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

In the paper

“IPE lowered non-HDL-C by 14% (control, 9.8%; active, -5.5%) and apo B by 9% (control, 7%; active, -2.2%).36”

What the sources say

• Disputed

  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.

  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 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Disputed

  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.

  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 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• Disputed

  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.

  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. sourceExperimental — accuracy not yet measured

In the paper

“The 2011 statement cited epidemiological evidence that a moderate elevation in triglycerides is often associated with increased atherosclerotic cardiovascular disease (ASCVD) risk.”

What the sources say

• Supported

  Section 3.3 (page not available in our copy) reports epidemiological meta-analyses linking higher triglyceride levels with higher CVD risk. The “Elevated Triglyceride Levels” section also describes an association between elevated triglycerides and increased CVD risk. The claim describes an association, not an independent or causal effect. (LLM, conf=0.90)

  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

In the paper

“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.”

What the sources say

• ?Could not verify

  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)

  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] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The paper’s “A High” recommendation identifies moderate- to high-intensity statins as first-line cholesterol-lowering drug therapy. In the citing sentence, the citation follows the statin-treatment premise; the subsequent assertion about the absence of IPE or O3CA monotherapy studies is not attributed to this source. (LLM, conf=0.88)

  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

In the paper

“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.”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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%.”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“In this trial, DHA increased LDL-C, LDL particle size, and HDL2, but EPA did not.62”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“This trial also reported an inverse relationship between triglyceride values and LDL particle size, whereas HDL-C was positively correlated with LDL particle size.”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Could not verify

  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)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Could not verify

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be 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
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not matched

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

  cites [81] 81. Lovaza (omega-3-acid ethyl esters) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2009.
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Supported

  Citation 108 is attached to “but not all” supplements, not to the later claim about effects on benefits. The Results (section 3.2) report that all 10 tested products met the recommended peroxide-value level; the two elevated anisidine readings were attributed to flavorings that interfere with that test. (LLM, conf=0.94)

  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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“Only 2 trials presented in Table 4 specified avoiding alcohol for at least 48 hours before testing.29,33”

What the sources say

• ?Not checked — no full text of the sourcecites [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.
• ?Could not verify

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“O3CA lowered non-HDL-C by 6% and apo B by 2%, 41”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“Use of n-3 FA may be accompanied by mild gastrointestinal complaints (such as”

In the paper

“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.”

In the paper

“n-3 FAs are highly purified oils and do not appear to be allergenic.97”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“but taking n-3 FA with meals may reduce gastrointestinal side effects and improve absorption of O3AEE and IPE.”

In the paper

“REDUCE-IT did not find an increase in hemoglobin A 1c or in new-onset diabetes mellitus.40”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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%).”

In the paper

“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%).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“In contrast, neither IPE 21 nor O3CA 22 significantly changed HDL-C.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“Fibrates, the most commonly used drug class (especially fenofibrate), lower triglycerides by 15% to 60%, with efficacy depending primarily on the baseline triglyceride level.”

What the sources say

• ?Not matched

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

In the paper

“Ezetimibe and proprotein con-vertase subtilisin kexin type 9 monoclonal antibodies have minimal to modest effects and are not indicated for triglyceride lowering.”

What the sources say

• ?Not matched

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

  cites [17] 17. Robinson JG. Clinical Lipid Management. 1st ed. West Islip, NY: Profes- sional Communications, Inc; 2016.
• ?Not checked — no full text of the sourcecites [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

In the paper

“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 paper

“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.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“Highintensity statins and niacin also may have substantial triglyceride-lowering effects, which are proportional to baseline triglycerides.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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).”

In the paper

“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.”

In the paper

“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.”

In the paper

“Such an approach has been recommended by the National Lipid Association 10 and International Atherosclerosis Society 117 for patients with HTG or VHTG.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”