. Metkus TS, Timpone J, Leaf D, Bidwell Goetz M, Harris WS, Brown TT. Omega-3 fatty acid therapy reduces triglycerides and interleu- kin-6 in hypertriglyeridemic HIV patients. HIV Med. 2013;14:530-539. doi: 10.1111/hiv.12046 source

      The Methods (Treatment; page unavailable) identify the active treatment as Lovaza, a mixture of EPA and DHA, not IPE. The Results (Effect of O3A ethyl esters on lipid parameters; page unavailable) report no between-group difference in LDL cholesterol and do not report the claimed −6%, 8.8%, or 2% LDL-C figures. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Findingcitation

    Six published monotherapy trials of 3 to 4 g/day n-3 fatty acids in patients with hypertriglyceridemia who were not taking other lipid-lowering medications met the inclusion criteria.

    “Six published trials in which 3 to 4 g/d n-3 FA was administered to people with HTG not taking other lipidlowering medications were identified as meeting the inclusion criteria listed above.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [28] 28. Roth EM, Bays HE, Forker AD, Maki KC, Carter R, Doyle RT, Stein EA. Prescription omega-3 fatty acid as an adjunct to fenofibrate therapy in hypertriglyceridemic subjects. J Cardiovasc Pharmacol. 2009;54:196-203. doi: 10.1097/FJC.0b013e3181b0cf71 source
    • cites [29] 29. Mackness MI, Bhatnagar D, Durrington PN, Prais H, Haynes B, Morgan J, Borthwick L. Effects of a new fish oil concentrate on plasma lipids and lipoproteins in patients with hypertriglyceridaemia. Eur J Clin Nutr. 1994;48:859-865. source
    • cites [33] 33. Bays HE, McKenney J, Maki KC, Doyle RT, Carter RN, Stein E. Effects of prescription omega-3-acid ethyl esters on non-high-density lipoprotein cholesterol when coadministered with escalating doses of atorvastatin. Mayo Clin Proc. 2010;85:122-128. doi: 10.4065/mcp.2009.0397 source

      The Patients and Methods section describes eligibility for this paper’s own trial, and its treatment-flow figure shows omega-3 fatty acids given with atorvastatin. Our copy does not report identifying six published monotherapy trials that met inclusion criteria; searches for that wording and for six omega-3 monotherapy trials found no such passage. Page numbers were not available in the indexed passages. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
  • Premisecitation

    More recent studies of hypertriglyceridemia support an effect on LDL particle size.

    “deed, such an effect on LDL particle size is supported by the results of more recent studies of HTG.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [24] 24. Sadovsky R, Kris-Etherton P. Prescription omega-3-acid ethyl esters for the treatment of very high triglycerides. Postgrad Med. 2009;121:145-153. doi: 10.3810/pgm.2009.07.2020 source
    • cites [25] 25. Dunbar RL, Nicholls SJ, Maki KC, Roth EM, Orloff DG, Curcio D, Johnson J, Kling D, Davidson MH. Effects of omega-3 carboxylic acids on lipoprotein particles and other cardiovascular risk markers in high-risk statin-treated patients with residual hypertriglyceridemia: a random- ized, controlled, double-blind trial. Lipids Health Dis. 2015;14:98. doi: 10.1186/s12944-015-0100-8 source
    • cites [26] 26. Maki KC, Bays HE, Dicklin MR, Johnson SL, Shabbout M. Effects of prescription omega-3-acid ethyl esters, coadministered with atorv- astatin, on circulating levels of lipoprotein particles, apolipoprotein CIII, and lipoprotein-associated phospholipase A2 mass in men and women with mixed dyslipidemia. J Clin Lipidol. 2011;5:483-492. doi: 10.1016/j.jacl.2011.09.001 source
  • May combine two claims. 54
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Findingcitation

    IPE lowered non-HDL-C by 14% and apo B by 9%.

    “IPE lowered non-HDL-C by 14% (control, 9.8%; active, -5.5%) and apo B by 9% (control, 7%; active, -2.2%).36”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] 36. Metkus TS, Timpone J, Leaf D, Bidwell Goetz M, Harris WS, Brown TT. Omega-3 fatty acid therapy reduces triglycerides and interleu- kin-6 in hypertriglyeridemic HIV patients. HIV Med. 2013;14:530-539. doi: 10.1111/hiv.12046 source

      The Methods (Treatment; page unavailable) identify the intervention as Lovaza, an EPA/DHA mixture, not IPE. The Results (Effect of O3A ethyl esters on lipid parameters; page unavailable) report no difference between groups in non-HDL cholesterol or other lipid parameters apart from triglycerides. The copy does not report an apo B reduction or the cited percentages. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    In a Japanese trial of about 600 patients with hypertriglyceridemia, 4 g/d O3AEE reduced triglycerides by about 22%, while 2 g/d O3AEE and 2 g/d IPE each reduced triglycerides by about 11% after 12 weeks.

    “Triglyceride reductions from baseline were ≈22% in the 4 g/d O3AEE group and ≈11% for both the O3AEE and IPE 2 g/d groups after 12 weeks”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [52] 52. Shearer GC, Pottala JV, Hansen SN, Brandenburg V, Harris WS. Effects of prescription niacin and omega-3 fatty acids on lipids and vascular func- tion in metabolic syndrome: a randomized controlled trial. J Lipid Res. 2012;53:2429-2435. doi: 10.1194/jlr.P022392 source

      The Methods (Study design; page unavailable) describe a 16-week trial with 60 participants assigned to placebo, 4 g/day prescription omega-3, 2 g/day niacin, or their combination—not the claimed 12-week, approximately 600-patient comparison of O3AEE and IPE doses. The Results (Effects on lipid and lipoprotein levels; page unavailable) report a 13% triglyceride reduction with omega-3 alone, rather than approximately 22%. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Although most trials presented in Table 4 specified direct LDL-C measurement when triglycerides >400 mg/dL, only 3 trials reported LDL-C results obtained from direct LDL measurement throughout the triglyceride range.

    “Although most trials presented in Table 4 specified direct LDL-C measurement in cases when triglycerides >400 mg/dL (as is standard for clinical practice), only 3 trials reported LDL-C results obtained from direct LDL measurement throughout the triglyceride range.28,30,45”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [28] 28. Roth EM, Bays HE, Forker AD, Maki KC, Carter R, Doyle RT, Stein EA. Prescription omega-3 fatty acid as an adjunct to fenofibrate therapy in hypertriglyceridemic subjects. J Cardiovasc Pharmacol. 2009;54:196-203. doi: 10.1097/FJC.0b013e3181b0cf71 source
    • cites [30] 30. Grundt H, Nilsen DW, Hetland O, Aarsland T, Baksaas I, Grande T, Woie L. Improvement of serum lipids and blood pressure during intervention with n-3 fatty acids was not associated with changes in insulin levels in subjects with combined hyperlipidaemia. J Intern Med. 1995;237:249-259. doi: 10.111/j.1365-2796.1995.tb01173.x source
    • cites [45] 45. Minihane AM, Khan S, Leigh-Firbank EC, Talmud P, Wright JW, Murphy MC, Griffin BA, Williams CM. ApoE polymorphism and fish oil supplementation in subjects with an atherogenic lipoprotein phenotype. Arterioscler Thromb Vasc Biol. 2000;20:1990-1997. source

      The Biochemical Analysis section states that this trial computed LDL-C using the Friedewald formula, rather than measuring LDL-C directly throughout the triglyceride range. Thus, the paper contradicts its apparent identification as one of the three trials using direct LDL-C measurement. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Moderate triglyceride elevation is often associated with increased atherosclerotic cardiovascular disease risk.

    “The 2011 statement cited epidemiological evidence that a moderate elevation in triglycerides is often associated with increased atherosclerotic cardiovascular disease (ASCVD) risk.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] 1. Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, Goldberg AC, Howard WJ, Jacobson MS, Kris-Etherton PM, Lennie TA, Levi M, Mazzone T, Pennathur S; on behalf of the American Heart As- sociation Clinical Lipidology, Thrombosis, and Prevention Committee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Car- diovascular Nursing; Council on the Kidney in Cardiovascular Disease. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. source

  • Classified as probably not a substantial claim.

    Premisecitation

    The 2002 American Heart Association scientific statement advised using EPA and DHA at 2 to 4 g/day to lower triglycerides in patients with elevated triglycerides.

    “In a 2002 American Heart Association scientific statement, the omega-3 fatty acids (n-3 FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were recommended (at a dose of 2-4 g/d) for reducing triglycerides in patients with elevated triglycerides.”
    • Also stated in: § E · plain
      “The 2002 AHA scientific statement on fish and n-3 FAs recommended increased dietary omega-3 intake plus dietary supplements to achieve 2 to 4 g/d n-3 FA (referring to the total amount of eicosapentaenoic acid [EPA] plus docosahexaenoic acid [DHA]) for triglyceride-lowering treatment (ie, medical management of HTG) under the supervision of a physician.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] 12. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/ AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in Circulation. 2019;139:e1182-e1186] source

      The guideline’s Section 3.1 (page not available) discusses triglyceride-lowering drugs but does not mention EPA, DHA, or the claimed dose. Searches of our copy for omega-3 fatty acids, the 2002 AHA statement, and 2–4 g/day found no passage addressing that recommendation. (LLM, conf=0.73)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Study design and conductcitation

    No published monotherapy studies of IPE or O3CA in hypertriglyceridemia exist because statins are considered first-line lipid treatment.

    “Because statins are considered to be first-line lipid treatment in patients with HTG, 11 there have been no published monotherapy studies of the more recently available IPE or O3CA in this population.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] 11. Jacobson TA, Maki KC, Orringer CE, Jones PH, Kris-Etherton P, Sikand G, La Forge R, Daniels SR, Wilson DP, Morris PB, Wild RA, Grundy SM, Daviglus M, Ferdinand KC, Vijayaraghavan K, Deedwania PC, Aberg JA, Liao KP, McKenney JM, Ross JL, Braun LT, Ito MK, Bays HE, Brown WV, Underberg JA; NLA Expert Panel. National Lipid Association recommen- dations for patient-centered management of dyslipidemia: part 2. J Clin Lipidol. 2015;9(suppl):S1-122.e1. doi: 10.1016/j.jacl.2015.09.002 source

  • May combine two claims.

    Premisecitation

    In monotherapy trials, the average triglyceride reduction was about 27%, with a range of 21% to 35%, except for a medical food study using 3.2 g/day EPA+DHA in people with very low n-3 fatty acid levels, which reported a 48% reduction.

    “On average, the triglyceride reduction was ≈27% (range, 21%-35%), apart from the study of a medical food (3.2 g/d EPA+DHA), which specifically recruited people with very low blood levels of n-3 FA and reported a 48% reduction.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [45] 45. Minihane AM, Khan S, Leigh-Firbank EC, Talmud P, Wright JW, Murphy MC, Griffin BA, Williams CM. ApoE polymorphism and fish oil supplementation in subjects with an atherogenic lipoprotein phenotype. Arterioscler Thromb Vasc Biol. 2000;20:1990-1997. source

      The Results and Discussion (page unavailable) report a 35.3% reduction in fasting triglycerides after fish-oil supplementation in this study, supporting the upper end of the stated range. They do not report a 27% average across monotherapy trials or the medical-food study's 48% reduction in people with very low n-3 fatty acid levels. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Mendelian randomization evidence suggests that elevated triglycerides linked to genetic variants may be a causal factor for atherosclerotic cardiovascular disease and possibly for premature all-cause mortality.

    “More recent evidence from mendelian randomization studies has shown that elevated triglycerides associated with genetic variants may be a causal factor for ASCVD and possibly for premature all-cause mortality.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [2] 2. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lan- cet. 2014;384:626-635. doi: 10.1016/S0140-6736(14)61177-6 source
    • cites [3] 3. Stitziel NO. Human genetic insights into lipoproteins and risk of cardiomet- abolic disease. Curr Opin Lipidol. 2017;28:113-119. doi: 10.1097/MOL. 0000000000000389 source

      In the section on triglycerides and coronary artery disease (page not provided), the review discusses Mendelian randomization and genetic variants linking triglyceride-rich lipoproteins to coronary disease risk; its annotated reference 25 explicitly describes evidence for a causal role. Our copy does not report an association with premature all-cause mortality, so that part of the claim is unsupported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [4] 4. Dewey FE, Gusarova V, Dunbar RL, O'Dushlaine C, Schurmann C, Gottesman O, McCarthy S, Van Hout CV, Bruse S, Dansky HM, Leader JB, Murray MF, Ritchie MD, Kirchner HL, Habegger L, Lopez A, Penn J, Zhao A, Shao W, Stahl N, Murphy AJ, Hamon S, Bouzelmat A, Zhang R, Shumel B, Pordy R, Gipe D, Herman GA, Sheu WHH, Lee IT, Liang KW, Guo X, Rotter JI, Chen YI, Kraus WE, Shah SH, Damrauer S, Small A, Rader DJ, Wulff AB, Nordestgaard BG, Tybjærg-Hansen A, van den Hoek AM, Princen HMG, Ledbetter DH, Carey DJ, Overton JD, Reid JG, Sasiela WJ, Banerjee P, Shuldiner AR, Borecki IB, Teslovich TM, Yancopou source

      The Results section reports that ANGPTL3 loss-of-function carriers had lower triglyceride levels and lower odds of coronary artery disease. That supports a genetic link to coronary disease, but the paper does not establish triglycerides themselves as the causal factor: carriers also had lower LDL and HDL cholesterol. The paper does not report premature all-cause mortality (searched: “premature all-cause mortality”). (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In four trials, 4 g/day O3AEE produced an average 26% reduction in triglycerides, while a dietary supplement study of 3 g/day EPA+DHA produced a 35% reduction.

    “In 4 trials, 4 g/d O3AEE averaged a 26% reduction in triglycerides, whereas the reduction in a dietary supplement study of 3 g/d EPA+DHA was 35%.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [44] 44. Bairati I, Roy L, Meyer F. Double-blind, randomized, controlled trial of fish oil supplements in prevention of recurrence of stenosis after coronary an- gioplasty. Circulation. 1992;85:950-956. source

      The Baseline Characteristics section (page not supplied) reports a triglyceride decrease from 2.3 to 1.5 mmol/L at one month—approximately 35%—in the fish-oil group. But the Study Design section specifies 4.5 g/day of EPA+DHA, not 3 g/day, and this single trial does not report an average 26% reduction across four O3AEE trials. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    In a small trial, DHA increased LDL-C, LDL particle size, and HDL2, but EPA did not.

    “In this trial, DHA increased LDL-C, LDL particle size, and HDL2, but EPA did not.62”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [62] 62. Allaire J, Couture P, Leclerc M, Charest A, Marin J, Lépine M-C, Talbot D, Tchernof A, Lamarche B. A randomized, crossover, head-to- head comparison of EPA and DHA supplementation to reduce inflam- mation markers in men and women: the Comparing EPA to DHA (Com- parED) Study. Am J Clin Nutr. 2016;104:280-287. doi: 10.3945/ajcn. 116.131896 source

      The Blood lipids section reports that DHA increased LDL-C more than EPA, but EPA also significantly increased LDL-C versus control (+2.2%). The LCn-3PUFA and plasma lipids section says increased LDL particle size with DHA was an inference requiring measurement. The paper reports increased HDL cholesterol, not specifically HDL2. (LLM, conf=0.91)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    That trial reported an inverse relationship between triglyceride values and LDL particle size, and a positive correlation between HDL-C and LDL particle size.

    “This trial also reported an inverse relationship between triglyceride values and LDL particle size, whereas HDL-C was positively correlated with LDL particle size.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [62] 62. Allaire J, Couture P, Leclerc M, Charest A, Marin J, Lépine M-C, Talbot D, Tchernof A, Lamarche B. A randomized, crossover, head-to- head comparison of EPA and DHA supplementation to reduce inflam- mation markers in men and women: the Comparing EPA to DHA (Com- parED) Study. Am J Clin Nutr. 2016;104:280-287. doi: 10.3945/ajcn. 116.131896 source

      The ‘LCn-3PUFA and plasma lipids’ discussion (page unavailable) says that lower triglycerides after DHA supplementation suggest larger LDL particles, but explicitly says this assumption needs verification by measuring LDL particle size. The Blood lipids results (page unavailable) report higher HDL cholesterol with DHA, not a positive correlation between HDL-C and LDL particle size. The trial therefore did not report either correlation as claimed. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Alpha-linolenic acid has not been shown to substantially reduce triglycerides and is not indicated for treating hypertriglyceridemia.

    “α-Linolenic acid, an 18-carbon plant-derived n-3 FA, has not been shown to reduce triglycerides substantially and is not indicated for the treatment of HTG.65,66”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [65] 65. Maki KC, Bobotas G, Dicklin MR, Huebner M, Keane WF. Effects of MAT9001 containing eicosapentaenoic acid and docosapentaenoic acid, compared to eicosapentaenoic acid ethyl esters, on triglycerides, lipopro- tein cholesterol, and related variables. J Clin Lipidol. 2017;11:102-109. doi: 10.1016/j.jacl.2016.10.010 Downloaded from http://ahajournals.org by on September 1, 2023 September 17, 2019 Circulation. 2019;140:e673-e691. DOI: 10.1161/CIR.0000000000000709 e690 CLINICAL STATEMENTS AND GUIDELINES source
    • cites [66] 66. Wendland E, Farmer A, Glasziou P, Neil A. Effect of alpha linolenic acid on cardiovascular risk markers: a systematic review. Heart. 2006;92:166-169. doi: 10.1136/hrt.2004.053538 source

      The Abstract and “Cholesterol and triglycerides” section report no significant triglyceride reduction with ALA, supporting the first part of the claim. The paper does not address whether ALA is indicated for treating hypertriglyceridemia; its recommendation concerns supplementation to reduce cardiovascular disease. Page numbers were not available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    When 4 g/day IPE was given with statins, placebo-adjusted decreases were 22% for triglycerides, 5% for HDL cholesterol, 14% for non-HDL cholesterol, 9% for apolipoprotein B, and 6% for LDL cholesterol, and LDL particle size modestly increased.

    “When IPE (4 g/d) was administered with statins, there were placebo-adjusted decreases of 22% in triglycerides, 5% in HDL-C, 14% in non-HDL-C, 9% in apo B, and 6% in LDL-C, 39 and LDL particle size was modestly increased.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [39] 39. Hedengran A, Szecsi PB, Dyerberg J, Harris WS, Stender S. n-3 PUFA es- terified to glycerol or as ethyl esters reduce non-fasting plasma triacylg- lycerol in subjects with hypertriglyceridemia: a randomized trial. Lipids. 2015;50:165-175. doi: 10.1007/s11745-014-3968-6 source
    • cites [47] 47. Leigh-Firbank EC, Minihane AM, Leake DS, Wright JW, Murphy MC, Griffin BA, Williams CM. Eicosapentaenoic acid and docosahexaenoic acid from fish oils: differential associations with lipid responses. Br J Nutr. 2002;87:435-445. doi: 10.1079/BJNBJN2002556 source

      The Plasma lipids, glucose, insulin section reports lower triglycerides, and the Discussion describes a shift toward larger LDL particles. But this was a trial of 6 g/day fish oil (EPA plus DHA), not 4 g/day IPE with statins; the reported percentages do not match, HDL cholesterol changed little, and LDL cholesterol increased rather than decreased. Our copy gives no corresponding non-HDL cholesterol or apo B reductions. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Omega-3 fatty acids lead to intracellular degradation of apo B, thereby diminishing VLDL assembly and decreasing VLDL secretion.

    “In addition, n-3 FAs lead to intracellular degradation of apo B, which may be a result of decreased triglyceride availability or autophagic destruction of apo B via post-Golgi oxidation, 90 thereby diminishing the assembly of VLDL particles in the hepatocyte and decreasing VLDL secretion.91,92”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [90] 90. Botolin D, Wang Y, Christian B, Jump DB. Docosahexaneoic acid (22:6,n- 3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk-and 26S proteasome-dependent pathways. J Lipid Res. 2006;47:181-192. doi: 10.1194/jlr.M500365-JLR200 source

      The Discussion reports that DHA accelerates degradation of nuclear SREBP-1 in rat hepatocytes, not apo B. Searches of our copy for apo B, VLDL assembly and VLDL secretion found no passage addressing the attributed mechanism or its proposed outcome. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [91] 91. Pan M, Maitin V, Parathath S, Andreo U, Lin SX, St Germain C, Yao Z, Maxfield FR, Williams KJ, Fisher EA. Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: a pathway for late-stage quality control. Proc Natl Acad Sci U S A. 2008;105:5862-5867. doi: 10.1073/pnas.0707460104 source

      The Abstract reports that omega-3 PUFAs increase presecretory apoB degradation and inhibit apoB secretion, and the Results describe DHA-induced intracellular aggregation preceding degradation. The Discussion places this destruction late in the secretory pathway, but the paper does not establish that it diminishes VLDL assembly specifically, rather than destroying apoB-containing particles before secretion. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [92] 92. Wang H, Chen X, Fisher EA. N-3 fatty acids stimulate intracellular degra- dation of apoprotein B in rat hepatocytes. J Clin Invest. 1993;91:1380- 1389. doi: 10.1172/JCI116340 source

      The Abstract and the discussion on p. 1387 report that EPA and DHA increased intracellular apoB degradation in rat hepatocytes, accounting for decreased secretion of newly synthesized apoB. The paper does not establish that degradation thereby diminishes VLDL assembly; on p. 1387 it treats interference with assembly as a possible cause of apoB degradation, rather than a demonstrated consequence. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Absorption of the ethyl ester formulations O3AEE and IPE is low in a fasting state but greatly increased when taken with food.

    “Absorption of the ethyl ester formulations (O3AEE and IPE), although low in a fasting state, is greatly increased by taking them with food, and they are so labeled.93”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [93] 93. Maitin V, Andreo U, Guo L, Fisher EA. Docosahexaenoic acid impairs the maturation of very low density lipoproteins in rat hepatic cells. J Lipid Res. 2014;55:75-84. doi: 10.1194/jlr.M043026 source

      The Abstract discusses how DHA and EPA affect apoB degradation, and the Results examine lipoprotein secretion in rat hepatic cells. Searches for O3AEE, IPE, fasting-state absorption, and food effects found no passage addressing the claimed absorption or labeling of these formulations. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Secondary post hoc analyses of previous trials of triglyceride-lowering pharmacotherapy support the finding with the primary but not the key secondary REDUCE-IT end point.

    “Secondary post hoc analyses of previous trials of triglyceride-lowering pharmacotherapy support the finding with the primary but not the key secondary REDUCE-IT end point.102,103”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [102] 102. Bhatt DL, Steg PG, Brinton EA, Jacobson TA, Miller M, Tardif JC, Ketchum SB, Doyle RT Jr, Murphy SA, Soni PN, Braeckman RA, Juliano RA, Circulation. 2019;140:e673-e691. DOI: 10.1161/CIR.0000000000000709 September 17, 2019 e691 CLINICAL STATEMENTS AND GUIDELINES

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [103] 103. Ballantyne CM; REDUCE-IT Investigators. Rationale and design of RE- DUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl-Inter- vention Trial. Clin Cardiol. 2017;40:138-148. doi: 10.1002/clc.22692 102. source

      The Discussion reports that subgroup and post hoc analyses of earlier trials suggest possible reductions in major cardiovascular events with triglyceride-lowering therapy. The Methods define the primary and key secondary REDUCE-IT endpoints, but this 2017 design paper does not say those analyses support a finding for the primary endpoint but not the key secondary endpoint; REDUCE-IT follow-up was still ongoing. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Those pediatric trials used lower doses (less than 2 g/d EPA+DHA) or had small sample sizes (fewer than 20 participants per arm), sometimes including patients with only mildly elevated triglycerides.

    “However, these trials used lower doses (<2 g/d EPA+DHA) 81 or had relatively small sample sizes (<20 participants per study arm) 79,81 that in some cases included patients with only mildly elevated triglycerides.81”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [81] 81. Lovaza (omega-3-acid ethyl esters) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2009.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [79] 79. Gidding SS, Prospero C, Hossain J, Zappalla F, Balagopal PB, Falkner B, Kwiterovich P. A double-blind randomized trial of fish oil to lower tri- glycerides and improve cardiometabolic risk in adolescents. J Pediatr. 2014;165:497-503.e2. doi: 10.1016/j.jpeds.2014.05.039 source

      The Methods report 42 adolescents in a crossover trial, supporting the description of a relatively small study, but the available passages do not establish fewer than 20 participants per study arm. The Methods also specify at least 1.5 g DHA plus 1.86 g EPA daily—more than 2 g combined, contrary to the dose attributed to this trial. Enrollment allowed triglycerides from 150 mg/dL, but the Results describe the groups overall as having severely increased triglycerides; they do not establish that participants had only mildly elevated levels. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Some but not all dietary n-3 FA supplements contain unacceptable levels of oxidation products that have been shown to interfere with the beneficial effects of n-3 FAs in some but not all studies.

    “Some, 107 but not all, 108 supplements also contain unacceptable levels of oxidation products that have been shown to interfere with the beneficial effects of n-3 FAs in some, 109,110 but not all, 111 studies.”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [107] 107. Ritter JC, Budge SM, Jovica F. Quality analysis of commercial fish oil prep- arations. J Sci Food Agric. 2013;93:1935-1939. doi: 10.1002/jsfa.5994 108. source
    • cites [108] 108. Nichols PD, Dogan L, Sinclair A. Australian and New Zealand fish oil prod- ucts in 2016 meet label omega-3 claims and are not oxidized. Nutrients. 2016;8:E703. doi: 10.3390/nu8110703 109. source
    • cites [109] 109. Rupp TP, Rupp KG, Alter P, Rupp H. Replacement of reduced highly unsatu- rated fatty acids (HUFA deficiency) in dilative heart failure: dosage of EPA/ DHA and variability of adverse peroxides and aldehydes in dietary supple- ment fish oils. Cardiology. 2013;125:223-231. doi: 10.1159/000350656 110. source
    • cites [110] 110. García-Hernández VM, Gallar M, Sánchez-Soriano J, Micol V, Roche E, García-García E. Effect of omega-3 dietary supplements with different oxidation levels in the lipidic profile of women: a random- ized controlled trial. Int J Food Sci Nutr. 2013;64:993-1000. doi: 10.3109/09637486.2013.812619 111. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    Only 2 trials presented in Table 4 specified avoiding alcohol for at least 48 hours before testing.

    “Only 2 trials presented in Table 4 specified avoiding alcohol for at least 48 hours before testing.29,33”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [29] 29. Mackness MI, Bhatnagar D, Durrington PN, Prais H, Haynes B, Morgan J, Borthwick L. Effects of a new fish oil concentrate on plasma lipids and lipoproteins in patients with hypertriglyceridaemia. Eur J Clin Nutr. 1994;48:859-865.
    • cites [33] 33. Bays HE, McKenney J, Maki KC, Doyle RT, Carter RN, Stein E. Effects of prescription omega-3-acid ethyl esters on non-high-density lipoprotein cholesterol when coadministered with escalating doses of atorvastatin. Mayo Clin Proc. 2010;85:122-128. doi: 10.4065/mcp.2009.0397 source

      The Patients and Methods section describes eligibility and exclusions, and the End Points passage describes fasting measurements, but neither specifies avoiding alcohol before testing. Searches for alcohol and a 48-hour restriction found no such instruction in our copy. This paper also cannot establish the citing document’s count of two trials in Table 4. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The Friedewald estimation of LDL-C is inappropriate with triglycerides >400 mg/dL and progressively loses accuracy even at more modest triglyceride elevations.

    “Although it is widely recognized that the Friedewald estimation of LDL-C is inappropriate with triglycerides >400 mg/dL, this estimation progressively loses accuracy even at more modest triglyceride elevations.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [115] 115. Martin SS, Blaha MJ, Elshazly MB, Toth PP, Kwiterovich PO, Blumenthal RS, Jones SR. Comparison of a novel method vs the Frie- dewald equation for estimating low-density lipoprotein cholesterol lev- els from the standard lipid profile. JAMA. 2013;310:2061-2068. doi: 10.1001/jama.2013.280532 source

      The Results (page unavailable) show that Friedewald estimates of LDL-C below 70 mg/dL agreed progressively less often with direct measurements across triglyceride ranges of 100–149, 150–199, and 200–399 mg/dL. The paper reports its comparison for triglycerides below 400 mg/dL, but the passages do not establish that Friedewald estimation is inappropriate above 400 mg/dL. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    In a crossover trial of more than 100 adults, 10 weeks of 2.7 g/d DHA increased both LDL-C and HDL-C more than 2.7 g/d EPA, while DHA was modestly more effective at reducing triglycerides.

    “10 weeks of supplementation with 2.7 g/d DHA increased both LDL-C and HDL-C more than 2.7 g/d EPA did, 61 whereas DHA was modestly more effective in reducing triglycerides.61”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] 61. Grimsgaard S, Bonaa KH, Hansen JB, Nordøy A. Highly purified eicosapen- taenoic acid and docosahexaenoic acid in humans have similar triacylglyc- erol-lowering effects but divergent effects on serum fatty acids. Am J Clin Nutr. 1997;66:649-659. doi: 10.1093/ajcn/66.3.649 source

  • May combine two claims.

    Findingcitation

    In two older monotherapy studies of dietary supplements providing 3 and 4.5 g/d EPA+DHA, LDL-C increased by 7% to 8% while triglycerides decreased by 35% and 39%.

    “In 2 older monotherapy studies of dietary supplements (providing 3 and 4.5 g/d total EPA+DHA) that included at least 50 people per arm, a 7% to 8% increase in LDL-C was reported (only marginally significant for the lower dose; P=0.054); however, these studies reported a 35% and 39% reduction in triglycerides. 28,31”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] 28. Roth EM, Bays HE, Forker AD, Maki KC, Carter R, Doyle RT, Stein EA. Prescription omega-3 fatty acid as an adjunct to fenofibrate therapy in hypertriglyceridemic subjects. J Cardiovasc Pharmacol. 2009;54:196-203. doi: 10.1097/FJC.0b013e3181b0cf71 source
    • cites [31] 31. Durrington PN, Bhatnagar D, Mackness MI, Morgan J, Julier K, Khan MA, France M. An omega-3 polyunsaturated fatty acid concentrate adminis- tered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. Heart. 2001;85:544-548. doi: 10.1136/heart.85.5.544 source

  • May combine two claims.

    Findingcitation

    In REDUCE-IT, non-HDL-C was reduced by 12.2% and apo B by 9.7%.

    “Similarly, in REDUCE-IT, non-HDL-C was reduced by 12.2% (control, 8.2%; active -4.0%) and apo B was reduced by 9.7% (control, 7.8%; active, -2.5%).40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] 40. Ballantyne CM, Bays HE, Kastelein JJ, Stein E, Isaacsohn JL, Braeckman RA, Soni PN. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110:984-92. doi: 10.1016/j.amjcard.2012.05.031 source

  • May combine two claims.

    Findingcitation

    O3CA 2 g/d reduced triglycerides by 9% versus 15% with 4 g/d.

    “With regard to O3CA, the 2-g/d dose examined in the ESPRIT trial (Epanova Combined with a Statin in Patients with Hypertriglyceridemia to Reduce Non-HDL Cholesterol; ≈1.5 g/d EPA+DHA) reduced triglycerides by 9% versus 15% with 4 g/d.41”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] 41. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11-22. doi: 10.1056/NEJMoa1812792 source

  • May combine two claims.

    Findingcitation

    In a 2-week open-label crossover comparison, 4 g/d MAT9001 reduced plasma triglycerides by 33%, significantly more than the 11% reduction with 4 g/d IPE in people with hypertriglyceridemia.

    “In a 2-week open-label crossover comparison of 4 g/d MAT9001 (containing unspecified amounts of free docosapentaenoic acid and EPA) versus 4 g/d IPE in people with HTG, plasma triglycerides were reduced 33% by MAT9001, which was significantly more than the 11% reduction with IPE.64”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] 64. Maki KC, Keane WF, Bouhajib M, Pop R, Bobotas G. Pharmacokinetics of MAT9001, an omega-3 fatty acid medication, compared with eicos- apentaenoic acid ethyl esters in hypertriglyceridemic subjects. FASEB J. 2016;30(suppl):1198.7. Abstract. source

  • May combine two claims.

    Findingcitation

    O3CA lowered non-HDL-C by 6% and apo B by 2%.

    “O3CA lowered non-HDL-C by 6% and apo B by 2%, 41”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] 41. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11-22. doi: 10.1056/NEJMoa1812792 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    Use of n-3 FA may be accompanied by mild gastrointestinal complaints such as fishy burps or nausea.

    “Use of n-3 FA may be accompanied by mild gastrointestinal complaints (such as”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Product inserts suggest substantial differences in rates of gastrointestinal side effects relative to placebo: O3CA 27% versus 8%; O3AEE 3% to 4% versus less than 1% to 2%; and IPE less than 1% to 7% versus 4% to 7%.

    “the product inserts suggest substantial differences in the rates of gastrointestinal side effects for each agent relative to placebo: O3CA, 27% versus 8%; O3AEE, 3% to 4% versus <1% to 2%; and IPE, <1% to 7% versus 4% to 7% for active agent compared with placebo, respectively.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation

    Omega-3 fatty acids are highly purified oils and do not appear allergenic.

    “n-3 FAs are highly purified oils and do not appear to be allergenic.97”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] 97. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K; Japan EPA Lipid Intervention Study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open- label, blinded endpoint analysis. Lancet. 2007;369:1090-1098. doi: 10.1016/S0140-6736(07)60527-3 source

  • May combine two claims.

    Findingcitation

    Risk for each individual component of the primary composite end point was also significantly reduced, including a 20% reduction in cardiovascular death.

    “Risk for each of the individual components of the primary composite end point was also significantly reduced, including a 20% reduction in cardiovascular death.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] 40. Ballantyne CM, Bays HE, Kastelein JJ, Stein E, Isaacsohn JL, Braeckman RA, Soni PN. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110:984-92. doi: 10.1016/j.amjcard.2012.05.031 source

  • May combine two claims.

    Findingreasoning

    When 4 g/d EPA+DHA or EPA-only is added to statin therapy, non-HDL-C and apo B are modestly reduced, suggesting a reduction in total atherogenic lipoproteins.

    “studies of 4 g/d EPA+DHA or EPA-only as adjuncts to statin therapy, non-HDL-C and apo B were modestly decreased, suggesting reductions in total atherogenic lipoproteins.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Findingnone given

    Taking n-3 FA with meals may reduce gastrointestinal side effects and improve absorption of O3AEE and IPE.

    “but taking n-3 FA with meals may reduce gastrointestinal side effects and improve absorption of O3AEE and IPE.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    REDUCE-IT did not find an increase in hemoglobin A1c or new-onset diabetes mellitus.

    “REDUCE-IT did not find an increase in hemoglobin A 1c or in new-onset diabetes mellitus.40”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] 40. Ballantyne CM, Bays HE, Kastelein JJ, Stein E, Isaacsohn JL, Braeckman RA, Soni PN. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110:984-92. doi: 10.1016/j.amjcard.2012.05.031 source

  • May combine two claims.

    Findingnone given

    In clinical trials of prescription omega-3 fatty acid agents, tolerability issues were generally minor and led to drug discontinuation in only a small percentage of subjects, usually less than 5%.

    “In clinical trials of prescription n-3 FA agents, tolerability issues have generally been relatively minor (see sections titled Gastrointestinal, Bleeding, Fish/Seafood Allergies, and Glycemic Control) and resulted in drug discontinuation in only a small percentage of subjects (usually <5%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    In REDUCE-IT, lipid effects included a placebo-adjusted triglyceride reduction of 20%, non-HDL-C -12.2%, LDL-C -6.6%, apo B -9.7%, and HDL-C -7.2%.

    “Notably, lipid effects were consistent with earlier IPE trials, with a placebo-adjusted triglyceride reduction of 20% at assessments at 4 months to 3 years and changes in non-HDL-C of -12.2% (control, 8.2%; active, -4.0%), in LDL-C of -6.6% (control, 10.2%; active, 3.1%), in apo B of -9.7% (control, 7.8%; active, -2.5%), and in HDL-C of -7.2% (control, 4.7%; active, -2.8%).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] 40. Ballantyne CM, Bays HE, Kastelein JJ, Stein E, Isaacsohn JL, Braeckman RA, Soni PN. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110:984-92. doi: 10.1016/j.amjcard.2012.05.031 source

  • May combine two claims.

    Findingcitation

    REDUCE-IT reported a trend toward increased bleeding events (2.7% versus 2.1%; P=0.06) but no significant increase at any site and no fatal bleeding events.

    “Similarly, REDUCE-IT reported a trend toward an increase in bleeding events (2.7% vs 2.1%; P=0.06) but no significant increase for any site (gastrointestinal, central nervous system, or other), and there were no fatal bleeding events in the trial.40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] 40. Ballantyne CM, Bays HE, Kastelein JJ, Stein E, Isaacsohn JL, Braeckman RA, Soni PN. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110:984-92. doi: 10.1016/j.amjcard.2012.05.031 source

  • May combine two claims.

    Findingcitation

    In JELIS, there was a small but statistically significant increase in total hemorrhagic events (1.1% for EPA versus 0.6% for control; P=0.0006), with no significant increase for cerebral hemorrhage as a single outcome.

    “there was a small but statistically significant increase in total hemorrhagic events (cerebral, fundal, epistaxis, or subcutaneous; 1.1% for EPA versus 0.6% for control; P=0.0006), although no significant increase was reported for cerebral hemorrhage as a single hemorrhagic outcome.96”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] 96. Harris WS. Fish oils and bleeding: where is the evidence? JAMA Intern Med. 2016;176:1405-1406. doi: 10.1001/jamainternmed.2016.3968 source

  • May combine two claims.

    Premisecitation

    Neither IPE nor O3CA significantly changed HDL cholesterol.

    “In contrast, neither IPE 21 nor O3CA 22 significantly changed HDL-C.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] 21. Pownall HJ, Brauchi D, Kilinç C, Osmundsen K, Pao Q, Payton-Ross C, Gotto AM Jr, Ballantyne CM. Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of high-density and low-density lipopro- teins. Atherosclerosis. 1999;143:285-297. doi: https://doi.org/10.1016/ S0021-9150(98)00301-3 source
    • cites [22] 22. Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN. Eicosapentaenoic acid ethyl ester (AMR101) therapy in pa- tients with very high triglyceride levels (from the Multi-center, plAcebo- controlled, Randomized, double-blINd, 12-week study with an open- label Extension [MARINE] trial). Am J Cardiol. 2011;108:682-690. doi: 10.1016/j.amjcard.2011.04.015 source

  • May combine two claims.

    Premisecitation

    Fibrates lower triglycerides by 15% to 60%, with the degree of efficacy depending mainly on the baseline triglyceride level.

    “Fibrates, the most commonly used drug class (especially fenofibrate), lower triglycerides by 15% to 60%, with efficacy depending primarily on the baseline triglyceride level.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] 16. Herink M, Ito MK. Medication induced changes in lipid and lipopro- teins. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, eds. Endotext. South Dartmouth, MA: MDText. com, Inc; 2000. Accessed December 5, 2018.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Ezetimibe and proprotein convertase subtilisin kexin type 9 monoclonal antibodies have minimal to modest triglyceride-lowering effects and are not indicated for lowering triglycerides.

    “Ezetimibe and proprotein con-vertase subtilisin kexin type 9 monoclonal antibodies have minimal to modest effects and are not indicated for triglyceride lowering.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] 17. Robinson JG. Clinical Lipid Management. 1st ed. West Islip, NY: Profes- sional Communications, Inc; 2016.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [18] 18. Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Car- diol. 2007;99:22C-31C. doi: 10.1016/j.amjcard.2006.11.018 source

  • May combine two claims.

    Interpretationnone given

    For treating hypertriglyceridemia, n-3 fatty acids containing EPA+DHA or EPA-only do not raise LDL cholesterol when used alone or with a statin.

    “n-3 FAs with EPA+DHA or with EPA-only appear roughly comparable for triglyceride lowering and do not increase low-density lipoprotein cholesterol when used as monotherapy or in combination with a statin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Full-dose prescription n-3 fatty acids at 4 g/day appear to lower triglycerides similarly to fibrates, although direct comparisons in very high triglycerides are lacking.

    “The degree of triglyceride lowering with full-dose prescription n-3 FA (4 g/d providing >3 g/d EPA+DHA) appears to be similar to that of fibrates, although studies directly comparing these 2 drug classes in patients with VHTG are lacking.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In patients with very high triglycerides between 500 and 2000 mg/dL, IPE did not raise LDL cholesterol and apolipoprotein B decreased.

    “In patients with VHTG (triglycerides, 500-2000 mg/dL), treatment with IPE did not raise LDL-C, and apo B decreased, suggesting differing effects from those of EPA+DHA.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] 21. Pownall HJ, Brauchi D, Kilinç C, Osmundsen K, Pao Q, Payton-Ross C, Gotto AM Jr, Ballantyne CM. Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of high-density and low-density lipopro- teins. Atherosclerosis. 1999;143:285-297. doi: https://doi.org/10.1016/ S0021-9150(98)00301-3 source

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    The review of n-3 fatty acid effects in hypertriglyceridemia included studies with 4 g/day prescription n-3 fatty acids or equivalent EPA+DHA above 3 g/day, baseline triglycerides of 200 to 499 mg/dL, at least 20 people per arm, and a placebo control.

    “To evaluate and summarize the existing clinical evidence for n-3 FA effects on HTG, we identified and compared studies meeting the following criteria: administration of 4 g/d prescription n-3 FA or an equivalent amount of EPA+DHA from dietary supplements (>3 g/d EPA+DHA), mean/median baseline triglyceride values between 200 and 499 mg/dL, results reported from at least 20 people per study arm, and”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    The O3AEE studies in very high triglycerides used monotherapy without background statin, while the IPE and O3CA studies included statin users at rates of 25% and 33%.

    “The studies of O3AEE in VHTG were of monotherapy with no background statin use, whereas more recent studies of IPE and O3CA in VHTG included subjects taking statins (25% and 33% of the study population, respectively).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] 21. Pownall HJ, Brauchi D, Kilinç C, Osmundsen K, Pao Q, Payton-Ross C, Gotto AM Jr, Ballantyne CM. Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of high-density and low-density lipopro- teins. Atherosclerosis. 1999;143:285-297. doi: https://doi.org/10.1016/ S0021-9150(98)00301-3 source
    • cites [22] 22. Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN. Eicosapentaenoic acid ethyl ester (AMR101) therapy in pa- tients with very high triglyceride levels (from the Multi-center, plAcebo- controlled, Randomized, double-blINd, 12-week study with an open- label Extension [MARINE] trial). Am J Cardiol. 2011;108:682-690. doi: 10.1016/j.amjcard.2011.04.015 source

  • May combine two claims.

    Premisenone given

    High-intensity statins and niacin can have substantial triglyceride-lowering effects, and these effects are proportional to baseline triglycerides.

    “Highintensity statins and niacin also may have substantial triglyceride-lowering effects, which are proportional to baseline triglycerides.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In patients given 130 mg/day fenofibrate plus 4 g/day O3AEE, triglyceride lowering was 61%, only marginally better than the 54% reduction with fenofibrate alone.

    “In patients treated with a combination of 130 mg/d fenofibrate and 4 g/d O3AEE, triglyceride lowering of 61% was observed, which was only marginally better (P=0.06)than the 54% reduction achieved with fenofibrate alone.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] 27. Maki KC, McKenney JM, Reeves MS, Lubin BC, Dicklin MR. Effects of add- ing prescription omega-3 acid ethyl esters to simvastatin (20 mg/day) on lipids and lipoprotein particles in men and women with mixed dyslipidemia. Am J Cardiol. 2008;102:429-433. doi: 10.1016/j.amjcard.2008.03.078 source

  • May combine two claims.

    Interpretationreasoning

    Prescription n-3 fatty acids containing EPA+DHA or EPA-only at 4 g/day are an effective and safe option for lowering triglycerides when used alone or with other lipid-lowering drugs.

    “We conclude that prescription n-3 FAs (EPA+DHA or EPA-only) at a dose of 4 g/d (>3 g/d total EPA+DHA) are an effective and safe option for reducing triglycerides as monotherapy or as an adjunct to other lipid-lowering agents.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The effects of n-3 fatty acids on triglycerides and lipoproteins observed in the reviewed trials apply to the broader population of patients with elevated triglycerides.

  • May combine two claims.

    Premisecitation

    Relative to baseline, fenofibrate plus O3AEE increased LDL cholesterol by 52%, decreased non-HDL cholesterol by 7%, and left apolipoprotein B unchanged.

    “Relative to baseline, the combination of fenofibrate and O3AEE resulted in LDL-C increases of 52%, although non-HDL-C significantly decreased by 7% and apo B was unchanged.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] 27. Maki KC, McKenney JM, Reeves MS, Lubin BC, Dicklin MR. Effects of add- ing prescription omega-3 acid ethyl esters to simvastatin (20 mg/day) on lipids and lipoprotein particles in men and women with mixed dyslipidemia. Am J Cardiol. 2008;102:429-433. doi: 10.1016/j.amjcard.2008.03.078 source

  • May combine two claims.

    Premisecitation

    In a third study where all patients were on a stable statin dose before O3AEE, there was a 25% reduction in triglycerides and a marginally significant increase in LDL cholesterol relative to placebo, with a median 3.5% increase and P=0.052.

    “In a third study, in which all patients were on a stable dose of statin before beginning O3AEE treatment, there was a 25% reduction in triglycerides and a marginally significant increase in LDL-C relative to placebo (median, 3.5% increase; P=0.052).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] 31. Durrington PN, Bhatnagar D, Mackness MI, Morgan J, Julier K, Khan MA, France M. An omega-3 polyunsaturated fatty acid concentrate adminis- tered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. Heart. 2001;85:544-548. doi: 10.1136/heart.85.5.544 source

  • May combine two claims.

    Premisecitation

    In two O3AEE studies where O3AEE was combined with statin as part of the trial design, triglycerides were reduced by 17% to 19% beyond the statin effect, non-HDL cholesterol decreased by 5% to 7%, and LDL cholesterol was unchanged compared with statin-only control.

    “Of the 5 O3AEE studies, 2 administered O3AEE in combination with statin therapy as part of the trial design, 26,32 and triglycerides were reduced 17% to 19% beyond the reduction achieved by statins, non-HDL-C was decreased 5% to 7%, and LDL-C was unchanged versus the statin-only control.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] 26. Maki KC, Bays HE, Dicklin MR, Johnson SL, Shabbout M. Effects of prescription omega-3-acid ethyl esters, coadministered with atorv- astatin, on circulating levels of lipoprotein particles, apolipoprotein CIII, and lipoprotein-associated phospholipase A2 mass in men and women with mixed dyslipidemia. J Clin Lipidol. 2011;5:483-492. doi: 10.1016/j.jacl.2011.09.001 source
    • cites [32] 32. Davidson MH, Stein EA, Bays HE, Maki KC, Doyle RT, Shalwitz RA, Ballantyne CM, Ginsberg HN; COMBination of prescription Omega-3 with Simvastatin (COMBOS) Investigators. Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double- blind, placebo-controlled study. Clin Ther. 2007;29:1354-1367. doi: 10.1016/j.clinthera.2007.07.018 source

  • May combine two claims.

    Interpretationreasoning

    Purified DHA may modestly increase LDL-C and HDL-C more than purified EPA but may also lower triglycerides more than EPA.

    “These data suggest that purified DHA may modestly increase LDL-C and HDL-C more than purified EPA but may also lower triglycerides more than EPA.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The unusual placebo effect on LDL-C in the two IPE trials and the lack of direct comparisons prevent firm conclusions about the comparative effects of the three agents on triglycerides, LDL-C, and other lipids.

    “The unusual placebo effect on LDL-C in the 2 IPE trials and the lack of trials directly comparing the 3 prescription n-3 FA agents prevent the drawing of any firm conclusions about the comparative effects of these agents on triglycerides, LDL-C, and other lipids and lipoproteins.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In hypertriglyceridemia (triglycerides 200-499 mg/dL), 4 g/d prescription omega-3 fatty acids effectively lower triglycerides by about 20% to 30% and do not significantly increase LDL-C.

    “In the context of HTG (triglycerides, 200-499 mg/dL), 4 g/d prescription n-3 FA effectively lowers triglycerides by ≈20% to 30% and does not significantly increase LDL-C.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    On the basis of available data, all prescription omega-3 fatty acid agents appear comparably effective, but head-to-head comparisons are lacking.

    “On the basis of available data, all prescription agents appear comparably effective, but head-to-head comparisons are lacking”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Prescription omega-3 fatty acids at 4 g/d consistently produced significant reductions in triglyceride levels in patients with hypertriglyceridemia or very high triglycerides, with a greater effect in very high triglycerides than in hypertriglyceridemia.

    “Prescription n-3 FA at a dose of 4 g/d has consistently produced significant reductions in triglyceride levels in patients with HTG or VHTG, and this effect is greater in patients with VHTG than in those with HTG (as for triglyceride-lowering agents in general).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    All forms of omega-3 fatty acid products have relatively benign side-effect profiles and are generally safe, though safety evidence for FDA-approved prescription agents comes primarily from short-term randomized trials.

    “All forms of n-3 FA products have relatively benign side-effect profiles and are generally safe; however, the evidence for safety of FDA-approved prescription n-3 FA agents comes primarily from short-term randomized clinical trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Prescription omega-3 fatty acids at 2 g/d provided roughly half the triglyceride-lowering efficacy of 4 g/d, with the 2 g/d dose in some cases not differing significantly from placebo.

    “Prescription n-3 FAs at doses of 2 g/d provided roughly one-half the triglyceride-lowering efficacy of 4 g/d, the former in some cases not differing significantly from placebo.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The National Lipid Association and International Atherosclerosis Society have recommended non-HDL-C over LDL-C for patients with HTG or VHTG.

    “Such an approach has been recommended by the National Lipid Association 10 and International Atherosclerosis Society 117 for patients with HTG or VHTG.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] 10. Ewald N, Hardt PD, Kloer HU. Severe hypertriglyceridemia and pancreati- tis: presentation and management. Curr Opin Lipidol. 2009;20:497-504. doi: 10.1097/MOL.0b013e3283319a1d source
    • cites [117] 117. Expert Panel on Dyslipidemia. An International Atherosclerosis So- ciety position paper: global recommendations for the manage- ment of dyslipidemia. Atherosclerosis. 2014;232:410-413. doi: 10.1016/j.atherosclerosis.2013.11.031 source

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Because of problems with typical measurement and interpretation of LDL-C levels in clinical care, non-HDL-C is preferred over LDL-C as a parameter of atherogenic lipids to guide therapy in patients with HTG and VHTG.

    “Because of the problems with typical measurement and interpretation of LDL-C levels in clinical care, non-HDL-C is preferred over LDL-C as a parameter of atherogenic lipids to guide therapy in patients with HTG and VHTG.”
    Quote in the paperSubstantial claim
60 of 60

  • The paper relies on this without support.

    The reviewed trials are sufficiently comparable that their results can be combined or compared to summarize the effects of prescription n-3 fatty acids in hypertriglyceridemia and very high triglycerides.

    “To evaluate and summarize the existing clinical evidence for n-3 FA effects on HTG, we identified and compared studies meeting the following criteria: administration of 4 g/d prescription n-3 FA or an equivalent amount of EPA+DHA from dietary supplements (>3 g/d EPA+DHA), mean/median baseline triglyceride values between 200 and 499 mg/dL, results reported from at least 20 people per study arm, and”

  • The paper relies on this without support.

    The effects of n-3 fatty acids on triglycerides and lipoproteins observed in the reviewed trials apply to the broader population of patients with elevated triglycerides.

    “We conclude that prescription n-3 FAs (EPA+DHA or EPA-only) at a dose of 4 g/d (>3 g/d total EPA+DHA) are an effective and safe option for reducing triglycerides as monotherapy or as an adjunct to other lipid-lowering agents.”

  • The paper relies on this without support.

    The REDUCE-IT result with EPA-only can support the use of n-3 fatty acids generally for improving atherosclerotic cardiovascular disease risk in patients with hypertriglyceridemia.

    “The use of n-3 FA (4 g/d) for improving atherosclerotic cardiovascular disease risk in patients with hypertriglyceridemia is supported by a 25% reduction in major adverse cardiovascular events in REDUCE-IT (Reduction of Cardiovascular Events With EPA Intervention Trial), a randomized placebo-controlled trial of EPA-only in high-risk patients treated with a statin.”

  • The paper relies on this without support.

    The lipid effects reported across different trials can be compared despite differences in populations, background therapies, and assay methods.

    “However, a descriptive comparison of the triglyceride and LDL-C effects in major studies of the 3 n-3 FA agents in patients with HTG is shown in the Figure.31,[39][40][41]”

  • The paper relies on this without support.

    No FDA-regulated n-3 FA preparations are available without a prescription.

    “there are no over-the-counter n-3 FA products; that is, no FDA-regulated n-3 FA preparations are available without a prescription.”

  • The paper relies on this without support.

    The potency, quality, and efficacy of dietary supplements are not initially reviewed or approved, nor subsequently monitored or assured by the FDA, so they are not indicated for the treatment of disease.

    “The potency, quality, and efficacy of dietary supplements are not initially reviewed or approved, nor are they subsequently monitored or assured by the FDA; thus, they are not indicated for the treatment of disease.”

  • The paper relies on this without support.

    Prescription n-3 FA agents are reviewed, approved, monitored, and assured by the FDA.

    “Prescription n-3 FA agents, in contrast, are reviewed, approved, monitored, and assured by the FDA.”

  • The paper relies on this without support.

    Dietary supplement omega-3 preparations are considerably less expensive per 1 g EPA+DHA than pharmaceutical products.

    “Dietary supplement omega-3 preparations are considerably less expensive (per 1 g EPA+DHA) than pharmaceutical products”

  • The paper relies on this without support.

    Many n-3 FA dietary supplements meet all their label claims and do not contain oxidation products or environmental contaminants.

    “Although many n-3 FA dietary supplements meet all their label claims and do not contain oxidation products or environmental contaminants”

  • The paper relies on this without support.

    Dietary supplement n-3 FA products are not indicated for the treatment of HTG or VHTG because they are not approved by the FDA for this purpose.

    “these products are not indicated for the treatment of HTG or VHTG because they are not approved by the FDA for this purpose.”

  • The authors state this as an assumption.

    The Friedewald equation assumes a constant triglycerides/cholesterol ratio of 5 in VLDL regardless of plasma triglyceride concentration.

    “The Friedewald equation assumes a constant triglycerides/cholesterol ratio of 5 in VLDL, regardless of the plasma triglyceride concentration.”

  • The paper relies on this without support.

    As total plasma triglyceride increases, the triglycerides carried by VLDL increase disproportionately to its cholesterol content.

    “As total plasma triglyceride increases, the triglycerides carried by VLDL increase disproportionately to its cholesterol content.”

  • The paper relies on this without support.

    Patients with HTG may have delayed postprandial clearance of chylomicrons.

    “because patients with HTG (in addition to VHTG) may have delayed postprandial clearance of chylomicrons”

  • The paper relies on this without support.

    No published data directly compare fasting and nonfasting triglycerides in the same patients.

    “no published data directly compare fasting and nonfasting triglycerides in the same patients”

  • The paper relies on this without support.

    Standard reference ranges do not currently exist for nonfasting triglyceride values.

    “standard reference ranges do not currently exist for nonfasting triglyceride values”
15 of 15

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?

  • The STRENGTH trial was terminated for futility, and its data remain unpublished.

    “The latter study was terminated for futility, and so far, data remain unpublished and thus difficult to speculate on.”

    From Effects of n-3 Fatty Acid Supplements in Elderly Patients After Myocardial Infarction (2021) · cites this paper as [36]

    In the cardiovascular outcome trials section (p. e673), the advisory describes STRENGTH as ongoing and says results were expected in 2020. It does not report termination for futility; its expectation of future results is consistent with results not yet being published at the time. (LLM, conf=0.90)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • The American Heart Association scientific statements currently recommend n-3 PUFA supplements for secondary prevention of coronary heart disease and in management of hypertriglyceridemia.

    “The American Heart Association scientific statements currently recommend n-3 PUFA supplements for secondary prevention of coronary heart disease 15 and in management of hypertriglyceridemia 16 .”

    From Effects of n-3 Fatty Acid Supplements in Elderly Patients After Myocardial Infarction (2021) · cites this paper as [16]

    The advisory concludes that prescription n-3 fatty acids at 4 g/day are useful for managing hypertriglyceridemia (Clinical Statements and Guidelines, p. e673). It distinguishes those prescription agents from dietary supplements: the latter were recommended in an earlier AHA statement, so the claim is too broad if “supplements” includes nonprescription products. Citation 16 is attached to hypertriglyceridemia, not the separate secondary-prevention claim. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • The lack of effects on ALT, HDL, and LDL may reflect the selective action of omega-3 fatty acids, whose lipid-lowering effects primarily target the triglyceride metabolic pathway while exerting weaker direct effects on cholesterol reverse transport and synthesis.

    “The lack of effects on ALT, HDL, and LDL may reflect the selective action of omega-3 fatty acids. Their lipid-lowering effects primarily target the triglyceride metabolic pathway, including promoting fatty acid oxidation and reducing lipogenesis by activating PPAR-α and inhibiting SREBP-1c,42,43 while exerting weaker direct effects on cholesterol reverse transport and synthesis.44,45”

    From The Impact of Omega-3 Fatty Acids on Triglyceride Levels in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease: A Meta-Analysis of Randomized Controlled Trials with Subgroup Analysis by Diabetes Status (2026) · cites this paper as [42]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • The magnitude of the absolute effect is a function of both baseline risk and efficacy of therapy.

    “Because the magnitude of the absolute effect is a function of both baseline risk and ef fi cacy of therapy, patients with higher baseline cardiovascular risk and those receiving higher doses of omega-3 FAs may demonstrate incremental absolute event reductions [12,13,18].”

    From Effect of omega-3 fatty acids on cardiovascular outcomes: A systematic review and meta-analysis (2021) · cites this paper as [18]

    The 'Cardiovascular Outcome Trials of n-3 FA in Statin-Treated Individuals With HTG' section reports cardiovascular event reduction with treatment and a greater relative reduction in one baseline-lipid subgroup. It does not state that the magnitude of absolute event reduction depends on both baseline cardiovascular risk and treatment efficacy, or establish the proposed effect of higher omega-3 doses on absolute event reductions. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Patients with higher baseline cardiovascular risk and those receiving higher doses of omega-3 fatty acids may demonstrate incremental absolute event reductions.

    “Because the magnitude of the absolute effect is a function of both baseline risk and ef fi cacy of therapy, patients with higher baseline cardiovascular risk and those receiving higher doses of omega-3 FAs may demonstrate incremental absolute event reductions [12,13,18].”

    From Effect of omega-3 fatty acids on cardiovascular outcomes: A systematic review and meta-analysis (2021) · cites this paper as [18]

    In “Cardiovascular Outcome Trials of N-3 FA in Statin-Treated Individuals With HTG” (page not specified), the advisory reports fewer cardiovascular events with 4 g/day of icosapent ethyl and suggests that patients with high triglycerides and low HDL-C may benefit most. It does not report absolute event reductions by baseline cardiovascular risk or establish that higher omega-3 doses produce incrementally greater event reductions. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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.

  • A purported monotherapy trial included statin users

    Minor

    The description of six trials says participants took no other lipid-lowering medication and includes the medical-food study. Table 4 reports that 20% of participants in the Shaikh medical-food study took a statin.

  • A 4-g Epanova dose does not provide more than 3 g EPA+DHA

    Minor

    The dosing statement applies the greater-than-3-g EPA+DHA description to prescription agents regardless of type. The product details give exactly 3 g EPA+DHA for a 4-g Epanova dose.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Robinson, JG. Clinical Lipid Management. 1st ed. West Islip, NY: Professional Communications, Inc; 2016.

Cited by

Sorted by citations

Related

Authors
Skulas-Ray, A. C., Wilson, P. W. F., Harris, W. S., Brinton, E. A., Kris-Etherton, P. M., Richter, C. K., Jacobson, T. A., Engler, M. B., Miller, M., Robinson, J. G., Blum, C. B., Rodriguez-Leyva, D., de Ferranti, S. D., Welty, F. K., & On behalf of the American Heart Association Council on Arteriosclerosis, T. A. V. B. C. O. L. A. C. H. C. O. C. D. I. T. Y. C. O. C. A. S. N. A. C. O. C. C.
Affiliations
Uniformed Services University of the Health Sciences (US)
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2019-09-17
Volume
140
Issue
12
Pages
e673-e691
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/cir.0000000000000709
OpenAlex
W2969523838
Semantic Scholar
ac70ecb78df51c94dbc3f1040f152c15e0b86612
Cited by
488
References
120
Citations by year
2026: 46 · 2025: 58 · 2024: 57 · 2023: 89 · 2022: 68 · 2021: 64 · 2020: 86 · 2019: 11 · 2018: 1
FWCI
31.94
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
omega-3 fatty acids, hypertriglyceridemia, eicosapentaenoic acid, docosahexaenoic acid, triglyceride lowering, LDL cholesterol, non-HDL cholesterol, apolipoprotein B
MeSH terms
American Heart Association, Cardiovascular Diseases, Clinical Trials as Topic, Humans, Risk, Triglycerides, United States, Hypertriglyceridemia

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-30.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-30.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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