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Chapter 89: Effects of Omega-3 Fatty Acids on Lipids and Glycemic Control in Type II Diabetes and the Metabolic Syndrome and on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis

A131668

Prepared for:

Agency for Healthcare Research and Quality

U.S. Department of Health and Human Services

540 Gaither Road

Rockville, MD 20850

www.ahrq.gov

Contract No. 290-02-0003

Prepared by:

Southern California/RAND Evidence-based Practice Center, Los Angeles, CA

Program Directors

Paul G. Shekelle, MD, PhD

Sally C. Morton, PhD

Project Director

Catherine H. MacLean, MD, PhD

Project Manager

Rena Hasenfeld Garland, BA

Statistician

Wenli Tu, MS

Programmer/Analyst

Lara K. Jungvig, BA

Scientific Reviewers

Walter A. Mojica, MD, MPH

James Pencharz, BSc (Kin)

Jennifer Grossman, MD

Puja Khanna, MD, MPH

Editor

Sydne J. Newberry, PhD

Technical Advisors

Ian Gralnek, MD, mshs

Alan Nissenson, MD

Librarians

Jessie McGowan, MLIS

Nancy Santesso, RD, MLIS

Staff Assistants

Donna Mead, BA

Shannon Rhodes, MFA

Shana Traina, MA

AHRQ Publication No. 04-E012-2

March 2004

ISBN: 1-58763-141-5

ISSN: 1530-4396

This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders.

This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

AHRQ is the lead Federal agency charged with supporting research designed to improve the quality of health care, reduce its cost, address patient safety and medical errors, and broaden access to essential services. AHRQ sponsors and conducts research that provides evidence-based information on health care outcomes; quality; and cost, use, and access. The information helps health care decisionmakers—patients and clinicians, health system leaders, and policymakers—make more informed decisions and improve the quality of health care services.

Suggested Citation:

MacLean CH, Mojica, WA, Morton SC, Pencharz J, Hasenfeld Garland R, Tu W, Newberry SJ, Jungvig LK, Grossman J, Khanna P, Rhodes S, Shekelle P. Effects of Omega-3 Fatty Acids on Lipids and Glycemic Control in Type II Diabetes and the Metabolic Syndrome and on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis. Evidence Report/Technology Assessment. No. 89 (Prepared by Southern California/RAND Evidence-based Practice Center, under Contract No. 290-02-0003). AHRQ Publication No. 04-E012-2. Rockville, MD: Agency for Healthcare Research and Quality. March 2004.

Prepared for:

Agency for Healthcare Research and Quality

U.S. Department of Health and Human Services

540 Gaither Road

Rockville, MD 20850

www.ahrq.gov

Contract No. 290-02-0003

Prepared by:

Southern California/RAND Evidence-based Practice Center, Los Angeles, CA

Program Directors

Paul G. Shekelle, MD, PhD

Sally C. Morton, PhD

Project Director

Catherine H. MacLean, MD, PhD

Project Manager

Rena Hasenfeld Garland, BA

Statistician

Wenli Tu, MS

Programmer/Analyst

Lara K. Jungvig, BA

Scientific Reviewers

Walter A. Mojica, MD, MPH

James Pencharz, BSc (Kin)

Jennifer Grossman, MD

Puja Khanna, MD, MPH

Editor

Sydne J. Newberry, PhD

Technical Advisors

Ian Gralnek, MD, mshs

Alan Nissenson, MD

Librarians

Jessie McGowan, MLIS

Nancy Santesso, RD, MLIS

Staff Assistants

Donna Mead, BA

Shannon Rhodes, MFA

Shana Traina, MA

AHRQ Publication No. 04-E012-2

March 2004

ISBN: 1-58763-141-5

ISSN: 1530-4396

Suggested Citation:

Preface

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. This report on Effects of Omega-3 Fatty Acids on Lipids and Glycemic Control in Type II Diabetes and the Metabolic Syndrome and on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis was requested and funded by the Office of Dietary Supplements, National Institutes of Health, through the EPC Program at the Agency for Healthcare Research and Quality. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.

To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.

AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.

We welcome written comments on this evidence report. They may be sent to: Director, Center for Outcomes and Evidence, Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD 20850.

Carolyn M. Clancy, M.D.

Director

Agency for Healthcare Research and Quality

Paul Coates, Ph.D.

Director, Office of Dietary Supplements

National Institutes of Health

Jean Slutsky, P.A., M.S.P.H.

Acting Director, Center for Outcomes and Evidence

Agency for Healthcare Research and Quality

The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service.

Acknowledgments

We thank Herbert D. Woolf, PhD, of BASF Corporation for providing us with unpublished data on omega-3 fatty acids. We thank Antonio LaCava, MD, PhD for providing translation of Italian studies, Takahiro Higashi, MD for providing translation of Japanese studies, Markus Rihl, MD for providing translation of German studies, and Anna Maria Björnsdotter, BA, for providing translation of Swedish studies.

Chapter 1 was written in collaboration with the Tufts-New England Medical Center Evidence-based Practice Center.

Structured Abstract

Context: Clinical trials report differing effects of omega-3 fatty acids on lipids and glycemic control in type II diabetes and the metabolic syndrome and on inflammatory bowel disease (IBD), rheumatic arthritis, renal disease, systemic lupus erythemosus (SLE), and osteoporosis.

Objectives: To assess the effect of omega-3 fatty acids on 1) total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and insulin resistance in type-II diabetes and the metabolic syndrome, 2) clinical score, sigmoidoscopic score, histologic score and requirement for immunosuppressive therapy in IBD, 3) pain, swollen and tender joint counts, acute phase reactants, patient global assessment, and requirement for anti-inflammatory or immunosuppressive therapy in rheumatoid arthritis, 4) renal function, progression to end-stage renal disease, hemodialysis graft patency, mortality, and requirement for immunosuppressive therapy in renal disease, 5) disease activity, damage, patient's perception of disease activity, and requirement for immunosuppressive therapy in SLE, and 6) bone mineral density and fracture rates.

Data Sources: We searched on-line databases to identify potentially relevant studies and contacted industry experts for unpublished data.

Study Selection: We screened 4,212 titles, reviewed 1,097 articles, and included 83 articles. We restricted to randomized controlled trials (RCTs), but included case-control and cohort studies for bone/fracture. We had no language restrictions.

Data Extraction: We abstracted data on study design, study population, and outcomes; source, amount, and duration of omega-3 fatty acid consumption; and randomization, dropouts, blinding, and allocation for RCTs.

Data Synthesis: We performed meta-analyses for diabetes, rheumatoid arthritis, and IBD; and qualitative analyses for the other conditions.

For diabetes, omega-3 fatty acids had a favorable effect on triglyceride levels but no significant effect on total cholesterol, HDL cholesterol, LDL cholesterol, fasting blood sugar, or glycosylated hemoglobin. There was no effect on plasma insulin or insulin resistance in type II diabetics or the metabolic syndrome.

For IBD, omega-3 fatty acids had variable effects on clinical score, sigmoidoscopic score, histologic score, induced remission, and relapse, and no effect on the relative risk of relapse in ulcerative colitis. There was a statistically non-significant reduction in requirement for corticosteroids. No studies evaluated requirement for other immunosuppressive agents.

For rheumatoid arthritis, omega-3 fatty acids had no effect on patient report of pain, swollen joint count, Erythrocyte Sedimentation Rate, and patient's global assessment. There was no effect on joint damage, contrary to a previous meta-analysis. There was a reduced requirement for anti-inflammatory drugs or corticosteroids. No studies assessed requirements for disease modifying antirheumatic drugs.

For renal disease, omega-3 fatty acids had varying effects on serum creatinine and creatinine clearance. Single studies respectively demonstrated reduced progression to end-stage renal disease and improvements on hemodialysis graft patencyrelative. No studies assessed requirements for corticosteroids or other immunosuppressive drugs.

For SLE, omega-3 fatty acids had variable effects on clinical activity. No studies assessed the effect on end organ damage, patient perception of disease, or requirements for other immunosuppressive drugs. One study showed no effect on corticosteroid requirements.

For bone mineral density, the effect of omega-3 fatty acids was variable. No studies assessed the effect on fracture.

Conclusions: The evidence for effects of omega-3 fatty acids on outcomes in the conditions assessed varies greatly. Omega-3 fatty acids appear to reduce serum triglycerides among type II diabetics, but have no effect on total cholesterol, HDL cholesterol, and LDL cholesterol. There appears to be no effect on most clinical outcomes in rheumatoid arthritis, although tender joint count may be reduced. There are insufficient data to draw conclusions about IBD, renal disease, SLE, bone density or fractures, requirement for anti-inflammatory or immunosuppressive drugs, or insulin resistance among type II diabetics.

Chapter 1. Introduction

This report is one of a group of evidence reports prepared by three Agency for Healthcare Research and Quality (AHRQ)-funded Evidence-Based Practice Centers (EPCs) on the role of omega-3 fatty acids (both from food sources and from dietary supplements) in the prevention or treatment of a variety of diseases. These reports were requested and funded by the Office of Dietary Supplements, National Institutes of Health. The three EPCs – the Southern California EPC (SCEPC, based at RAND), the Tufts-New England Medical Center (NEMC) EPC, and the University of Ottawa EPC – have each produced evidence reports. To ensure consistency of approach, the three EPCs collaborated on selected methodological elements, including literature search strategies, rating of evidence, and data table design.

The aim of these reports is to summarize the current evidence on the effects of omega-3 fatty acids on prevention and treatment of cardiovascular diseases, cancer, child and maternal health, eye health, gastrointestinal/renal diseases, asthma, immune-mediated diseases, tissue/organ transplantation, mental health, and neurological diseases and conditions. In addition to informing the research community and the public on the effects of omega-3 fatty acids on various health conditions, it is anticipated that the findings of the reports will also be used to help define the agenda for future research.

This report focuses on the effects of omega-3 fatty acids on immune-mediated diseases, bone metabolism, and gastrointestinal/renal diseases. Subsequent reports from the SCEPC will focus on cancer and neurological diseases and conditions.

This chapter provides a brief review of the current state of knowledge about the metabolism, physiological functions, and sources of omega-3 fatty acids.

The Recognition of Essential Fatty Acids

Dietary fat has long been recognized as an important source of energy for mammals, but in the late 1920s, researchers demonstrated the dietary requirement for particular fatty acids, which came to be called essential fatty acids. It was not until the advent of intravenous feeding, however, that the importance of essential fatty acids was widely accepted: Clinical signs of essential fatty acid deficiency are generally observed only in patients on total parenteral nutrition who received mixtures devoid of essential fatty acids or in those with malabsorption syndromes. These signs include dermatitis and changes in visual and neural function. Over the past 40 years, an increasing number of physiological functions, such as immunomodulation, have been attributed to the essential fatty acids and their metabolites, and this area of research remains quite active.^1, ²

Fatty Acid Nomenclature

The fat found in foods consists largely of a heterogeneous mixture of triacylglycerols (triglycerides)--glycerol molecules that are each combined with three fatty acids. The fatty acids can be divided into two categories, based on chemical properties: saturated fatty acids, which are usually solid at room temperature, and unsaturated fatty acids, which are liquid at room temperature. The term “saturation” refers to a chemical structure in which each carbon atom in the fatty acyl chain is bound to (saturated with) four other atoms, these carbons are linked by single bonds, and no other atoms or molecules can attach; unsaturated fatty acids contain at least one pair of carbon atoms linked by a double bond, which allows the attachment of additional atoms to those carbons (resulting in saturation). Despite their differences in structure, all fats contain approximately the same amount of energy (37 kilojoules/gram, or 9 kilocalories/gram).

Note: Appendixes and Evidence Tables are provided electronically at

http://www.ahrq.gov/clinic/epcindex.htm

The class of unsaturated fatty acids can be further divided into monounsaturated and polyunsaturated fatty acids. Monounsaturated fatty acids (the primary constituents of olive and canola oils) contain only one double bond. Polyunsaturated fatty acids (PUFAs) (the primary constituents of corn, sunflower, flax seed and many other vegetable oils) contain more than one double bond. Fatty acids are often referred to using the number of carbon atoms in the acyl chain, followed by a colon, followed by the number of double bonds in the chain (e.g., 18:1 refers to the 18-carbon monounsaturated fatty acid, oleic acid; 18:3 refers to any 18-carbon PUFA with three double bonds).

Table 1.1 Nomenclature of omega-3 fatty acids

Names		Abbreviations
Trivial	IUPAC*	Carboxyl-reference	Omega-reference	Other
Linolenic acid	9,12,15-octadecenoic acid	18:3Δ^{9 12 15}	18:3n-3	ALA
			18:3 (ω-3)	α-LA
				LNA
				α-LNA

Docosahexaenoic acid	4,8,12,15,19- docosahexaenoic acid	22:6Δ^{4 8 12 15 19}	22:6n-3	DHA
			22:6 (ω-3)

Docosapentaenoic acid	7,10,13,16,19- docosapentaenoic acid	22:5Δ^{7 10 13 16 19}	22:5n-3	DPA
			22:5 (ω-3)

Eicosapentaenoic acid	5,8,11,14,17- eicosapentaenoic acid	20:5Δ^{5 8 11 14 17}	20:5n-3	EPA
Icosapentaenoic acid			20:5 (ω-3)
Timnodonic acid

IUPAC=International Union of Pure and Applied Chemistry

PUFAs are further categorized on the basis of the location of their double bonds. An omega or n notation indicates the number of carbon atoms from the methyl end of the acyl chain to the first double bond. Thus, for example, in the omega-3 (n-3) family of PUFAs, the first double bond is 3 carbons from the methyl end of the molecule. The trivial names, chemical names and abbreviations for the omega-3 fatty acids are detailed in Table 1.1.

Finally, PUFAs can be categorized according to their chain length. The 18-carbon n-3 and n-6 short-chain PUFAs are precursors to the longer 20- and 22-carbon PUFAs, called long-chain PUFAs (LCPUFAs).

Fatty Acid Metabolism

Mammalian cells can introduce double bonds into all positions on the fatty acid chain except the n-3 and n-6 position. Thus, the short-chain alpha-linolenic acid (ALA, chemical abbreviation: 18:3n-3) and linoleic acid (LA, chemical abbreviation: 18:2n-6) are essential fatty acids. No other fatty acids found in food are considered ‘essential’ for humans, because they can all be synthesized from the short chain fatty acids.

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Figure 1.1 Classical omega-3 and omega-6 fatty acid (more...)

Figure 1.1 Classical omega-3 and omega-6 fatty acid synthesis pathways and the role of omega-3 fatty acid in regulating health/disease markers

Following ingestion, ALA and LA can be converted in the liver to the long chain, more-unsaturated n-3 and n-6 LCPUFAs by a complex set of synthetic pathways that share several enzymes (Figure 1

). LC PUFAs retain the original sites of desaturation (including n-3 or n-6).

The omega-6 fatty acid LA is converted to gamma-linolenic acid (GLA, 18:3n-6), an omega-6 fatty acid that is a positional isomer of ALA. GLA, in turn, can be converted to the longer-chain omega-6 fatty acid, arachidonic acid (AA, 20:4n-6). AA is the precursor for certain classes of an important family of hormone-like substances called the eicosanoids (see below).

The omega-3 fatty acid ALA (18:3n-3) can be converted to the long-chain omega-3 fatty acid, eicosapentaenoic acid (EPA; 20:5n-3). EPA can be elongated to docosapentaenoic acid (DPA 22:5n-3), which is further desaturated to docosahexaenoic acid (DHA; 22:6n-3). EPA and DHA are also precursors of several classes of eicosanoids and are known to play several other critical roles, some of which are discussed further below.

The conversion from parent fatty acids into the LC PUFAs - EPA, DHA, and AA - appears to occur slowly in humans. In addition, the regulation of conversion is not well understood, although it is known that ALA and LA compete for entry into the metabolic pathways.

Physiological Functions of EPA and AA

As stated earlier, fatty acids play a variety of physiological roles. The specific biological functions of a fatty acid are determined by the number and position of double bonds and the length of the acyl chain.

Both EPA (20:5n-3) and AA (20:4n-6) are precursors for the formation of a family of hormone-like agents called eicosanoids. Eicosanoids are rudimentary hormones or regulating -molecules that appear to occur in most forms of life. However, unlike endocrine hormones, which travel in the blood stream to exert their effects at distant sites, the eicosanoids are autocrine or paracrine factors, which exert their effects locally – in the cells that synthesize them or adjacent cells. Processes affected include the movement of calcium and other substances into and out of cells, relaxation and contraction of muscles, inhibition and promotion of clotting, regulation of secretions including digestive juices and hormones, and control of fertility, cell division, and growth.³

The eicosanoid family includes subgroups of substances known as prostaglandins, leukotrienes, and thromboxanes, among others. As shown in Figure 1.1

, the long-chain omega-6 fatty acid, AA (20:4n-6), is the precursor of a group of eicosanoids that include series-2 prostaglandins and series-4 leukotrienes. The omega-3 fatty acid, EPA (20:5n-3), is the precursor to a group of eicosanoids that includes series-3 prostaglandins and series-5 leukotrienes. The AA-derived series-2 prostaglandins and series-4 leukotrienes are often synthesized in response to some emergency such as injury or stress, whereas the EPA-derived series-3 prostaglandins and series-5 leukotrienes appear to modulate the effects of the series-2 prostaglandins and series-4 leukotrienes (usually on the same target cells). More specifically, the series-3 prostaglandins are formed at a slower rate and work to attenuate the effects of excessive levels of series-2 prostaglandins. Thus, adequate production of the series-3 prostaglandins seems to protect against heart attack and stroke as well as certain inflammatory diseases like arthritis, lupus, and asthma.³

EPA (22:6 n-3) also affects lipoprotein metabolism and decreases the production of substances - including cytokine, interleukin 1β (IL-1β), and tumor necrosis factor a (TNF-a) - that have pro-inflammatory effects (such as stimulation of collagenase synthesis and the expression of adhesion molecules necessary for leukocyte extravasation [movement from the circulatory system into tissued]) ² The mechanism responsible for the suppression of cytokine production by omega-3 LC PUFAs remains unknown, although suppression of omega-6-derived eicosanoid production by omega-3 fatty acids may be involved, because the omega-3 and omega-6 fatty acids compete for a common enzyme in the eicosanoid synthetic pathway, delta-6 desaturase.

DPA (22:5n-3) (the elongation product of EPA) and its metabolite DHA (22:6n-3) are frequently referred to as very long chain n-3 fatty acids (VLCFA). Along with AA, DHA is the major PUFA found in the brain and is thought to be important for brain development and function. Recent research has focused on this role and the effect of supplementing infant formula with DHA (since DHA is naturally present in breast milk but not in formula).

Dietary Sources and Requirements

Both ALA and LA are present in a variety of foods. LA is present in high concentrations in many commonly used oils, including safflower, sunflower, soy, and corn oil. ALA is present in some commonly used oils, including canola and soybean oil, and in some leafy green vegetables.

Table 1.2 Sources and proportions of omega-3 fatty (more...)

Table 1.2 Sources and proportions of omega-3 fatty acids in common foods and supplements

Food/supplement	EPA	DHA	DPA	ALA
	20:5n-3	22:6n-3	22:5n-3	18:3n-3
Foods in which Total Omega-3 Fatty Acids account for more than 50% of Total PUFA
Fish
Anchovy
Halibut
Herring
Mackerel
Salmon
Sardine
Tuna Canned, waterpacked
Fresh Bluefin

Oils/Supplements
Cod liver oils
Coromega *
Fish oil capsules*
Flaxseed/linseed oil*
Herring oil
MaxEPA*
Menhaden oil
Neuromins*
Omacor*
Ropufa*
Salmon oil
Sardine oil

Seeds
Flaxseeds/Linseeds

Foods/Supplements in which total Omega 3 fatty acids are 10–50% of total PUFA
Oils
Black currant oil
Canola oil**
Mustard seed oils
Soybean oil
Walnut oil
Wheat germ oil

Other foods
Wheat germ
Human milk

Foods/Supplements in which total Omega 3 fatty acids are less than 10% of total PUFA
Efamol Marine*
Soybeans
Walnuts

Dietary Supplement

Also called rapeseed oil

Thus, the major dietary sources of ALA and LA are PUFA-rich vegetable oils. The proportion of LA to ALA as well as the proportion of those PUFAs to others varies considerably by the type of oil. With the exception of flaxseed, canola, and soybean oil, the ratio of LA to ALA in vegetable oils is at least 10 to 1. The ratios of LA to ALA for flaxseed, canola, and soy are approximately 1: 3.5, 2:1, and 8:1, respectively; however, flaxseed oil is not typically consumed in the North American diet. It is estimated that on average in the U.S., LA accounts for 89% of the total PUFAs consumed, and ALA accounts for 9%. Another estimate suggests that Americans consume 10 times more omega-6 than omega-3 fatty acids.⁴ Table 1.2 shows the proportion of omega 3 fatty acids for a number of foods.

Table 1.3 Good food sources* of omega 3 fatty acids (more...)

Table 1.3 Good food sources* of omega 3 fatty acids

	EPA+DHA	ALA		EPA+DHA	ALA
Fish (3oz. Cooked)			Oils (1 Tbs.)
Anchovy			Canola

Halibut			Cod liver

Herring, Atlantic			Flaxseed/linseed

Pacific			Herring

Mackerel, Atlantic			Menhaden

Pacific			Salmon

Salmon, Atlantic**			Sardine

Sardines			Soybean

Trout, Rainbow			Walnut

Tuna, Albacore			Wheat germ
Canned light, water-packed
Canned white, water-packed
Fresh Bluefin

Organ Meats (3 oz. Cooked)			Seeds

Brain, lamb			Flaxseeds/linseeds (1 Tbs.)

Brain, pork

Thymus, calf

Other Foods

Caviar (1 oz.)#

Human breast milk (1c)#

Soybeans, cooked (1/2c)

Tofu, regular (1/2c)

Walnuts (1/4c)

Wheat germ (1/4c)#

Source: Figures adapted from USDA, 2003; *Foods that provide (per serving) 10% or more of the Adequate Intake (AI) for ALA or the Acceptable Macronutrient Distribution Range (AMDR) for EPA and DHA (10% of the AMDR for ALA); an AI is a recommended average daily intake level based on observed or experimentally determined estimates of nutrient intake by a group of apparently healthy people (thus, assumed to be adequate) when an RDA cannot be determined; an AMDR is defined as “a range of intakes for a particular energy source that is associated with reduced risk of chronic disease while providing adequate intake of essential nutrients.”⁵

# Standard serving size not established; **Farm-raised Atlantic salmon have nearly identical omega-3 fatty acid levels to wild Atlantic salmon and significantly more omega-3 fatty acids than wild Pacific salmon.

Several lines of research have suggested that the high ratio of omega 6s to omega 3s currently consumed in the U.S. promotes a number of chronic diseases.⁴ Because of the slow rate of elongation and further desaturation of the essential FA, the importance of LC PUFAs to many physiological processes, and the overwhelming ratio of omega 6s to omega 3s in the average U.S. diet, nutrition experts are increasingly recognizing the need for humans to augment the body's synthesis of omega 3 LC PUFAs by consuming foods that are rich in these compounds. According to data from two population-based surveys, the major dietary sources of LC omega-3 fatty acids in the U.S. population are fish, fish oil, vegetable oils (principally canola and soybean), walnuts, wheat germ, and some dietary supplements, and the primary dietary sources of omega-6 LC PUFAs are meats and dairy products. These surveys, the Continuing Food Survey of Intakes by Individuals 1994-98 (CSFII) and the third National Health and Nutrition Examination (NHANES III) 1988-94 surveys, are the main sources of dietary intake data for the U.S. population. The CSFII has the advantage of collecting dietary recall data over a period of several days, which may permit estimates of omega-3 intake that more accurately reflect individual intakes than do those of NHANES. However, NHANES intake data have the advantage of being able to be linked to health outcomes. Table 1.3 provides a list of food sources of omega-3 fatty acids.

Table 1.4 Estimates of the mean intake of LA, ALA, (more...)

Table 1.4 Estimates of the mean intake of LA, ALA, EPA, and DHA in the U.S. Population from analysis of NHANES III data.*

	Grams/day		Percent energy intake/day
	Mean ± SEM	Median (range)**	Mean ± SEM	Median (range)**
LA (18:2n-6)	14.1 ± 0.2	9.9 (0 – 168)	5.79 ± 0.05	5.30 (0 – 39.4)

ALA (18:3n-3)	1.33 ± 0.02	0.90 (0 – 17)	0.55 ± 0.004	0.48 (0 – 4.98)

EPA (20:5n-3)	0.04 ± 0.003	0.00 (0 – 4.1)	0.02 ± 0.001	0.00 (0 – 0.61)

DHA (22:6n-3)	0.07 ± 0.004	0.00 (0 – 7.8)	0.03 ± 0.002	0.00 (0 – 2.86)

*Based on analysis of a single 24-hour dietary recall from NHANES III data; **Distributions are not adjusted for the over-sampling of Mexican –Americans, non-Hispanic African Americans, children 5 years old and under, and adults 60 years and over in the NHANES III dataset.

Table 1.5 Mean, range, and median usual daily Intakes (more...)

Table 1.5 Mean, range, and median usual daily Intakes (ranges) of n-6 and n-3 PUFAs, in the U.S. population, from analysis of CSFII data (1994 to 1998).*

	Mean (gms/d) (± SEM)**	Range of Means (gms/d) (±SEM)	Median (gms/d) (± SEM)**
LA (18:2n-6)	13.0 ± 0.1	6.7 ± 0.1-17.6 ± 0.5	12.0 ± 0.1

Total n-3 FA	1.40 ± 0.01	0.72 ± 0.02 – 1.86 ± 0.04	1.30 ± 0.01

ALA (18:3n-3)	1.30 ± 0.01	0.72 ± 0.02 – 1.73 ± 0.04	1.21 ± 0.01

EPA (20:5n-3)	0.028	0.002 – 0.049	0.004

DPA (22:5n-3)	0.013	0.001 – 0.019	0.005

DHA (22:6n-3)	0.057 ± 0.018	< 0.0005 ± 0.001	0.046 ± 0.013

Source: Adapted from Dietary Reference Intakes Report;⁵ *Estimates are based on respondents’ intakes on the first day of survey and were adjusted using the Iowa State University method; **For all individuals.

Table 1.4 shows the mean and median intakes of omega-3 and omega-6 fatty acids reported by NHANES III.¹ Table 1.5 shows the mean and median intakes of omega-3 and omega-6 fatty acids reported by CSFII.

Lacking sufficient evidence from research on the effects or correction of dietary deficiencies to establish Recommended Dietary Allowances (RDAs) for the essential fatty acids, the Food and Nutrition Board (FNB) of the Institute of Medicine⁵ has set adequate intakes² (AI) for the essential fatty acids, based on the average intakes of healthy CSFII participants. The AIs for the essential fatty acids vary by age group and sex, as well as for particular conditions such as pregnancy and breastfeeding. For ALA, the AI for men 19 and older, is 1.6 grams/day and the AI for (non-pregnant, non-breastfeeding) women is 1.1 grams/day. The AI for LA is 17 grams/day for men and 11 grams/day for women.

Table 1.6 The omega-3 fatty acid content, in grams (more...)

Table 1.6 The omega-3 fatty acid content, in grams per 100 g food serving, of a representative sample of commonly consumed fish, shellfish, and fish oils, and nuts and seeds, and plant oils that contain at least 5 g omega-3 fatty acids per 100 g

Food item	EPA	DHA	ALA
Fish (Raw^a)
Anchovy, European	0.6	0.9	-
Bass, Freshwater, Mixed Sp.	0.2	0.4	0.1
Bass, Striped	0.2	0.6	trace
Bluefish	0.2	0.5	-
Carp	0.2	0.1	0.3
Catfish, Channel	trace	0.2	0.1
Cod, Atlantic	trace	0.1	trace
Cod, Pacific	trace	0.1	trace
Eel, Mixed Sp.	trace	trace	0.4
Flounder & Sole Sp.	trace	0.1	trace
Grouper, Mixed Sp.	trace	0.2	trace
Haddock	trace	0.1	trace
Halibut, Atlantic and Pacific	trace	0.3	trace
Halibut, Greenland	0.5	0.4	trace
Herring, Atlantic	0.7	0.9	0.1
Herring, Pacific	1.0	0.7	trace
Mackerel, Atlantic	0.9	1.4	0.2
Mackerel, Pacific and Jack	0.6	0.9	trace
Mullet, Striped	0.2	0.1	trace
Ocean Perch, Atlantic	trace	0.2	trace
Tuna, Fresh, Yellowfin	trace	0.2	trace
Tuna, Light, Canned in Oil ^e	trace	0.1	trace
Tuna, Light, Canned in Water ^e	trace	0.2	trace
Tuna, White, Canned in Oil ^e	trace	0.2	0.2
Tuna, White, Canned in Water ^e	0.2	0.6	trace
Whitefish, Mixed Sp.	0.3	0.9	0.2
Whitefish, Mixed Sp., Smoked	trace	0.2	-
Wolf fish, Atlantic	0.4	0.3	trace
Shellfish (Raw)
Abalone, Mixed Sp.	trace	-	-
Clam, Mixed Sp.	trace	trace	trace
Crab, Blue	0.2	0.2	-
Crayfish, Mixed Sp., Farmed	trace	0.1	trace
Lobster, Northern	-	-	-
Mussel, Blue	0.2	0.3	trace
Oyster, Eastern, Farmed	0.2	0.2	trace
Oyster, Eastern, Wild	0.3	0.3	trace
Oyster, Pacific	0.4	0.3	trace

Based on evidence suggesting a role in prevention or treatment of some chronic diseases, the FNB has also established Acceptable Macronutrient Distribution Ranges (AMDR) for the essential fatty acids. An AMDR is defined as “a range of intakes for a particular energy source that is associated with reduced risk of chronic disease while providing adequate intake of essential nutrients.”⁵ The AMDR is expressed as a percentage of total energy intake: The AMDR for LA is set at 5 to 10 percent of usual energy intake, and the AMDR for ALA is 0.6 to 1.2 percent of energy intake. Of this amount, up to 10 percent can be consumed as EPA and/or DHA, the omega-3 LC PUFAs. For a person who consumes 2000 kcal/day, ALA intake should range from 1.3 to 2.6 grams/day, and EPA/DHA intake can substitute for 0.13 to 0.26 of that quantity. Table 1.3 lists foods that provide 10 percent or more of these recommended intakes per serving, which may be referred to as “good sources.” ³ Table 1.6 provides the actual omega-3 content per 100 gm for a variety of foods.

Rationale for and Organization of this Report

Studies show that tissue levels of AA and EPA-derived eicosanoids influence many physiological processes, including platelet aggregation, vessel wall constriction, and immune cell function (IOM), resulting in protection against heart attack and stroke as well as certain inflammatory diseases like arthritis, systemic lupus erythematosus, and asthma. Epidemiological studies have suggested that groups of people who consume diets high in omega 3 FAs may experience a lower prevalence of these conditions, and many small trials have attempted to assess the effects of adding omega 3 fatty acids to the diet, either as omega-3 FA-rich foods or as dietary supplements (primarily fish oils). In addition, dietary omega 3FA have been found to increase calcium absorption, rates of bone formation, and bone strength in rodents and birds. In response to this evidence, a number of omega-3 FA-containing dietary supplements that claim to protect against a variety of conditions have appeared on the market. Thus, AHRQ and the NIH Office of Dietary Supplements have requested a synthesis of the research to date on the health effects of diets rich in omega-3 FA.

The remainder of this report is organized into four chapters. Chapter Two describes the methods we used to identify and review studies related to the role of omega-3 fatty acids in immune-mediated diseases, bone metabolism, and gastrointestinal/renal diseases. Chapter Three presents our findings related to the effects of omega-3 fatty acids on those diseases/conditions. Chapter Four presents our conclusions and recommendations for future research in this area.

Chapter 2. Methodology

Objectives

The topic of this report was nominated by the National Institutes of Health (NIH) Office of Dietary Supplements (ODS). The three participating Evidence-Based Practice Centers (EPCs) were asked to examine the effects of omega-3 fatty acids, in general, and on the following conditions: Cardiovascular Disease, Transplantation, Immune-Mediated Diseases, Gastrointestinal/Renal Diseases, Cancer, Neurology, Asthma, Child/Maternal Health, Eye Health, and Mental Health. The Southern California EPC (SCEPC) was responsible for examining Immune-Mediated Diseases and Gastrointestinal/Renal Diseases in Year 1 of the project and Cancer and Neurology in Year 2 of the project.

Scope of Work

The methodology that we used for this study included the following:

Refining the preliminary questions provided by AHRQ,
Convening a technical expert panel to advise the SCEPC on the study,
Identifying sources of evidence in the scientific literature,
Establishing inclusion/exclusion criteria for the articles identified in the scientific literature,
Identifying potential evidence with attention to controlled clinical trials using omega-3 fatty acids,
Evaluating potential evidence for methodological quality and relevance,
Extracting data from studies meeting methodological and clinical criteria,
Synthesizing the results,
Performing further statistical analysis on selected studies,
Performing pooled analyses where appropriate,
Submitting the results to technical experts for peer review,
Incorporating reviewers' comments into a final report for submission to AHRQ.

Original Proposed Key Questions

Preliminary questions for the project were developed by ODS in collaboration with the following NIH Institutes: (a) National Cancer Institute (NCI); (b) National Eye Institute (NEI); (c) National Heart, Lung, and Blood Institute (NHLBI); (d) National Institute of Alcohol Abuse and Alcoholism (NIAAA); (e) National Institute of Allergy and Infectious Diseases (NIAID); (f) National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); (g) National Institute of Child Health and Human Development (NICHD); (h) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); (i) National Institute of Mental Health; and (j) National Institute of Neurological Disorders and Stroke (NINDS).

Note: Appendixes and Evidence Tables cited in this report are provided electronically at http://www.ahrq.gov/clinic/epcindex.htm

The general and disease-specific questions that were originally proposed are detailed in Appendix A.1, “Methodologic Approach.”

Technical Expert Panel

Each AHRQ evidence report is guided by a Technical Expert Panel (TEP). The TEP advises the SCEPC on refining the preliminary questions, determining the proper inclusion/exclusion criteria for the study and the populations of interest, establishing the proper outcomes measures, and conducting the appropriate analyses.

We convened three TEPs that focused on the following conditions: 1) rheumatoid arthritis (RA), systemic lupus erythematosis (SLE), and bone density/osteoporosis; 2) renal disease and diabetes; and 3) gastrointestinal (GI) diseases. The TEPs were composed of distinguished basic scientists and clinicians, with established expertise in the following areas: omega-3 fatty acids, human nutrition, dietary assessment methods, gastroenterology, nephrology, diabetes, osteoporosis, immunology, and rheumatology. In addition to the experts that we identified, AHRQ and the relevant NIH Institute(s) recommended a number of industry experts. The members of our technical expert panels and a summary of their key comments and recommendations are listed in Appendix A.2.

Key Questions Addressed in this Report

Based on input from our three TEPs, the preliminary disease-specific questions were revised. Additionally, in consultation with the Task Order Officer and the other participating EPCs, we added several questions to our scope of work that had previously been assigned to the NEMC/EPC because they were related to topics we were reviewing. Similarly, a question that had been assigned to the SCEPC for year two was reassigned to the NEMC-EPC. Lastly, one additional question (pertaining to rheumatoid arthritis - number of tender joints) was suggested by a TEP member after reviewing the draft report and was assessed post-hoc. The questions that are addressed in this report are as follows:

Diabetes

What is the evidence in adults or children with a) type II diabetes, or b) insulin resistance/the metabolic syndrome for the efficacy of omega-3 fatty acids in treatment of:

total cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides

What is the evidence in adults and children for an effect of omega-3 fatty acids on insulin sensitivity in a) type II diabetes, or b) the metabolic syndrome?

Inflammatory Bowel Disease

What is the evidence for the efficacy of omega-3 fatty acids in treatment of Crohn's disease and ulcerative colitis?

What is the evidence that in adults or children with inflammatory bowel disease, omega-3 fatty acids can replace steroids or other immunosuppressive drugs?

What is the evidence that the benefits of omega-3 fatty acids are influenced by the concomitant administration of various immunosuppressive agents in the treatment of inflammatory bowel disease?

Rheumatoid Arthritis

What is the evidence that in adults or children with rheumatoid arthritis, omega-3 fatty acids affect:

pain
number of swollen joints
disease activity
patient's global assessment
joint damage
number of tender joints

What is the evidence that in adults or children with rheumatoid arthritis, omega-3 fatty acids can replace other more potent anti-inflammatory or immunosuppressive drugs such as steroids and NSAIDs?

What is the evidence that the benefits of omega-3 fatty acids are influenced by the concomitant administration of various immunosuppressive agents in the treatment of rheumatoid arthritis?

Renal Disease

What is the evidence for the efficacy of omega-3 fatty acids in treatment of renal inflammation and glomerulosclerosis?

What is the evidence that in adults or children with immune-mediated renal disease, omega-3 fatty acids can replace steroids or other immunosuppressive drugs?

What is the evidence that the benefits of omega-3 fatty acids are influenced by the concomitant administration of various immunosuppressive agents in the treatment of immune-mediated renal disease?

Systemic Lupus Erythematosus

What is the evidence that in adults or children with systemic lupus erythematosus, omega-3 fatty acids affect disease activity, damage, or patient perceptions of outcomes?

What is the evidence that in adults or children with systemic lupus erythematosus, omega-3 fatty acids can replace steroids or other immunosuppressive drugs?

What is the evidence that the benefits of omega-3 fatty acids are influenced by the concomitant administration of various immunosuppressive agents in the treatment of systemic lupus erythematosus?

Bone Density/Osteoporosis

What is the evidence that omega-3 fatty acids help maintain bone mineral status?

For each of the study questions we also assessed 1) the effect of omega-3 fatty acids on sub-populations, 2) the effects of covariates, dose, source, and exposure duration on the outcomes of interest, and 3) the sustainment of effect.

Assessment of Adverse Events

In addition to assessing the efficacy of omega-3 fatty acids as specified above, we evaluated the data on adverse events that were reported in the studies we reviewed. We recognized, a priori, that adverse events are not reported in a standard way across clinical trials either in terms of the specific adverse events assessed or in the reporting of these adverse events. Hence, the purpose of this analysis was to define in general terms adverse events that occur with omega-3 fatty acids in order to identify specific adverse events that might warrant further investigation.

From each study, we extracted the number of adverse events reported for both intervention and placebo groups. We grouped the adverse events into the following categories:

Clinical bleeding
Gastrointestinal complaints or nausea
Diarrhea
Headache
Dermatological
Withdrawal due to adverse event

We calculated rates of adverse events within the intervention and placebo groups. Adverse event rates were calculated as the percentage of patients pooled across all conditions who had one of the adverse events. Reporting of adverse events varied greatly across studies. Many studies did not report on adverse events. If a study did not report on an adverse event (i.e. missing value), it was not used in that adverse event calculation. If a study reported not having an adverse event (i.e. adverse event rate of 0%), it was used in the calculation. Studies that did not specify the group allocation of the adverse events were excluded. We also excluded studies that reported the number of adverse events but did not report the group sample sizes.

Identification of Literature Sources

Potential evidence for our study came from three sources: on-line library databases, the reference lists of all relevant articles, and industry experts.

Jessie McGowan, Senior Information Scientist, and Nancy Santesso, Knowledge Translation Specialist, at the University of Ottawa were responsible for developing a common search strategy for omega-3 fatty acids for the 3 participating EPCs. Nancy Santesso developed a core omega-3 search strategy in collaboration with project librarians, biochemists, nutritionists, and clinicians, who also provided biochemical names, abbreviations, food sources, and commercial product names for omega-3 fatty acids. The literature search was not restricted by language of publication or by study design, except with the MeSH term, “dietary fats,” in order to increase specificity. When possible, the searches were limited to studies involving human subjects. The core search strategy is detailed in Appendix A.3.

For the SCEPC, this core search strategy was incorporated into 6 specific searches that focused on our relevant disease categories: rheumatoid arthritis, bone density, SLE, renal disease, diabetes, and gastrointestinal diseases. The strategies for these searches are detailed in Appendix A.3.

The following databases were searched: Medline (1966-July, 2003), Premedline (July 8, 2003), Embase (1980-Week 27, 2003), Cochrane Central Register of Controlled Trials (2nd Quarter, 2003), CAB Health (1973-June 2003), Dissertation Abstracts (1861-to December 2002). All of these databases were searched using the Ovid interface, except CAB Health, which was searched through SilverPlatter. Any duplicate records were identified and removed within each search question using Reference Manager software, except for the last update, which was imported into EndNote. The citations obtained from these literature searches were sent to the SCEPC via e-mail.

The citations were transferred to a secured Internet-based software system (termed D2D) that enabled us to view article titles and abstracts electronically. Two reviewers, Walter Mojica and James Pencharz, used the computerized software system to independently evaluate the citations and abstracts using the review form in Figure B.1, Appendix B, which was loaded onto the computerized system.

The reviewers flagged article titles that focused on omega-3 fatty acids and any of the following disease conditions: diabetes mellitus, inflammatory bowel disease (ulcerative colitis and Crohn's disease), rheumatoid arthritis, SLE, renal disease, osteoporosis, or bone mineral status. In addition, they flagged article titles that pertained to the disease conditions of the other participating EPCs (i.e., cardiovascular disease or asthma). Language was not a barrier to inclusion. Articles that either reviewer flagged were ordered, as well as those articles in which it was unclear from the title or abstract whether the article was relevant. The articles were ordered from the RAND library, the UCLA library, or Kessler-Hancock, a San Francisco-based literature retrieval firm with contacts around the world. The literature was tracked using ProCite and Access software.

In addition, we sent letters to industry experts recommended by the Office Dietary Supplements to obtain any unpublished data (Figure A.3.1).

Evaluation of Evidence

Two reviewers independently reviewed each article that was ordered to determine whether it should be accepted for further study using a structured screening form (shown in Figure B.2, Appendix B) that included a defined set of inclusive/exclusive criteria (Table A.4.1, Appendix A.4). Walter Mojica reviewed all of the articles; James Pencharz and Jennifer Grossman each reviewed a portion of the articles. The reviewers resolved any disagreements by consensus.

Extraction of Data

For the articles that passed our screening criteria, two reviewers independently abstracted detailed data onto a specialized quality review form (QRF) (Figure B.3, Appendix B). Walter Mojica and Jennifer Grossman reviewed all of the articles except those pertaining to diabetes, which were reviewed by Walter Mojica and Puja Khanna. We consulted with several outside scientists to complete QRFs for foreign-language articles. The reviewers resolved differences through consensus, and a senior physician researcher resolved any disagreements that could not be resolved through this method.

The QRF included questions about the trial design; the outcomes of interest; the quality of the trial; the number and characteristics of the patients; details on the intervention, such as the dose, frequency, and duration; the types of outcome measures; adverse events; and the elapsed time between the intervention and outcome measurements.

Grading Evidence

Methodologic Quality of Randomized Controlled Trials

To evaluate the quality of the design and execution of trials, we also collected information on the QRF about the study design, appropriateness of randomization, blinding, description of withdrawals and dropouts, and concealment of allocation.^6, ¹¹³ A score for quality was calculated for each trial using a system developed by Jadad (Appendix A.5, Figure A.5.1). The Jadad score rates studies on a scale of 0 to 5. Empirical evidence has shown that studies scoring 2 or less report exaggerated results compared with studies scoring 3 or more.^114, ¹¹⁵ Thus, studies with a Jadad score of 3 or more are referred to as “high quality,” and studies scoring 2 or less are referred to as “poor quality.” For our purposes, if a trial was associated with more than one study, its quality score was equal to the maximum score calculated across its associated studies. Additionally, a generic summary quality score (A, B, C) was assigned to each study based upon the combination of its Jadad score and reporting of concealment of allocation (Appendix A.5, Table A.5.1).

Applicability

In this report, the focus is on the U.S. population. To capture the potential applicability of studies to the different populations of interest as defined in the scope of work (namely Americans with inflammatory bowel disease, rheumatoid arthritis, renal disease, systemic lupus erythematosus or osteoporosis), we categorized the populations in the studies we reviewed in terms of 1) applicability to the U.S. population and 2) health state (Appendix A.5, Table A.5.2). In the summary tables, each study receives a combined applicability grade consisting of the applicability and health state.

Data Synthesis

We performed both a qualitative and quantitative synthesis of the evidence. We performed a meta-analysis for those studies that sufficiently assessed interventions, populations, and outcomes to justify pooling. For the remaining studies, we performed a qualitative analysis.

Meta-Analysis

Our meta-analytic methods are sufficiently comparable across conditions and outcomes that we describe them in general in this section. Individual approaches and decisions are discussed as necessary and appropriate in the discussion of results for particular conditions and outcomes.

Selection of Trials for Descriptive Analysis or Meta-Analysis

For each condition, we identified a set of relevant outcomes, e.g., cholesterol outcomes for the condition of diabetes, based on input from our TEP. Trials were considered for further analysis if they contained information on a chosen outcome collected within a follow-up interval for which measures were considered clinically comparable.

For some trials, several publications presented the same outcome data. In these cases, we picked the most informative of the duplicates; for example, if one publication was a conference abstract with preliminary data and the second was a full journal article, we chose the latter. The publications dropped for duplicate data do not appear in the evidence table but are noted in the results text. We note that multiple citations of the same article were removed at the title screening stage of the project.

In order for a trial to be included in further analysis, the associated publication(s) had to report on the outcome, and contain sufficient statistical information for the calculation of a summary statistic. A trial also had to provide data prior to the crossover point if the trial was a crossover design to mirror the data available from a non-crossover trial, i.e., to enable the inclusion of a treatment effect uncontaminated by other treatments. Had data been included after the cross-over, the uncontaminated placebo or control group outcome would not have been available for example.

Trial Summary Statistics

Each trial contained one control or placebo group. Some trials contained more than one treatment (omega-3) group. In order not to double-count patients, we chose the most clinically relevant treatment group to enter our analysis, or in some cases combined treatment groups. For those outcomes that were dichotomous, the summary statistic was a risk ratio, that is, the risk of the outcome in the treatment (omega-3) group divided by the risk of the outcome in the control or placebo group. A risk ratio greater than one indicates that the risk of the outcome in the treatment group is larger than that in the control or usual care arm. For example, if the risk ratio is 1.10, then patients in the treatment group are 1.10 times as likely to have the outcome as those in the control or placebo group.

For each study, we estimated the log risk ratio and its standard deviation. We conducted the analysis on the logarithmic scale for variance-stabilization reasons.⁷ We then back-transformed to the risk ratio scale for interpretability.

For those outcomes that were continuous, we extracted the follow-up means and standard deviations for the treatment and control or placebo groups respectively. If a study did not report a follow-up mean, or a follow-up mean could not be calculated from the given data, the study was excluded from analysis. For studies that did not report a standard deviation or for which a standard deviation could not be calculated from the given data, we imputed the standard deviation by using those studies and groups that did report a standard deviation and weighting all groups equally, or we assumed that the standard deviation was 0.25 of the theoretical range for the specific measure in the study. For example, if a study measured pain on a 0–100 scale, we assumed the standard deviation was 25.

If all studies measured the outcome on the same scale or the measures could all be converted to the same scale, e.g., cholesterol measurements measured in mg/dL or mmol/L which could all be converted to mg/dL, the summary statistic was the mean difference (MD) between the treatment group follow-up mean and the control or placebo group follow-up mean:

Mean difference = treatment follow-up mean - control follow-up mean

We estimated the standard deviation for that mean difference.⁸ If the studies used different measurements of the same outcome and we could not convert them all to the same scale, the summary statistic was an effect size. The effect size is the mean difference at follow-up divided by the pooled standard deviation. This summary statistic is unitless and indicates the number of standard deviations by which the treatment and control or placebo group means differ. We estimated an unbiased estimate⁹ of Hedges' g effect size¹⁰ and its standard deviation. A negative mean difference or effect size indicates that the treatment is associated with a decrease in the outcome at follow-up as compared with the control or usual care group.

Stratification of Trials

For each condition, we performed, as permissible given available data, stratified analyses on subgroups of studies defined by patient population, type of omega-3, and dose of omega-3. We will discuss the particular strata definitions for each condition in the relevant results sections in Chapter 3. In general, a paucity of available data precluded us from pooling data separately in most strata. However, we do discuss the results qualitatively in each stratum when possible.

Performance of Meta-Analysis

In some cases, the trials were judged too clinically heterogeneous to combine. Furthermore, for each outcome, condition, and trial stratum combination, we required that at least three trials be available for pooling. In heterogeneous settings and those with insufficient data, we conduct only a descriptive analysis and present the study-level summary statistics but do not estimate a pooled effect.

For those conditions for which trials were determined to be clinically comparable and for which there were at least three trials, we estimated a pooled random-effects estimate¹¹ by combining summary statistics across trials. We also report the chi-squared test of heterogeneity p-value.⁹

Forest plots were constructed for each setting. Each individual trial summary statistic is shown as a box whose area is inversely proportional to the estimated variance of the summary statistic in that trial. The trial's confidence interval is shown as a horizontal line through the box. The pooled estimate and its confidence interval are shown as a diamond at the bottom of the plot with a dotted vertical line indicating the pooled estimate value. A vertical solid line at one for dichotomous outcomes or at zero for continuous outcomes indicates no treatment effect.

Sensitivity Analyses

We conducted post hoc sensitivity analysis for meta-analyses that exhibited significant (p<0.05) heterogeneity based on the chi-squared test of heterogeneity. In these sensitivity analyses, we removed the most outlying study chosen based on a visual inspection of the forest plot of the original meta-analysis, and estimated a new pooled estimate. We compared this pooled estimate to the original result as well as observed whether significant heterogeneity still remained.

Publication Bias

We assessed the possibility of publication bias by evaluating a funnel plot of summary statistics for asymmetry, which can result from the nonpublication of small trials with negative results. These funnel plots include a horizontal line at the fixed-effects pooled estimate and pseudo-95% confidence limits.⁹ If bias due to nonpublication exists, the distribution is asymmetric or skewed. Because graphical evaluation can be subjective, we also conducted an adjusted rank correlation test¹⁰ and a regression asymmetry test⁹ as formal statistical tests for publication bias. The correlation approach tests whether the correlation between the effect sizes and their variances is significant, and the regression approach tests whether the intercept of a regression of the effects sizes on their precision differs from zero; that is, both formally test for asymmetry in the funnel plot. We acknowledge that other factors, such as differences in trial quality or true study heterogeneity, could produce asymmetry in funnel plots.

Interpretation of the Results

The mean difference pooled results are readily interpretable as they are measured in a clinically interpretable metric. To aid in interpreting the pooled effect size and risk ratio, whenever possible we back-transformed each pooled estimate to a specific metric. In order to do this, we multiplied each pooled effect size estimate by the average standard deviation of the most clinically relevant outcome measured across the trials, e.g., pain on the VAS scale, included in the pooled estimate. For each pooled risk ratio, we estimated a number needed to treat (NNT) or number needed to harm (NNH) depending on whether the risk ratio was less than or greater to one, by assuming that the population outcome risk was equal to the average control group risk observed across the trials. By average in either calculation, we mean a simple average across relevant placebo/control and/or treatment groups in the relevant studies. We note these back-transformations require assuming a particular underlying standard deviation or outcome risk. Readers may wish to apply their own standard deviation or underlying risk, based on the particular patient population to which they wish to apply the results. We conducted all analyses and drew all graphs using the statistical package Stata.¹¹

Peer Review

This draft report was sent for review to a select group of experts in omega-3 fatty acids, epidemiology, nutrition, rheumatoid arthritis, SLE, IBD, nephrology, osteoporosis, and diabetes. The names, expertise, and affiliations of the peer reviewers are listed in Table A.6.1, Appendix A. Additionally, the report was sent to the members of the TEP for review. We entered all comments that we received into a database and collated those pertaining to similar sections of the report. For each comment or group of related comments, we prepared a response detailing how we changed the report or why we did not believe a change was justified. The complete list of peer reviewed comments and our responses are included in Appendix D. Service as a peer reviewer or as a technical expert panelist does not imply agreement or endorsement of the findings of this report.

Chapter 3. Results

Results of Literature Search

An external file that holds a picture, illustration, etc., usually as some form of binary object. The name of referred object is er-03lipidsf2.jpg.

Figure 3.1 Literature flow

Figure 3.1 Literature flow

* One article reported both lupus and renal outcomes.

Figure 3.1

displays the flow of the literature review. The University of Ottawa EPC e-mailed us a total of 4,212 citations as a result of their computerized library searches. Our two reviewers considered 1,384 of these article titles to be relevant to our research topics. Of these, a senior researcher rejected 347 titles as not being relevant. We also received 25 citations from the literature searches conducted by New England Medical Center (NEMC) EPC, and we identified 42 articles by hand searching the reference lists of articles that we reviewed. Thus, we identified a total of 1,105 relevant article titles. We were able to retrieve all but 8 of these articles.

Of the 1,097 articles retrieved, 115 were accepted for further review, because they reported on results from randomized clinical trials or controlled clinical trials of omega-3 fatty acids in the treatment of RA, IBD, diabetes, renal disease, and SLE or reported results from randomized clinical trials, controlled clinical trials, or case series of omega-3 fatty acids on the effects on bone mineral metabolism. Of those articles that were rejected at this stage, 149 reported on a condition other than those of interest, 301 reported on a topic other than omega-3 fatty acids, 22 did not report on a population of interest, and 504 were rejected for study design (i.e., descriptive studies or editorials/commentaries, previous reviews or meta-analyses, and observational studies in all topic areas except bone mineral metabolism). Three articles were duplicates of articles already on file, and four were not reviewed due to language.

Of the 115 articles that went to further review, 10 were rejected because they did not report on outcomes of interest, 15 because they did not report a difference in omega-3 content among study arms, and 7 because they were duplicate reports of the same trial. Thus, a total of 83 articles were accepted for supplementary analysis. Of these, 21 articles reported on RA, 13 articles reported on IBD, 34 articles reported on diabetes, 9 articles reported on renal, 3 articles reported on lupus, and 4 articles reported on bone mineral metabolism. One article reported outcomes for both SLE and renal disease.

Due to the limited number of articles found for renal failure, SLE, and bone mineral metabolism, these outcomes are discussed qualitatively.

Ten trials^16–25 were included in the meta-analysis of RA outcomes (not all trials were included for each outcome). Eleven trials were not included in meta-analysis for the following reasons: insufficient statistics^26–35 and no outcome of interest.³⁸

Three trials^39–41 were included in the meta-analysis of remission/relapse in ulcerative colitis. Ten trials were not included in meta-analysis for the following reasons: insufficient statistics,^42, ^43, ⁹⁵ no outcome of interest,^44, ^46, ^52, ^53, ⁹⁴ and wrong disease (Crohn's disease, not ulcerative colitis).^54, ⁵⁵

Eighteen trials^56–73 were included in the meta-analysis of diabetes outcomes (not all trials were included for each outcome). Sixteen articles were not included in meta-analysis for insufficient statistics.^74–83, ^86–91

In addition, as a result of our request to industry experts for unpublished data, Herbert Woolf, Technical Marketing Manager for BASF Corporation, sent us the following document: “Food Labeling: Health Claims and Label Statement - Omega-3 Fatty Acids and Coronary Heart Disease,” prepared by members of the Joint Task Group (CHPA, CRN, NFI), FDA Docket No: 91N‐0103.¹⁵

Appendixes and Evidence Tables cited in this report are provided electronically at http://www.ahrq.gov/clinic/epcindex.htm

DIABETES

Summaries of all evaluated diabetes studies can be found in appendix C.1.

Diabetes: Total Cholesterol

Table 3.1 Diabetes: mean difference for total cholesterol (more...)

Table 3.1 Diabetes: mean difference for total cholesterol

	Intervention		Control		Mean Difference
Trial	Source	n	Source	n	(mg/dl) (95% CI)
Alekseeva⁶⁵	Linseed oil	30	Placebo	30	2.32 (-24.97, 29.60)
Annuzzi⁵⁷	Max EPA (Fish oil)	4	Placebo	4	6.80 (-21.65, 34.00)
Chan⁵⁸	Omacor	12	Placebo	13	-11.58 (-36.35, 13.19)
	Omacor/Atorvastatin	11	Atorvastatin	13	11.58 (-9.59, 32.76)
Dunstan⁵⁹	Fish oil/light exercise	12	Placebo	12	-19.31 (-46.67, 8.06)
	Fish/moderate exercise	14	Placebo	11	7.72 (-19.28, 34.73)
Hendra⁶⁰	Max EPA (fish oil)	40	Placebo	40	-11.58 (-30.89, 7.72)
Meshcheriakova⁶⁶	Linseed oil/Eiconol	60	Low-fat/Low sodium diet	60	4.63 (-15.75, 25.01)
Morgan⁶¹	Fish oil	10	Placebo	10	-13.13 (-37.43, 11.18)
	Fish oil	10	Placebo	10
Morgan⁶⁷	Low dosage Fish oil	7	Placebo	6	-37.00 (-96.98, 22.98)
	High dosage Fish oil	6	Placebo	6	24.00 (-5.75, 53.75)
Patti⁶⁸	Fish oil	8	Placebo	8	-19.31 (-57.98, 19.37)

Pelikanova⁶²	Fish oil	10	Placebo	10	18.92 (-12.96, 50.80)

Petersen⁶³	Futura 1000 (fish oil)	20	Placebo	22	16.99 (-5.97, 39.95)

Sarkkinen⁷⁰	Rapeseed (LEAR) oil	17	Sunflower oil	14	-17.76 (-45.21, 9.69)

Shimizu⁵⁶	EPA-E	29	Placebo	16	12.40 (-2.30, 27.10)

Woodman⁷²	EPA	17	Placebo	16	-4.75 (-22.48, 12.97)
	DHA	18

Pooled Random Effects Estimate*					0.72 (-5.90, 7.33)

*Chi-squared test of heterogeneity p-value = 0.22

An external file that holds a picture, illustration, etc., usually as some form of binary object. The name of referred object is er-03lipidsf3.jpg.

Figure 3.2 Diabetes: total cholesterol

Figure 3.2 Diabetes: total cholesterol

Overall effect. We identified 32 studies^56–72, ^75–83, ^86–91 that evaluated the effect to of omega-3 fatty acids on total cholesterol in type II diabetics. Among these, 14 contained sufficient data to be included in a meta-analysis. (Table 3.1) The pooled random effects estimate of the mean difference between omega-3 fatty acids and placebo for total cholesterol is 0.72 mg/dl (95% CI, -5.90, 7.33) (Table 3.1 and Figure 3.2

Sub-populations. None of the studies evaluated the differential effects of omega-3 fatty acids on distinct subpopulations. There were insufficient data to perform pooled analyses on subpopulations across studies.

Covariates. One study⁵⁸ assessed the effects of fish oil alone, atorvastatin alone, and combined fish oil and atorvastatin. Both atorvastatin alone and combined fish oil and atorvastatin reduced total cholesterol significantly, relative to placebo; there was an insignificant reduction with fish oil alone. The reduction for atorvastatin alone was greater than that for the other groups, although statistical testing was not reported.

Effects of dose, source and exposure duration. None of the studies specifically assessed the effects of dose, source, or exposure duration. A pooled analysis of dose effect using meta-regression revealed no significant dose effect. On stratified analysis of source, the pooled random effects estimates of the mean difference between omega-3 fatty acids and placebo, for studies using a fish-oil and studies using a plant source, respectively, were 1.21 mg/dl (95% CI, -6.51, 8.49) and -1.82 (95% CI, -5.87, 12.20).

Sustainment of effect. Sustainment of effect was not assessed in any of the reports.

Table 3.2 Relationship between methodologic quality (more...)

Table 3.2 Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on total cholesterol among people with type II diabetes

Methodological Quality
Applicability		A	B			C
	I		Study	n	Mean difference (95% CI)	Study	n	Mean difference (95% CI)
			Hendra⁶⁰	80	-11.58 (-30.89, 7.72)	Shimizu⁵⁶	45	12.40 (-2.30, 27.10)
			Morgan⁶⁷	13	-37.00 (-96.98, 22.98)	Morgan⁶¹	40	-13.13 (-37.43, 11.18)
				12	24.00 (-5.75, 53.75)
			Petersen⁶³	42	16.99 (-5.97, 39.95)	Patti⁶⁸	16	-19.31 (-57.98, 19.37)
						Sarkkinen⁷⁰	31	-17.76 (-45.21, 9.69)
	II		Chan⁵⁸	25	-11.58 (-36.35, 13.19)	Annuzzi⁵⁷	8	6.18 (-21.65, 34.00)
				24	11.58 (-9.59, 32.76)
			Woodman⁷²	51	-4.75 (-22.48, 12.97)	Dunstan⁵⁹	24	-19.31 (-46.67, 8.06)
							25	7.72 (-19.28, 34.73)
						Pelikanova⁶²	20	18.92 (-12.96, 50.80)
	III

Quality and applicability. Among studies that entered the meta-analysis, none had both an applicability rating of I (representative of general adult population with type II diabetes), and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Table 3.2). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with type II diabetes. Of note, no studies were identified that assessed the effect of omega-3 fatty acids among children with type II diabetes.

Diabetes: HDL Cholesterol

Table 3.4 Relationship between methodologic quality (more...)

Table 3.4 Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on HDL among people with type II diabetes

		Methodological Quality

Applicability		A	B			C
	I		Study	n	Mean difference (95% CI)	Study	n	Mean difference (95% CI)
			Hendra⁶⁰	80	-7.72 (-14.68, -0.76)	Shimizu⁵⁶	45	5.80 (-2.70, 14.30)
			Morgan⁶⁷	13	9.00 (-3.49, 21.49)	Morgan⁶¹	40	2.70 (-6.18, 11.58)
				12	9.00 (-13.03, 31.03)
			Petersen⁶³	42	6.56 (0.13, 13.00)	Patti⁶⁸	14	-2.32 (-10.78, 6.14)
						Sarkkinen⁷⁰	31	-3.09 (-9.84, 3.67)
	II		Chan⁵⁸	25	-0.77 (-6.33, 4.78)	Annuzzi⁵⁷	8	0.00 (-3.21, 3.21)
				24	8.11 (0.63, 15.59)
			Woodman⁷²	51	2.02 (-4.44, 8.48)	Dunstan⁵⁹	24	4.63 (-3.90, 13.16)
							25	0.39 (-8.03, 8.80)
	III

Table 3.3 Diabetes: mean difference for high-density (more...)

Table 3.3 Diabetes: mean difference for high-density lipoprotein (HDL)

	Intervention		Control		Mean Difference

Trial	Source	n	Source	n	(mg/dl) (95% Cl)
Annuzzi⁵⁷	Max EPA (Fish oil)	4	Placebo	4	0.00 (-3.21, 3.21)

Chan⁵⁸	Omacor	12	Placebo	13	-0.77 (-6.33, 4.78)
	Omacor/Atorvastatin	11	Atorvastatin	13	8.11 (0.63, 15.59)

Dunstan⁵⁹	Fish oil/light exercise	12	Placebo	12	4.63 (-3.90, 13.16)
	Fish oil/mod. exercise	14	Placebo	11	0.39 (-8.03, 8.80)

Hendra⁶⁰	Max EPA (fish oil)	40	Placebo	40	-7.72 (-14.68, -0.76)

Morgan⁶¹	Fish oil	10	Placebo	10	2.70 (-6.18, 11.58)
	Fish oil	10	Placebo	10
Maffettone⁷³	Fish oil	8	Placebo	8	-2.32 (-10.69, 6.06)

Morgan⁶⁷	Low dosage Fish oil	7	Placebo	6	9.00 (-3.49, 21.49)
	High dosage Fish oil	6	Placebo	6	9.00 (-13.03, 31.03)

Patti⁶⁸	Fish oil	8	Placebo	8	-2.32 (-10.78, 6.14)

Petersen⁶³	Futura 1000 (fish oil)	20	Placebo	22	6.56 (0.13, 13.00)

Sarkkinen⁷⁰	Rapeseed (LEAR) oil	17	Sunflower oil	14	-3.09 (-9.84, 3.67)

Shimizu⁵⁶	EPA-E	29	Placebo	16	5.80 (-2.70, 14.30)

Woodman⁷²	EPA	17	Placebo	16	2.02 (-4.44, 8.48)
	DHA	18

Pooled Random Effects Estimate*					1.17 (-1.08, 3.42)

*Chi-squared test of heterogeneity p-value = 0.13

An external file that holds a picture, illustration, etc., usually as some form of binary object. The name of referred object is er-03lipidsf4.jpg.

Figure 3.3 Diabetes: high density lipoprotein (HDL) (more...)

Figure 3.3 Diabetes: high density lipoprotein (HDL)

Overall effect. We identified 30 studies^56–61, ^63, ^64, ^67–73, ^75–83, ^86–91 that evaluated the effect to of omega-3 fatty acids on HDL cholesterol in type II diabetics. Among these studies, 12 contained sufficient data to be included in a meta-analysis. (Table 3.4) The pooled random effects estimate of the mean difference between omega-3 fatty acids and placebo for HDL cholesterol is 1.17 mg/dl (95% CI, -1.08, 3.42) (Table 3.3 and Figure 3.3

). Although a large number of the studies identified were not included in this meta-analysis, the results presented here are consistent with the results of another meta-analysis¹¹⁶ studies evaluated the differential effects of omega-3 fatty acids on distinct subpopulations. There were insufficient data to perform pooled analyses on subpopulations across studies.

Covariates. One study assessed the effects of fish oil alone, atorvastatin alone, and combined fish oil and atorvastatin.⁵⁸ There was an insignificant increase and decrease in HDL with atorvastatin alone and fish oil alone, respectively, and a significant increase with a combination of fish oil and atorvastatin.

Effects of dose, source, and exposure duration. None of the studies specifically assessed the effects of dose, source or exposure duration. A pooled analysis of dose effect using meta-regression revealed no significant dose effect. In one study, plants were the source of omega-3 fatty acids. In this study,⁷⁰ the mean difference between omega-3 fatty acids and placebo for HDL cholesterol was -3.09 mg/dl (95% CI, -9.84, 3.67). Restricting the pooled analysis to the remaining studies, which used a fish source, the pooled random effects estimate of the mean difference between omega-3 fatty acids and placebo for HDL cholesterol was 1.53 mg/dl (95% CI, -0.82, 3.87).

Sustainment of effect. Sustainment of effect was not assessed in any of the reports.

Quality and applicability. Among studies that entered the meta-analysis, none had both an applicability rating of I (representative of general adult population with type II diabetes), and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Table 3.4). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with type II diabetes. Of note, no studies were identified that assessed the effect of omega-3 fatty acids among children with type II diabetes.

Diabetes: LDL Cholesterol

Table 3.5 Diabetes: mean difference for low-density (more...)

Table 3.5 Diabetes: mean difference for low-density lipoprotein (LDL)

	Intervention		Control		Mean Difference
Trial	Source	n	Source	n	(mg/dl) (95% CI)
Annuzzi⁵⁷	Max EPA (Fish oil)	4	Placebo	4	23.17 (-9.22, 55.56)
Chan⁵⁸	Omacor	12	Placebo	13	-5.79 (-20.88, 9.29)
	Omacor/Atorvastatin	11	Atorvastatin	13	11.97 (-4.51, 28.45)
Dunstan⁵⁹	Fish oil/light exercise	12	Placebo	12	5.02 (-21.44, 31.48)
	Fish oil/mod. exercise	14	Placebo	11	19.31 (-6.81, 45.42)
Hendra⁶⁰	Max EPA (fish oil)	40	Placebo	40	-3.86 (-22.97, 15.25)
Morgan⁶¹	Fish oil	10	Placebo	10	8.11 (-19.46, 35.67)
	Fish oil	10	Placebo	10
Maffettone⁷³	Fish oil	8	Placebo	8	-0.39 (-47.32, 46.55)
Morgan⁶⁷	Low dosage Fish oil	7	Placebo	6	8.00 (-52.53, 68.53)
	High dosage Fish oil	6	Placebo	6	23.00 (-31.39, 77.39)
Petersen⁶³	Futura 1000 (fish oil)	20	Placebo	22	21.62 (2.79, 40.45)
Rivellese⁶⁹	Fish oil	8	Placebo	8	-0.39 (-47.31, 46.54)
Sarkkinen⁷⁰	Rapeseed (LEAR) oil	17	Sunflower oil	14	-10.04 (-37.38, 17.30)
Woodman⁷²	EPA	17	Placebo	16	0.50 (-13.80, 14.79)
	DHA	18

Pooled Random Effects Estimate*					5.12 (-1.02, 11.25)

*Chi-squared test of heterogeneity p-value = 0.62

An external file that holds a picture, illustration, etc., usually as some form of binary object. The name of referred object is er-03lipidsf5.jpg.

Figure 3.4 Diabetes: low density lipoprotein (LDL)

Figure 3.4 Diabetes: low density lipoprotein (LDL)

Overall effect. We identified 28 studies that evaluated the effect of omega-3 fatty acids on LDL cholesterol in type II diabetics^57–61, ^63, ^64, ^67, ^69–73, ^75–83, ^86–91. Among these, 11 contained sufficient data to be included in a meta-analysis. (Table 3.5) The pooled random effects estimate of the effect of omega-3 fatty acids on LDL cholesterol is 5.12 mg/dl (95% CI, -1.02, 11.25) (Table 3.5 and Figure 3.4

). Although a large number of the studies identified were not included in this meta-analysis, the results presented here are consistent with the results of another meta-analysis,¹¹⁶ that included a number of the studies that were excluded here, although the results in the other meta-analysis were statistically significant.

Covariates. One study⁵⁸ assessed the effects of fish oil alone, atorvastatin alone, and a combination of fish oil and atorvastatin. Atorvastatin alone and combined fish oil and atorvastatin reduced LDL cholesterol with significantly relative to placebo; fish oil alone reduced LDL cholesterol relative to placebo, though not significantly. The reduction was greatest for atorvastatin alone, although statistical testing between atorvastatin and fish oil groups was not reported.

Effects of dose, source and exposure duration. None of the studies specifically assessed the effects of dose, source or exposure duration. A pooled analysis of dose effect using meta-regression revealed no significant dose effect. In one study, plants were the source of omega-3 fatty acids. In this study,⁷⁰ the mean difference between omega-3 fatty acids and placebo for LDL cholesterol was -10.04 mg/dl (95% CI, -37.38, 17.30). Restricting the pooled analysis to the remaining studies, which used a fish source, the pooled random effects estimate of the mean difference between omega-3 fatty acids and placebo for LDL cholesterol was 5.92 mg/dl (95% CI, -0.38, 12.22).

Sustainment of effect. Sustainment of effect was not assessed in any of the reports.

Table 3.6 Relationship between methodologic quality (more...)

Table 3.6 Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on LDL among people with type II diabetes

		Methodological Quality
Applicability		A	B			C
	I		Study	n	Mean difference (95% CI)	Study	n	Mean difference (95% CI)
			Hendra⁶⁰	80	-3.86 (-22.97, 15.25)	Morgan⁶¹	40	8.11 (-19.46, 35.67)
			Morgan⁶⁷	13	8.00 (-52.53, 68.53)	Rivallese⁶⁹	16	-0.39 (-47.31, 46.54)
				12	23.00 (-31.39, 77.39)
			Petersen⁶³	42	21.62 (2.79, 40.45)	Sarkkinen⁷⁰	31	-10.04 (-37.38, 17.30)
	II		Chan⁵⁸	25	-5.79 (-20.88, 9.29)	Annuzzi⁵⁷	8	23.17 (-9.22, 55.56)
				24	11.97 (-4.51, 28.45)
			Woodman⁷²	51	0.50 (-13.80, 14.79)	Dunstan⁵⁹	24	5.02 (-21.44, 31.48)
							25	19.31 (-6.81, 45.42)
	III

Quality and applicability. Among studies that entered the meta-analysis, none had both an applicability rating of I (representative of general adult population with type II diabetes) and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Table 3.6). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with type II diabetes. Of note, no studies were identified that assessed the effect of omega-3 fatty acids among children with type II diabetes.

Diabetes: Triglycerides

Table 3.7 Diabetes: mean difference for triglycerides (more...)

Table 3.7 Diabetes: mean difference for triglycerides

	Intervention		Control		Mean Difference

Trial	Source	n	Source	n	(mg/dl) (95% CI)
Annuzzi⁵⁷	Max EPA (Fish oil)	4	Placebo	4	-32.74	(-84.25, 18.77)

Alekseeva⁶⁵	Linseed oil	30	Placebo	30	53.10	(-33.54, 139.74)

Chan⁵⁸	Omacor	12	Placebo	13	-123.89	(-366.93, 119.14)
	Omacor/Atorvastatin	11	Atorvastatin	13	-17.70	(-52.99, 17.59)

Dunstan⁵⁹	Fish oil/light exercise	12	Placebo	12	-115.04	(-195.84, -34.24)
	Fish oil/moderate exercise	14	Placebo	11	-53.10	(-132.84, 26.65)

Hendra⁶⁰	Max EPA (fish oil)	40	Placebo	40	-44.25	(-89.80, 1.31)

Meshcheriakova⁶⁶	Linseed oil/Eiconol	60	Low-fat/Low sodium diet	60	-35.40	(-88.83, 18.03)

Morgan⁶¹	Fish oil	10	Placebo	10	-346.90	(-656.00, -37.81)
	Fish oil	10	Placebo	10

Morgan⁶⁷	Low dosage Fish oil	7	Placebo	6	-116.00	(-267.44, 35.44)
	High dosage Fish oil	6	Placebo	6	-7.00	(-110.19, 96.19)

Patti⁶⁸	Fish oil	8	Placebo	8	-19.47	(-89.24, 50.30)

Pelikanova⁶²	Fish oil	10	Placebo	10	-36.28	(-101.90, 29.33)

Petersen⁶³	Futura 1000 (fish oil)	20	Placebo	22	-80.53	(-175.69, 14.63)

Sarkkinen⁷⁰	Rapeseed (LEAR) oil	17	Sunflower oil	14	-23.01	(-80.05, 34.03)

Shimizu⁵⁶	EPA-E	29	Placebo	16	30.40	(-23.37, 84.17)

Woodman⁷²	EPA	17	Placebo	16	-39.52	(-68.98, -10.06)
	DHA	18

Pooled Random Effects Estimate*					-31.61	(-49.58, -13.64)

Chi-squared test of heterogeneity p-value = 0.16

An external file that holds a picture, illustration, etc., usually as some form of binary object. The name of referred object is er-03lipidsf6.jpg.

Figure 3.5 Diabetes: triglycerides

Figure 3.5 Diabetes: triglycerides

Overall effect. We identified 33 studies that evaluated the effect to of omega-3 fatty acids on triglycerides in type II diabetics.^56–72, ^74–83, ^86–91 Among these, 14 contained sufficient data to be included in a meta-analysis. (Table 3.7) The pooled random effects estimate of the mean difference between omega-3 fatty acids and placebo for triglycerides is -31.61 mg/dl (95% CI, -49.58, -13.64) (Table 3.7 and Figure 3.5

Covariates. One study⁵⁸ assessed the effects of fish oil alone, atorvastatin alone and combined fish oil and atorvastatin. Fish oil alone, atorvastatin alone and combined fish oil and atorvastatin reduced triglycerides significantly relative to placebo. The reduction for combined atorvastatin and fish oil was greater that for either drug alone, although statistical testing was not reported.

One study assessed the independent and combined effects of aerobic exercise and dietary fish intake on serum lipids and glycemic control.⁹³ There was a significant reduction in triglycerides and an increase in glycosylated hemoglobin with a diet high in fish. With combined moderate exercise and the fish diet, reduction in triglycerides was maintained and glycosylated hemoglobin did not increase.

Effects of dose, source, and exposure duration. None of the studies specifically assessed the effects of dose, source, or exposure duration. A pooled analysis of dose effect using meta-regression revealed no significant dose effect. On stratified analysis of source, the pooled random effects estimates of the mean difference between omega-3 fatty acids and placebo, for studies using a fish-oil and studies using a plant source, respectively, were -35.93 mg/dl (95% CI, -56.02, -15.83) and -12.08 (95% CI, -56.90, 32.73).

Sustainment of effect. Sustainment of effect was not assessed in any of the reports.

Table 3.8 Relationship between methodologic quality (more...)

Table 3.8 Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on triglycerides among people with type II diabetes

Methodological Quality
Applicability		A	B			C
	I		Study	n	Mean difference (95% CI)	Study	n	Mean difference (95% CI)
			Hendra⁶⁰	80	-44.25 (-89.80, 1.31)	Shimizu⁵⁶	45	30.40 (-23.37, 84.17)
			Morgan⁶⁷	13	-116.00 (-267.44, 35.44)	Morgan⁶¹	40	-346.90 (-656.00, -37.81)
				12	-7.00 (-110.19, 96.19)
			Petersen⁶³	42	-80.53 (-175.69, 14.63)	Patti⁶⁸	14	-19.47 (-89.24, 50.30)
						Sarkkinen⁷⁰	31	-23.01 (-80.05, 34.03)
	II		Chan⁵⁸	25	-123.89 (-366.93, 119.14)	Annuzzi⁵⁷	8	-32.74 (-84.25, 18.77)
				24	-17.70 (-42.99, 17.59)
			Woodman⁷²	51	-39.52 (-68.98, -10.06)	Dunstan⁵⁹	24	-115.04 (-195.84, -34.24)
							25	-53.10 (-132.84, 26.65)
						Pelikanova⁶²	20	-36.28 (-101.90, 29.33)
	III

Quality and applicability. Among studies that were included in the meta-analysis, none had both an applicability rating of I (representative of general adult population with type II diabetes), and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Table 3.8). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with type II diabetes. Of note, no studies that assessed the effect of omega-3 fatty acids among children with type II diabetes were identified.

Diabetes: Insulin Sensitivity/Glycemic Control

Overall effect. We identified 3 studies that evaluated the effect to of omega-3 fatty acids on plasma insulin in type II diabetics,^57, ^82, ⁹³ and 1 that evaluated this effect in the metabolic syndrome.⁹² We did not perform meta-analysis because the outcomes used for measuring plasma insulin in these studies were sufficiently different to preclude pooling across studies.

In one study among type II diabetics, glucose-stimulated plasma insulin response during a hyperglycemic clamp was not influenced by fish oil.⁵⁷ In the second study, there was no effect on fasting serum insulin or insulin as measured by area under the curve during a fasting glucose tolerance test.⁹³ In the third study, there was no difference in insulin suppression of hepatic glucose production or in insulin stimulation of whole-body glucose disposal measured by the euglycemic-hyperinsulinemic clamp.⁸²

In the study of metabolic syndrome, fish oil had no effect on insulin resistance estimated by Homeostatic Model Assessment.⁹²

Table 3.9 Diabetes: mean difference of fasting blood (more...)

Table 3.9 Diabetes: mean difference of fasting blood glucose

	Intervention		Control		Mean Difference
Trial	Source	n	Source	n	(mg/dl) (95% CI)
Annuzzi⁵⁷	Max EPA (Fish oil)	4	Placebo	4	-7.93 (-66.18, 50.32)

Alekseeva⁶⁵	Linseed oil	30	Placebo	30	9.01 (-24.30, 42.32)

Dunstan⁵⁹	Fish oil/light exercise	12	Placebo	12	9.01 (-33.00, 51.02)
	Fish oil/mod. exercise	14	Placebo	11	3.60 (-37.85, 45.06)

Hendra⁶⁰	Max EPA (fish oil)	40	Placebo	40	21.62 (-18.06, 61.3)

Morgan⁶¹	Fish oil	10	Placebo	10	-14.41 (-52.95, 24.12)
	Fish oil	10	Placebo	10

Morgan⁶⁷	Low dosage Fish oil	7	Placebo	6	-41.00 (-114.16, 32.16)
	High dosage Fish oil	6	Placebo	6	-17.00 (-89.43, 55.43)

Patti⁶⁸	Fish oil	8	Placebo	8	10.81 (-28.67, 50.29)

Sirtori⁶⁴	Esepent (fish oil)	203	Placebo	211	4.30 (-2.82, 11.42)

Woodman⁷²	EPA	17	Placebo	16	19.81 (2.25, 37.37)
	DHA	18

Pooled Random Effects Estimate*					5.87 (-0.15, 11.88)

Chi-squared test of heterogeneity p-value = 0.76

An external file that holds a picture, illustration, etc., usually as some form of binary object. The name of referred object is er-03lipidsf7.jpg.

Figure 3.6 Diabetes: fasting blood glucose

Figure 3.6 Diabetes: fasting blood glucose

We identified 26 studies that evaluated the effect of omega-3 fatty acids on fasting blood sugar in type II diabetics.^57, ^59–61, ^63–65, ^67–72, ^75–83, ^86, ^87, ^89–91 Among these, 9 contained sufficient data to be included in a meta-analysis. (Table 3.9) The pooled random effects estimate of the mean difference between omega-3 fatty acids and placebo for fasting blood sugar is 5.87 mg/dl (95% CI, -0.15, 11.88) (Table 3.9 and Figure 3.6

). Although a large number of the studies identified with this outcome were not included in this meta-analysis, the results presented here are consistent with the results of another meta-analysis,¹¹⁶ that included a number of the studies that were excluded here.

Table 3.11 Diabetes: effect size of hemoglobin A1c (more...)

Table 3.11 Diabetes: effect size of hemoglobin A1c (HbA1c)

	Intervention		Control
Trial	Source	n	Source	n	(%) (95% CI)
Morgan⁶¹	Fish Oil	10	Placebo	10	-0.10 (-1.25, 1.05)
	Fish Oil	10	Placebo	10

Morgan⁶⁷	Low dosage Fish oil	7	Placebo	6	-1.30 (-3.42, 0.82)
	High dosage Fish oil	6	Placebo	6	0.70 (-0.68, 2.08)

Patti⁶⁸	Fish Oil	8	Placebo	8	0.60 (-0.79, 1.99)

Pelikanova⁶²	Fish oil	10	Placebo	10	0.90 (0.02, 1.78)

Shimizu⁵⁰	EPA-E	29	Placebo	16	0.06 (-8.44, 8.56)

Sirtori⁶⁴	Esepent (fish oil)	203	Placebo	211	0.17 (-0.12, 0.46)

Westerveld⁷¹	EPA-E	8	Placebo	8	-1.30 (-3.55, 0.95)
	EPA-E	8

Woodman⁷²	EPA	17	Placebo	16	0.23 (-0.28, 0.75)
	DHA	18

Pooled Random Effects Estimate*					0.21 (-0.01, 0.44)

*Chi-squared test of heterogeneity p-value = 0.52

An external file that holds a picture, illustration, etc., usually as some form of binary object. The name of referred object is er-03lipidsf13.jpg.

Figure 3.12 RA: patient global assessment

Figure 3.12 RA: patient global assessment

We identified 23 studies that evaluated the effect of omega-3 fatty acids on glycosylated hemoglobin in type II diabetics.^56, ^57, ^61–64, ^67–69 ^71, ^72, ^74–76, ^78, ^79, ^80–83, ^86, ^87, ^90, ⁹¹ Among these 8 contained sufficient data to be included in a meta-analysis. (Table 3.11) The pooled random effects estimate of the mean difference between omega-3 fatty acids and placebo for glycosylated hemoglobin is 0.21 (%) (95% CI, -0.01, 0.44) (Table 3.11 and Figure 3.12

Sub-populations. The effects of omega-3 fatty acids on insulin were assessed in type II diabetes and metabolic syndrome.

Covariates. One study assessed the effects of fish oil alone, atorvastatin alone and combined fish oil and atorvastatin.⁹² There were increases in HOMA scores with fish oil alone, atorvastatin alone and combined fish oil and atorvastatin relative to placebo, though none were significant. Statistical testing was not reported, except the comparisons with placebo.

One study assessed the independent and combined effects of aerobic exercise and dietary fish intake on serum lipids and glycemic control.⁹³ There was a significant reduction in triglycerides and an increase in glycosylated hemoglobin with fish diet. With a combination of moderate exercise and fish diet, reduction in triglycerides was maintained and glycosylated hemoglobin did not increase.

Effects of dose, source, and exposure duration. None of the studies specifically assessed the effects of dose, source, or exposure duration. A pooled analysis of dose effect using meta-regression revealed no significant dose effect on fasting blood glucose or glycosylated hemoglobin. No studies were identified that assessed the effects of omega-3 fatty acids from a plant source on insulin sensitivity or glycemic control.

Sustainment of effect. Sustainment of effect was not assessed in any of the reports.

Table 3.10 Relationship between methodologic quality (more...)

Table 3.10 Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on fasting blood sugar among people with type II diabetes

Methodological Quality
Applicability		A	B			C
	I		Study	n	Mean difference (95% CI)	Study	n	Mean difference (95% CI)
			Hendra⁶⁰	80	21.62 (-18.06, 61.30)	Morgan⁶¹	40	-14.41 (-52.95, 24.12)
			Morgan⁶⁷	13	-41.00 (-114.16, 32.16)	Patti⁶⁸	16	10.81 (-28.67, 50.29)
				12	-17.00 (-89.43, 55.43)
			Sirtori⁶⁴	414	4.30 (-2.82, 11.42)
	II		Woodman⁷²	51	19.81 (2.25, 37.37)	Annuzzi⁵⁷	8	-7.93 (-66.18, 50.32)
						Dunstan⁵⁹	24	9.01 (-33.00, 51.02)
							25	3.60 (-37.85, 45.06)
	III

Table 3.12 Relationship between methodologic quality (more...)

Table 3.12 Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on glycosylated hemoglobin among people with type II diabetes

Methodological Quality
Applicability		A	B			C
	I		Study	n	Mean difference (95% CI)	Study	n	Mean difference (95% CI)
			Morgan⁶⁷	13	-1.30 (-3.42, 0.82)	Morgan⁶¹	40	-0.10 (-1.25, 1.05)
				12	0.70 (-0.68, 2.08)
			Sirtori⁶⁴	414	0.17 (-0.12, 0.46)	Patti⁶⁸	16	0.60 (-0.79, 1.99)
			Westerveld ⁷¹	24	1.30 (-3.55, 0.95)
	II		Woodman⁷²	51	0.23 (-0.28, 0.75)	Pelikanova⁶²	20	0.90 (0.02, 1.78)
	III

Quality and applicability. Among studies that were included in the meta-analysis for fasting blood glucose and glycosylated hemoglobin, none had both an applicability rating of I (representative of general adult population with type II diabetes), and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Tables 3.10 and 3.12). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with type II diabetes. Of note, no studies that assessed the effect of omega-3 fatty acids among children with type II diabetes were identified.

INFLAMMATORY BOWEL DISEASE

Summaries of all inflammatory bowel disease studies that were evaluated can be found in appendix C.2.

Inflammatory Bowel Disease: Clinical Effect

Overall effect. The effect of omega-3 fatty acids on each of the following outcomes was assessed: clinical score, sigmoidoscopic score, histologic score, induced remission and relapse. In total, 13 studies described in 14 reports were identified that reported these outcomes. All outcomes were assessed separately for ulcerative colitis and Crohn's disease. There were sufficient data to perform meta-analysis only for relapse and only for ulcerative colitis. Clinical score was described for ulcerative colitis in 5 studies; two reported no effect^39, ⁵² and three reported statistically significant improvement with omega-3 fatty acids.^44, ^46, ⁹⁴ Clinical score was described for Crohn's disease in only 1 study, which reported no effect.⁵²

Sigmoidoscopic score was reported for ulcerative colitis in 3 studies,^44, ^52, ⁹⁴ each of which reported a statistically significant improvement with omega-3 fatty acids. Sigmoidoscopic score was reported for Crohn's disease in 1 study,⁵² which showed a statistically significant improvement with omega-3 fatty acids. Histologic score was reported for ulcerative colitis in 3 studies; 2 reported no effect^42, ⁴⁶ and 1 statistically significant improvement.⁴⁴ Histologic score was not reported in any of the studies of Crohn's disease.

Induction of remission was reported for ulcerative colitis in 2 studies,^44, ⁹⁵ both of which showed improvement with omega-3 fatty acids. However, neither was statistically significant, and in one study,⁴⁴ comparable data for the placebo group was not reported. Induction of remission was not reported in the studies of Crohn's disease.

Table 3.13 Ulcerative colitis disease: relative risk (more...)

Table 3.13 Ulcerative colitis disease: relative risk of relapse

	Intervention		Control
Trial	Source	n	Source	n	Relative Risk (95% CI)
Hawthorne⁴¹	Hi EPA	35	Placebo	34	1.32 (0.71, 2.46)

Loeschke³⁹	Fish oil	31	Placebo	33	1.06 (0.69, 1.64)

Mantzaris⁴⁰	Max EPA (fish oil)	22	Placebo	18	0.98 (0.36, 2.70)

Pooled Random Effects Estimate*					1.13 (0.81, 1.57)

Chi-squared test of heterogeneity p-value = 0.82

Table 3.14 Relationship between methodological quality (more...)

Table 3.14 Relationship between methodological quality and applicability for estimates of effect of omega-3 fatty acid consumption with ulcerative colitis disease for relapse/remission

Methodological Quality
Applicability		A	B			C
	I		Study	n	Relative Risk (95%, CI)
			Loeschke³⁹	64	1.06 (0.69, 1.64)
			Mantzaris⁴⁰	40	0.98 (0.36, 2.70)
	II
	III		Hawthorne⁹⁶	69	1.32 (0.71, 2.46)

An external file that holds a picture, illustration, etc., usually as some form of binary object. The name of referred object is er-03lipidsf8.jpg.

Figure 3.7 Diabetes: hemoglobin A1_c (HgA1_c)

Figure 3.7 Diabetes: hemoglobin A1_c (HgA1_c)

Relapse was described for ulcerative colitis in 5 studies, 3 of which could be used for meta-analysis. Among these studies, 1 reported a lower relapse rate with omega-3 fatty acids than with placebo,⁴² 2 found no difference and 2 reported an increased rate of relapse.^39, ⁴³ However, the results were not statistically significant in any of these studies. The pooled random effect estimate of the risk of relapse for omega-3 fatty acids relative to placebo for ulcerative colitis was 1.13 (95% CI: 0.81, 1.57) (Table 3.13 , Figure 3.7

). The data yield an average control group risk of 38% (all studies weighted equally). Combining these yields a NNH of 21. So the number of patients needed to treat on average to result in one relapse is 21. Among the studies not included in the meta-analysis, one reported a lower relapse rate and one reported a higher relapse rate with omega-3 fatty acids.

Relapse was described for Crohn's disease in two studies; one reported a significantly lower relapse rate with omega-3 fatty acids than with placebo.⁵⁴

Sub-populations. Among the 13 studies identified, the study sample was restricted to patients with ulcerative colitis in 10^39–44, ^46, ^53, ^94, ⁹⁵ and to Crohn's disease in two;^54, ⁵⁵ one study included both patients with ulcerative colitis and those with Crohn's disease and reported data separately for each disease.⁵² In this study, the effect of omega-3 fatty acids on clinical score was the same for subjects with ulcerative colitis and Crohn's disease (no effect). The effect on histologic score was also the same; however the improvement reached statistical significance only when diseases were pooled.

Covariates. Reported covariates included use of other drugs, previous surgery and presence of fistulae. However, no comparisons of the effects of covariates on outcomes were identified.

Effects of dose, source, and exposure duration. All studies identified used fish oil as the source of omega-3 fatty acids. No studies compared the effect of different doses of omega-3 fatty acids. There were too few studies that assessed the effects of any single outcome to perform a pooled analysis of dose effect.

Of note, one study administered the fish oil via an enteric-coated capsule, which was designed to deliver the omega-3 fatty acids to the small bowel. ⁵⁴ This study, which included only patients with Crohn's disease, demonstrated a reduced relapse rate relative to placebo.

Duration of exposure varied from 2 to 24 months across the studies. Too few studies assessed any single outcome across similar time periods to analyze the effect of duration of exposure.

Sustainment of effect. Sustainment of the assessed effects was not evaluated in any of the studies.

Quality and applicability. Among studies that entered the meta-analysis, none had both an applicability rating of I (representative of general population with IBD) and a summary quality score of A (Jadad score = 5 with concealment of allocation). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with IBD. Of note, no studies that assessed the effect of omega-3 fatty acids among children with IBD were identified.

Inflammatory Bowel Disease: Effect on Requirement for Steroids/Other Immunosuppressive Drugs

Overall effect. We identified only 2 studies that assessed the effect of omega-3 fatty acids on requirements for corticosteroids or other immunosuppressive agents, both of which assessed the effect on corticosteroid requirement.^44, ⁵³ Both of these studies found a reduced requirement for corticosteroids with omega-3 fatty acid treatment relative to placebo, but the differences were not statistically significant. Sustainment of effect after discontinuation of the omega-3 fatty acids was not assessed.

We found no data on the effect of omega-3 fatty acids on requirements for steroids and other immunosuppressive drugs for different subpopulations, doses, exposures and sources.

RHEUMATOID ARTHRITIS

Summaries of all rheumatoid arthritis studies we evaluated can be found in Appendix C.3.

Rheumatoid Arthritis: Pain

Table 3.15 RA: effect size for patient assessment of (more...)

Table 3.15 RA: effect size for patient assessment of pain

	Intervention		Control
Trial	Source	n	Source	n	Effect Size (95% CI)
Cleland¹⁶	Max EPA (fish oil)	23	Placebo	23	-0.02 (-0.60, 0.56)

Geusens¹⁷	Fish oil	21	Placebo	20	-0.04 (-0.57, 0.50)
	Fish oil	19
Kremer¹⁹	Fish oil	20	Placebo	12	-0.04 (-0.69, 0.61)
	Fish oil	17
Kremer¹⁸	Max EPA (fish oil)	17	Placebo	20	-0.13 (-0.78, 0.51)

Magaro²¹	Max EPA (fish oil)	10	Placebo	10	0.41 (-0.48, 1.29)

Nielsen²²	Pikasol (fish oil)	27	Placebo	24	-0.85 (-1.42, -0.27)

Nordstrom²³	Flaxseed oil	11	Placebo	11	-0.21 (-1.04, 0.63)

Skoldstam²⁵	Max EPA (fish oil)	22	Placebo	21	0.04 (-0.56, 0.63)

Tulleken²⁴	Fish oil	13	Placebo	14	-0.72 (-1.5, 0.06)

Pooled Random Effects Estimate*					-0.19 (-0.43, 0.06)

Chi-squared test of heterogeneity p-value = 0.23

An external file that holds a picture, illustration, etc., usually as some form of binary object. The name of referred object is er-03lipidsf9.jpg.

Figure 3.8 Ulcerative colitis disease: relative risk (more...)

Figure 3.8 Ulcerative colitis disease: relative risk of relapse

Overall effect. The effect of omega-3 fatty acids on patient-assessed pain in rheumatoid arthritis was described in 19 studies, 9 of which could be used for meta-analysis. Among these studies, 3 reported significant improvement relative to placebo,^17, ^29, ³⁴ and 4 reported significant improvement from baseline.^16, ^21, ^26, ³⁰ There were no significant effects in twelve studies.^18, ^19, ^22–25, ^28, ^31–33, ^35, ³⁸ The pooled random estimate of effect size for the effect of omega-3 fatty acids on pain relative to placebo is -0.19 (95% CI, -0.43, 0.06) (Table 3.15, Figure 3.8

). An effect size of 1.0 is equivalent to 2.72 cm units on the Visual Analogue Scale. Hence, an effect size of -0.19 translates to a 0.52 cm decrease on the visual analog scale. Of note, among the 10 studies that were not included in the meta-analysis, 8 did not demonstrate a significant effect from omega-3 fatty acids, and 2 did demonstrate such an effect.^29, ³⁴

Sub-populations. None of the studies assessed the effects of omega-3 fatty acids on different subpopulations of patients with RA.

Covariates. One study assessed the effect of different diets (Western versus modified lacto-vegetarian) combined with omega-3 fatty acids on pain in RA.²⁶ In this study, among subjects treated with fish oil, there was a reduction in pain among patients on a modified lacto-vegetarian diet relative to a Western diet (P<0.01)

Effects of dose, source, and exposure duration. One study assessed the effect of different doses of omega-3 fatty acids on outcomes in RA.¹⁹ In this study, the effect of fish oil on pain did not differ among doses. There were insufficient data across studies to perform a pooled analysis of dose or source effect.

In 1 study, plants were the source of omega-3 fatty acids. In this study²³ the effect size for omega-3 fatty acids for pain was -0.21 (95% CI, -1.04, 0.63). Restricting the pooled analysis to the remaining studies, which used a fish source, the pooled random effects estimate of the effect size for pain is unchanged at -0.19 (95% CI, -0.46, 0.09).

Only 1 study assessed the effects of different durations of exposure on outcomes in RA.¹⁹ In this study, there was no effect on pain at 24 and 36 weeks, although statistical testing of the effect between these time points was not performed. There were insufficient data across studies to perform a pooled analysis of exposure duration effect.

Sustainment of effect. Two studies assessed the sustainment of effects of omega-3 fatty acids on outcomes in RA.^18, ²⁸ In 1 study, pain worsened in a fish oil-treated arm 3 months after discontinuation of the fish oil (p<0.05). In the other study, 100% of the control arm (evening primrose oil) and 80% of the fish oil group “returned to baseline or became worse.” Although pain, joint swelling, and acute phase reactants were assessed in this study, the parameters on which this assessment was made were not specified. There were insufficient data across studies to perform a pooled analysis of sustainment of effect.

Table 3.16 Relationship between methodologic quality (more...)

Table 3.16 Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on pain among people with rheumatoid arthritis

Methodological Quality
Applicability		A	B			C
	I		Study	n	Effect Size(95% CI)	Study	n	Effect Size(95% CI)
			Cleland¹⁶	46	-0.02 (-0.60, 0.56)	Kremer¹⁹	49	-0.04 (-0.69, 0.61)
			Geusens¹⁷	60	-0.04 (-0.57, 0.50)
			Kremer¹⁸	37	-0.13 (-0.78, 0.51)
			Skoldstam²⁵	43	0.04 (-0.56, 0.63)
	II		Tulleken²⁴	27	-0.72 (-1.5, 0.06)	Magaro ²¹	20	0.41 (-0.48, 1.29)
	III

Quality and applicability. Among studies that entered the meta-analysis, none had both an applicability rating of I (representative of general adult population with rheumatoid arthritis), and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Table 3.16). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with RA. Of note, no studies that assessed the effect of omega-3 fatty acids on pain among children with Juvenile RA (JRA) were identified.

Rheumatoid Arthritis: Swollen Joints

Table 3.17 RA: effect size for swollen joint count

	Intervention		Control
Trial	Source	n	Source	n	Effect Size (95% CI)
Cleland¹⁶	Max EPA (fish oil)	23	Placebo	23	0.04 (-0.54, 0.62)

Kremer¹⁹	Fish oil	20	Placebo	12	-0.63 (-1.30, 0.03)
	Fish oil	17

Kremer¹⁸	Max EPA (fish oil)	17	Placebo	20	-0.02 (-0.66, 0.63)

Magalish²⁰	Omega-3 fatty acid (source not specified)	65	Placebo	47	-0.13 (-0.51, 0.25)

Nielsen²²	Pikasol (fish oil)	27	Placebo	24	0.00 (-0.55, 0.55)

Nordstrom²³	Flaxseed oil	11	Placebo	11	-0.06 (-0.90, 0.77)

Tulleken²⁴	Fish oil	13	Placebo	14	-0.26 (-1.02, 0.50)

Pooled Random Effects Estimate					-0.13 (-0.35, 0.08)

Chi-squared test of heterogeneity p-value = 0.81

An external file that holds a picture, illustration, etc., usually as some form of binary object. The name of referred object is er-03lipidsf10.jpg.

Figure 3.9 RA: patient assessment of pain

Figure 3.9 RA: patient assessment of pain

Overall effect. The effect of omega-3 fatty acids on swollen joint count in RA was described in 15 studies, 6 of which could be included in meta-analysis. Among these studies, 2 reported significant improvement relative to placebo^29, ³³ and 4 reported significant improvement from baseline.^19, ^25, ^26, ³⁰ There were no significant effects in 9 studies.^18, ^22–24, ^28, ^31, ^35, ³⁸ In one study, swollen joint count was significantly worse with omega-3 treatment relative to placebo.¹⁶ The pooled random effect estimate for the effect of omega-3 fatty acids on swollen joint count relative to placebo is -0.13 (95% CI, -0.35, 0.08 (Table 3.17, Figure 3.9

). In this analysis, an effect size of 1.0 is equivalent to 3.21 swollen joints. So an effect size of -0.13 is equivalent to a reduction in the swollen joint count by 0.42 joints. Among the 9 studies that were excluded from meta-analysis, 2 reported statistically significant improvements with omega-3 fatty acids and 7 did not. Among the 2 that reported significant improvements, one²⁹ was of poor methodologic quality (Jadad score =1, concealment of allocation not reported) and the other, ³³ although of good methodologic quality (Jadad score = 4, concealment of allocation not reported) was a cross-over study and did not include a wash-out period.

The effect of omega-3 fatty acids on swollen joints in rheumatoid arthritis has also been assessed in a previously published meta-analysis. ⁹⁷ This meta-analysis reported improvement favoring fish oil over placebo that was not statistically significant (estimate not reported).

Sub-populations. No studies assessed the effect on specific subpopulations.

Covariates. One study assessed the effect of two different diets (Western versus modified lacto-vegetarian) combined with omega-3 fatty acids on joint swelling in RA.²⁶ In this study, among subjects treated with fish oil, there was a reduction in the number of swollen joints among patients on a modified lacto-vegetarian diet relative to a Western diet (p < 0.01)

Effects of dose, source, and exposure duration. One study assessed the effect of two different doses of omega-3 fatty acids on outcomes in RA.¹⁹ In this study, there was a significant improvement in the number of swollen joints at 24 and 36 weeks relative to baseline for subjects treated with a lower dose of fish oil. Among patients treated with a higher dose of fish oil, the improvement relative to baseline was significant only at 24 weeks. There were insufficient data across studies to perform a pooled analysis of dose effect.

In one study, plants were the source of omega-3 fatty acids. In this study²³ the effect size of omega-3 fatty acids for swollen joints was -0.06 (95% CI, -0.90, 0.77). Restricting the pooled analysis to the remaining studies, which a fish source, the pooled random effects estimate of the effect size for swollen joints unchanged at -0.14 (95% CI, -0.36, 0.09).

Sustainment of effect. Two studies assessed the sustainment of effects of omega-3 fatty acids on outcomes in RA.^18, ²⁸ In one study, there was no change in swollen joint count in a fish oil-treated arm 1–2 months after discontinuation of the fish oil (p<0.05). In the other study, 100% of the control arm (evening primrose oil) and 80% of the fish oil group “returned to baseline or became worse.” Although pain, joint swelling, and acute phase reactants were assessed in this study, the parameters on which this assessment was made were not specified. There were insufficient data across studies to perform a pooled analysis of sustainment of effect.

Table 3.18 Relationship between methodologic quality (more...)

Table 3.18 Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on swollen joints among people with rheumatoid arthritis

Methodological Quality
Applicability		A	B			C
	I		Study	n	Effect Size(95% CI)	Study	n	Effect Size(95% CI)
			Cleland¹⁶	46	0.04 (-0.54, 0.62)	Kremer¹⁹	49	-0.63 (-1.30, 0.03)
			Kremer¹⁸	37	-0.02 (-0.66, 0.63)
	II		Tulleken²⁴	27	-0.26 (-1.02, 0.50)
	III

Quality and applicability. Among studies that entered the meta-analysis, none had both an applicability rating of I (representative of general adult population with rheumatoid arthritis), and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Table 3.18). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with RA. Of note, no studies that assessed the effect of omega-3 fatty acids on swollen joints among children with JRA were identified.

Rheumatoid Arthritis: Disease Activity (Erythrocyte Sedimentation Rate)

Table 3.19 RA: effect size for ESR

	Intervention		Control
Trial	Source	n	Source	n	Effect Size (95% CI)
Kremer¹⁸	Max EPA (fish oil)	17	Placebo	20	-0.44 (-1.1, 0.21)

Magaro²¹	Max EPA (fish oil)	10	Placebo	10	-0.16 (-1.04, 0.72)

Nielsen²²	Pikasol (fish oil)	27	Placebo	24	0.06 (-0.49, 0.61)

Nordstrom²³	Flaxseed oil	11	Placebo	11	0.13 (-0.71, 0.96)

Skoldstam²⁵	Max EPA (fish oil)	22	Placebo	21	0.04 (-0.55, 0.64)

Tulleken²⁴	Fish oil	13	Placebo	14	-1.82 (-2.71, -0.92)

Pooled Random Effects Estimate					-0.32 (-0.83, 0.19)

Chi-squared test of heterogeneity p-value = 0.01

An external file that holds a picture, illustration, etc., usually as some form of binary object. The name of referred object is er-03lipidsf11.jpg.

Figure 3.10 RA: swollen joint count

Figure 3.10 RA: swollen joint count

Overall effect. The effect of omega-3 fatty acids on disease activity (Erythrocyte Sedimentation Rate [ESR]) in rheumatoid arthritis was described in 16 studies, 6 of which could be used for meta-analysis. Among these studies, 1 (in which the population had JRA) reported significant improvement relative to placebo²⁷ and 1 reported significant improvement from baseline.²¹ There were no significant effects in 13 studies.^16, ^18, ^19, ^22–24, ^25, ^28, ^29, ^32–35, ³⁸ The pooled random effect estimate for the effect of omega-3 fatty acids on ESR relative to placebo is -0.32 (95% CI, -0.83, 0.19) (Table 3.19, Figure 3.10

). In this analysis and effect size of 1.0 is equivalent to 23.79 mm/hr. So, an effect size of -0.32 is equivalent to a reduction in ESR by 7.6 mm/hr. Among the studies excluded from the meta-analysis, one reported a benefit for omega-3 relative to placebo, but in a special population, JRA; none of the remaining studies reported a significant benefit relative to placebo.

Of note, there was significant heterogeneity among these studies (chi-squared test of heterogeneity =0.01). Visual inspection of the Forest plot identified one outlier study.²⁴ With this study removed from the pooled analysis, the pooled random effects estimate for the effect of omega-3 fatty acids on ESR relative to placebo is -0.07 (95% CI, -0.37, 0.23), and the chi-squared test for heterogeneity is not significant (p = .77). The outlier study is similar to the other studies in the pooled analysis in terms of study design, source, dose, and duration of omega-3 fatty acid treatment. The characteristics of the study population in the outlier study are also similar to those of the other studies in the pooled analysis in terms of age, disease duration, number of swollen joints, and number of tender joints. However, the baseline ESR and C-Reactive Protein (CRP) values for the control group in the outlier study were significantly higher than for the experimental group (p<0.05). This observation suggests that the disease activity may have been higher in the control group than in the experimental group, which could bias toward a more favorable estimate of the effect of omega-3 fatty acids.

The effect of omega-3 fatty acids on ESR in rheumatoid arthritis has also been assessed in a previously published meta-analysis. ⁹⁷ This meta-analysis reported improvement with fish oil relative to placebo; however, this improvement was not statistically significant (estimate not reported).

Sub-populations. One study assessed the effect of cod liver oil on ESR among children with JRA. This study demonstrated a significant reduction in ESR for cod liver oil relative to placebo.²⁷

Covariates. The effect of covariates on the efficacy of omega-3 fatty acids was not specifically assessed in any of the studies identified.

Effects of dose, source, and exposure duration.One study assessed the effect of two different doses of omega-3 fatty acids on outcomes in RA.¹⁹ In this study, there was a significant improvement in ESR at 24 and 36 weeks relative to baseline for subjects treated with a lower dose of fish oil. Among patients treated with a higher dose of fish oil, the improvement relative to baseline was significant only at 24 weeks. There were insufficient data across studies to perform a pooled analysis of dose or source effect.

In one study, plants were the source of omega-3 fatty acids. In this study,²³ the effect size of omega-3 fatty acids for ESR was 0.13 (95% CI, -0.71, 0.96). Restricting the pooled analysis to the remaining studies, which used a fish source, the pooled random effects estimate of the effect size for ESR was -0.41 (95% CI, -0.99, 0.18).

Sustainment of effect.The sustainment of effects of omega-3 fatty acids on ESR or CRP in RA was not clearly described in any studies. In one study,²⁸ 100% of the control arm (evening primrose oil) and 80% of the fish oil group “returned to baseline or became worse.” Although pain, joint swelling, and ESR were assessed in this study, the parameters on which this assessment was made were not specified.

Table 3.20 Relationship between methodologic quality (more...)

Table 3.20 Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on ESR among people with rheumatoid arthritis

Methodological Quality
Applicability		A	B			C
	I		Study	n	Effect Size(95% CI)	Study	n	Effect Size(95% CI)
			Kremer¹⁸	37	-0.44 (-1.10, 0.21)
			Skoldstam²⁵	43	0.04 (-0.55, 0.64)
	II		Tulleken²⁴	27	-1.82 (-2.71, -0.92)	Magaro ²¹	20	-0.16 (-1.04, 0.72)
	III

Quality and applicability. Among studies that entered the meta-analysis, none had both an applicability rating of I (representative of general adult population with rheumatoid arthritis), and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Table 3.20). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with RA. Of note, one study that assessed the effect of omega-3 fatty acids on ESR among children with JRA was identified.

Rheumatoid Arthritis: Patient's Global Assessment

Table 3.21 RA: effect size for patient global assessment (more...)

Table 3.21 RA: effect size for patient global assessment

	Intervention		Control

Trial	Source	n	Source	n	Effect Size (95% CI)
Geusens¹⁷	Fish oil	21	Placebo	20	-1.38 (-1.97, -0.79)
	Fish oil	19

Kremer¹⁹	Fish oil	20	Placebo	12	-0.13 (-0.78, 0.52)
	Fish oil	17

Kremer¹⁸	Max EPA (fish oil)	17	Placebo	20	-0.24 (-0.89, 0.41)

Nordstrom²³	Flaxseed oil	11	Placebo	11	0.26 (-0.58, 1.10)

Skoldstam²⁵	Max EPA (fish oil)	22	Placebo	21	0.11 (-0.49, 0.71)

Pooled Random Effects Estimate					-0.30 (-0.90, 0.30)

Chi-squared test of heterogeneity p-value = 0.002

An external file that holds a picture, illustration, etc., usually as some form of binary object. The name of referred object is er-03lipidsf12.jpg.

Figure 3.11 RA: ESR

Figure 3.11 RA: ESR

Overall effect. The effect of omega-3 fatty acids on patient's global assessment in RA was described in 8 studies, 5 of which could be used for meta-analysis. Among these studies, 1 reported significant improvement relative to placebo,¹⁷ and 3 reported significant improvement from baseline.^25, ^26, ³⁰ There were no significant effects in 4 studies.^16, ^18, ^19, ³¹ The pooled random effect estimate for the effect of omega-3 fatty acids on patient's global assessment relative to placebo is -0.30 (95% CI, -0.90, 0.30) (Table 3.21, Figure 3.11

). In this analysis, an effect size of 1.0 is equivalent to 0.7 units on the patient global assessment scale. So, an effect size of -0.30 is equivalent to a decrease on the scale by 0.21 units. None of the studies that were excluded from the meta-analysis demonstrated a significant of omega-3 fatty acids on patient's global assessment.

Of note, there was significant heterogeneity among these studies (chi-squared test of heterogeneity =0.002). Visual inspection of the Forest plot identified one outlier study.¹⁷ With this study removed from the pooled analysis, the pooled random effect estimate for the effect of omega-3 fatty acids on patient global assessment relative to placebo is -0.02 (95% CI, -0.36, 0.31) and the chi-squared test for heterogeneity is not significant (p = .76). On qualitative review of the outlier study, we could find no characteristics that differed from the other studies. The outlier study is similar to the other studies in the pooled analysis in terms of study design, source, and dose of omega-3 fatty acid. The characteristics of the study population in the outlier study are similar to those of the other studies in the pooled analysis in terms of age, disease duration, number of swollen joints, and number of tender joints. Although the study duration is longer (12 months) in the outlier study than in the other studies (3–9 months), a common time point for assessment (3 months) was used in the pooled analysis.

The effect of omega-3 fatty acids on patient's global assessments in RA has also been assessed in a previously published meta-analysis.⁹⁷ This meta-analysis reported improvement with fish oil relative to placebo; however, this improvement was not statistically significant (estimate not reported).

Sub-populations. No studies assessed the effects across sub-populations.

Covariates. One study assessed the effect of combining different diets (Western versus modified lacto-vegetarian) with omega-3 fatty acids on patient's global assessment in RA.²⁶ In this study, among subjects treated with fish oil, there was a reduction in patient's global assessment among patients on a modified lacto-vegetarian diet relative to a Western diet (p<0.01)

Effects of dose, source, and exposure duration. One study assessed the effect of different doses of omega-3 fatty acids on outcomes in RA.¹⁹ In this study, the effect of fish oil on patient's global assessment did not differ between doses. There were insufficient data across studies to perform a pooled analysis of dose or source effect.

In one study plants were the source of omega-3 fatty acids. In this study,²³ the effect size of omega-3 fatty acids for patient global assessment was 0.26 (95% CI, -0.58, 1.10). Restricting the pooled analysis to the remaining studies, which used a fish source, the pooled random effects estimate of the effect size for patient global assessment was -0.42 (95% CI, -1.09, 0.26).

One study assessed the effects of omega-3 fatty acids on outcomes in RA for different durations of exposure.¹⁹ In this study, there was no effect on patient's global assessment at 24 and 36 weeks, although statistical testing of the effect between these time points was not performed.

Sustainment of effect. One study assessed the sustainment of effects of omega-3 fatty acids on patient's global assessment in RA.¹⁸ In this study, patient's global assessment worsened in a group that had been in a fish oil-treated arm, 3 months after discontinuation of the fish oil (p<0.05).

Table 3.22 Relationship between methodologic quality (more...)

Table 3.22 Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on global assessment among people with rheumatoid arthritis

Methodological Quality
Applicability		A	B			C
	I		Study	n	Effect Size(95% CI)	Study	n	Effect Size(95% CI)
			Geusens¹⁷	60	-1.38 (-1.97, -0.79)	Kremer¹⁹	49	-0.13 (-0.78, 0.52)
			Kremer¹⁸	37	-0.24 (-0.89, 0.41)
			Skoldstam²⁵	43	0.11 (-0.49, 0.71)
	II
	III

Table 3.23 Summary of reported adverse events.*

		Sample Size		Adverse evenet count
Adverse Event	Total # of studies	N for Omega 3	N for Placebo/ Control	N for Omega 3	N for Placebo/ Control	Adverse event rate Omega 3	Adverse event rate Placebo
Clinical bleeding	1	73	NR**	2	0	2.74%	----

GI complaint or nausea	13	885	685	72	34	8.14%	4.96%

Diarrhea	3	159	104	11	5	6.92%	4.81%

Headaches	2	31	26	2	0	6.45%	0.00%

Withdrawal due to adverse event	10	353	228	13	9	3.68%	3.95%

Dermatological	4	190	159	5	10	2.63%	6.29%

• N = number of individuals with an adverse event. **Not reported. No placebo arm reported on clinical bleeding.

Quality and applicability. Among studies that entered the meta-analysis, none had both an applicability rating of I (representative of general adult population with rheumatoid arthritis), and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Table 3.22 ). Similarly there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with RA. Of note, no studies that assessed the effect of omega-3 fatty acids on patient's global assessment among children with JRA were identified.

Rheumatoid Arthritis: Joint Damage

Overall effect. We identified one study that assessed the effect of omega-3 fatty acids on joint damage in RA.²⁹ In this study, the Larsen score of radiographic damage was not affected by administering the omega-3 fatty acids in the form of a diet high in fish.

Rheumatoid Arthritis: Tender Joint Count

Overall effect. The effect of omega-3 fatty acids on tender joint count in RA has been assessed in a previously published meta-analysis. ⁹⁷ Inclusion criteria for this meta-analysis were 1) double blind, placebo controlled trial, 2) use of at least one of seven predetermined outcome measures, including tender joint count, 3) results reported for both placebo and treatment groups at baseline and follow-up, 4) randomization, and 5) parallel or cross-over design. A Medline search through 1991 identified 10 trials that met the inclusion criteria, 6 of which were analyzed for tender joint count. The rate difference between fish oil and placebo for tender joint count was -2.9 (95% CI, -3.8, -2.1).

Analysis of subpopulations and covariates, effects of dose, source, and exposure duration, and sustainment of effect were not addressed in this meta-analysis.

Rheumatoid Arthritis: Effect on Anti-inflammatory/ Immunosuppressive Drug Requirement

Overall effect. We identified 7 studies that assessed the effect of omega-3 fatty acids on anti-inflammatory and/or immunosuppressive drug requirements among patients with RA. All 7 studies assessed the effect on requirement for anti-inflammatory drugs. Among these studies, there was significant improvement relative to placebo for omega-3 treated subjects in 3,^30–32 significant improvement relative to baseline requirements in 3,^25, ^26, ²⁸ and no difference in NSAID requirement in 1.²⁹ One study, which assessed the effect of omega-3 fatty acids on steroid requirements, demonstrated significant improvement relative to placebo.³⁰ We did not identify any studies that assessed the effect of omega-3 fatty acids on disease modifying antirheumatic drug (DMARD) requirement.

Sub-populations. Not assessed in any identified studies.

Covariates. Not assessed in any identified studies.

Effects of dose, source, and exposure duration. The effects of dose, source, and exposure duration were not specifically assessed in any of the studies.

Sustainment of effect. Two studies demonstrated that the effect of omega-3 fatty acids on the requirement for NSAIDs in RA was not sustained.^30, ³¹

RENAL DISEASE

Summaries of all renal disease studies we evaluated can be found in Appendix C.4.

Renal Disease: Clinical Effect

Overall effect. The effect of omega-3 fatty acids on each of the following was assessed in patients with renal disease: serum creatinine, creatinine clearance, progression to end stage renal disease (ESRD), hemodialysis graft thrombosis/patency, and mortality. A total of studies were identified that reported these outcomes. There were insufficient data to perform meta-analysis on any of the outcomes.

Effects on serum creatinine were described in 4 studies: 1 reported a statistically significant improvement with fish oil relative to placebo,⁹⁸ 1 reported no effect,⁹⁹ and 2 reported worsening.^100, ¹⁰¹ Among the studies that reported worsening, neither reported testing of statistical significance between the omega-3 and control arms, and in one, there was worsening for both the omega-3 and control group.

Creatinine clearance was reported in 3 studies: 1 reported a statistically significant improvement with fish oil relative to placebo,⁹⁸ and 2 reported worsening.^100, ¹⁰¹ Among the studies that reported worsening, neither reported testing of statistical significance between the omega-3 and control arms, and in one, there was worsening for both the omega-3 and control groups.

Progression to ESRD was reported in 2 studies:^98, ¹⁰⁰ one demonstrated a favorable effect for fish oil relative to placebo,⁹⁸ and the other demonstrated no effect.

Hemodialysis graft thrombosis/patency was described in 2 studies.^102, ¹⁰³ In one, graft patency was significantly better for fish oil than for placebo.¹⁰² There were no graft thromboses in either the omega-3 fatty acid or the control groups.¹⁰³

Mortality was reported in two studies.^98, ¹⁰⁴ Statistical testing for between group mortality rates was not reported in either. In one, mortality over 5 years was 2.0% in the placebo group and 1.8% in the omega-3 group;⁹⁸ in the other, the mortality over 5 years was zero in a low-dose fish oil group and 6% in a high-dose fish oil group.¹⁰⁴

Meta-Analysis. Across the studies identified, only three were sufficiently homogeneous in terms of the population studies and the outcomes reported to consider for meta-analysis. These studies evaluated the effects of omega-3 fatty acids on Immunoglobulin A(IgA) nephropathy.^98, ^100, ¹⁰¹ These studies, along with two other studies^117, ¹¹⁸ that were identified but not included in this report because they did not meet our inclusion criteria, have been evaluated in a previously published meta-analysis.¹⁰⁵ This meta-analysis calculated effect sizes for treatment effect based on either serum creatinine concentration or creatinine clearance. Although the pooled effect size for the five studies was positive (i.e. favoring treatment over control), it was small (0.25) and not statistically significant (p=0.27).

Sub-populations. No studies that assessed the differential effect of omega-3 fatty acids across distinct subpopulations of renal disease were identified. Among the studies identified, the renal disease in the study sample was IgA nephropathy in four,^98, ^100, ^101, ¹⁰⁴lupus nephritis in one,⁹⁹ glomerular disease in one,¹⁰⁶ and ESRD requiring dialysis in two.^102, ¹⁰³

Covariates. The effect of omega-3 fatty acids on covariates was not assessed in any of the identified studies.

Dose and source effect. Dose and source effects of omega-3 fatty acids were not assessed in any of the identified studies.

Exposure duration. Effect of exposure duration of omega-3 fatty acids was not assessed in any of the identified studies.

Sustainment of effect. Sustainment of effect after discontinuation of omega-3 fatty acids was not assessed in any of the identified studies.

Renal Disease: Effect on Corticosteroid/Other Immunosuppressive Drug Requirement

We did not identify any studies that assessed the effects of omega-3 fatty acids on requirements for corticosteroids or other immunosuppressive drugs.

SYSTEMIC LUPUS ERYTHEMATOSUS

Summaries of all systemic lupus erythematosus studies we evaluated can be found in Appendix C.5.

Systemic Lupus Erythematosus: Clinical Effect

Overall effect. The effect of omega-3 fatty acids on each of the following was assessed in patients with SLE: disease activity, damage, and patient perception of disease. A total of 3 studies was identified that reported disease activity;^99, ^107, ¹⁰⁸ no studies that assessed the other outcomes were identified. There were insufficient data to perform meta-analysis on disease activity.

Disease activity was described using clinical and laboratory scores. Improvement in disease activity was reported in one study, which used a clinical score developed for that study (validity of score not described).¹⁰⁷ The other studies reported no effect on the SLE Disease Activity Index (SLEDAI)⁹⁹ or on another clinical score developed for the study (validity of instrument not described).¹⁰⁸ Levels of anti-DNA antibodies and complement levels were assessed in two of the studies;^99, ¹⁰⁸ neither demonstrated an omega-3 fatty acid effect. No studies were identified that assessed effect on damage or patient perception of disease.

Sub-populations. No studies that assessed the differential effect of omega-3 fatty acids across distinct subpopulations of SLE were identified.

Covariates. The effect of omega-3 fatty acids on covariates were not assessed in any of the identified studies.

Dose and source effect. Dose and source effects of omega-3 fatty acids were not assessed in any of the identified studies.

Exposure duration. Effect of exposure duration of omega-3 fatty acids was not assessed in any of the identified studies.

Sustainment of effect. One study was designed to evaluate for sustainment of effect after discontinuation of omega-3 fatty acids.¹⁰⁸ However, in this study, no main effect was demonstrated before discontinuation of the omega-3 fatty acid.

Systemic Lupus Erythematosus: Effect on Steroid/Other Immunosuppressive Drug Requirement

We identified one study that assessed the effects of omega-3 fatty acids on requirements for corticosteroids.⁹⁹ In this study, omega-3 fatty acids had no effect on steroid requirements. We identified no studies that assessed the effects of omega-3 fatty acids on requirements for other immunosuppressive drugs.

BONE DENSITY/OSTEOPOROSIS

Summaries of all bone density/osteoporosis studies evaluated can be found in Appendix C.6.

Bone Density/Osteoporosis: Clinical Effect

Overall effect. The effects of omega-3 fatty acids on bone mineral density and fracture rate were assessed. In total, 5 studies described in 4 reports were identified that reported bone mineral density;^109–112 no studies of fracture rate were identified. There were insufficient data to perform meta-analysis on bone mineral density.

Improvement in bone mineral density for omega-3 fatty acids relative to placebo was described in one study;¹¹¹ improvement relative to baseline was described in one study.¹¹⁰ In two studies, omega-3 fatty acids had no effect on bone mineral density.^109, ¹¹²

Sub-populations. One report described separate studies performed in pre-menopausal and post-menopausal women. No effect was seen in either population.

Covariates. The effect of omega-3 fatty acids on covariates was not assessed in any of the identified studies.

Dose and source effect. Dose and source effects of omega-3 fatty acids were not assessed in any of the identified studies.

Exposure duration. Effect of exposure duration of omega-3 fatty acids was not assessed in any of the identified studies.

Sustainment of effect. Sustainment of effect after discontinuation of omega-3 fatty acids was not assessed in any of the identified studies.

Publication Bias

There was no evidence of publication bias on the funnel plots and adjusted rank correlation testing (not shown) performed for studies that entered meta-analysis.

Adverse Events

Among 83 articles across the six topic areas of this report that were reviewed for adverse events, 28 reported adverse events, which are summarized in Table 3.22.

Chapter 4. Discussion

Overview

We screened 4,212 titles, from which we reviewed 1,097 full text articles. Among these, 83 articles met our inclusion criteria; 34 for diabetes/ metabolic syndrome, 13 for inflammatory bowel disease, 21 for rheumatoid arthritis, 9 for renal disease, 3 for systemic lupus erythematosus and 4 for bone density and fractures. All articles except one were randomized controlled trials; one was an observational study of bone density.

Most of the studies assessed the effect of omega-3 fatty acids in the form of fish oil; however, some assessed the effect of diets rich in fish. Across all conditions and studies, only 4 studies evaluated omega-3 fatty acids derived from plant oils; three for diabetes ^65, ^66, ⁷⁰ and 1 for RA.²³ Few studies assessed dose or source effect, effect of treatment duration, or the sustainment of effect after discontinuation of omega-3 fatty acid consumption.

Main Findings

Diabetes/metabolic syndrome. Among 13 studies of type II diabetes or the metabolic syndrome, that were assessed by meta-analysis, omega-3 fatty acids had a favorable effect on triglyceride levels relative to placebo (pooled random effects estimate: -31.61; 95% CI, -49.58, -13.64) but had no effect on total cholesterol, HDL cholesterol, LDL cholesterol, fasting blood sugar, or glycosylated hemoglobin, by meta-analysis. Omega-3 fatty acids had no effect on plasma insulin or insulin resistance in type II diabetics or patients with the metabolic syndrome, by qualitative analysis of four studies.

These results are consistent with the results of another meta-analysis for fish oil,¹¹⁶ which found significant triglyceride-lowering and LDL-raising effects and no significant effect on fasting blood glucose, glycosylated hemoglobin, total cholesterol, or HDL cholesterol among diabetics. Although the analysis presented here did not find a significant effect on LDL, the point estimate is consistent with a LDL raising effect and the confidence interval barely crosses null (95% CI, -1.02, 11.25).

The effects of omega-3 fatty acids on triglycerides in diabetics presented here and elsewhere are consistent with the triglyceride-lowering effects of omega-3 fatty acids that have been demonstrated for the general population and are being detailed in a separate evidence report “Effects of Omega-3 Fatty Acids on Cardiovascular Risk Factors” (in preparation at the New England Medical Center Evidence Based Practice Center). Regarding the lack of effect that omega-3 fatty acids have on insulin sensitivity, it is possible that any beneficial effects of omega-3 fatty acids on insulin sensitivity could be attenuated by their high calorie content.

Inflammatory bowel disease. Among 13 studies reporting outcomes in patients with inflammatory bowel disease, variable effects of omega-3 fatty acids on clinical score, sigmoidoscopic score, histologic score, induced remission, and relapse were reported. In ulcerative colitis, omega-3 fatty acids had no effect on the relative risk of relapse in a meta-analysis of 3 studies. There was a statistically non-significant reduction in requirement for corticosteroids for omega-3 fatty acids relative to placebo in 2 studies. No studies evaluated the effect of omega-3 fatty acids on requirement for other immunosuppressive agents.

Appendixes and Evidence Tables cited in this report are provided electronically at http://www.ahrq.gov/clinic/epcindex.htm

Rheumatoid arthritis. Among 9 studies reporting outcomes in patients with rheumatoid arthritis, omega-3 fatty acids had no effect on patient report of pain, swollen joint count, ESR, and patient's global assessment by meta-analysis. The one study that assessed the effect on joint damage found no effect. In a qualitative analysis of 7 studies that assessed the effect of omega-3 fatty acids on anti-inflammatory drug or corticosteroid requirement, 6 demonstrated reduced requirement for these drugs. No studies assessed the effect on requirements for disease modifying anti-rheumatic drugs. None of the studies used a composite score that incorporates both subjective and objective measures of disease activity, such as the American College of Rheumatology response criteria.

A previously performed meta-analysis⁹⁷ reached the same conclusions for swollen joint count, ESR, and patient's global assessment. That meta-analysis found a statistically significant improvement in tender joint count compared to placebo (rate difference= -2.9, 95% CI -3.8, -2.1).

Renal disease. In a qualitative analysis of nine studies that assessed the effect of omega-3 fatty acids in renal disease, there were varying effects on serum creatinine and creatinine clearance; one study demonstrated less progression to end stage renal disease with omega-3 fatty acids relative to control. In a single study that assessed the effect on hemodialysis graft patency, graft patency was significantly better with fish oil than with placebo. No studies that assessed the effects of omega-3 fatty acids on requirements for corticosteroids or other immunosuppressive drugs for the treatment of renal disease were identified.

Systemic lupus erythematosus. Among 3 studies that assessed the effects of omega-3 fatty acids in SLE, variable effects on clinical activity were reported. No studies were identified that assessed effect on damage or patient perception of disease. Omega-3 fatty acids had no effect on corticosteroid requirements in 1 study. No studies were identified that assessed the effects of omega-3 fatty acids on requirements for other immunosuppressive drugs for SLE. None of the studies used a measure of disease activity that incorporates both subjective and objective measures of disease activity.

Bone mineral density/fracture. Among five studies described in 4 reports the effect of omega-3 fatty acids on bone mineral density was variable. No studies that assessed the effect of omega-3 fatty acids on fracture were identified.

Dose, source, duration effects and sustainment of effect. Among studies that assessed the effects of omega-3 fatty acids in diabetes, there was no dose effect for any outcome by meta-regression. There are insufficient data to draw conclusions about source or duration effects, or about sustainment of effect.

Adverse events. Across all conditions, the incidence of gastrointestinal complaints or nausea, diarrhea, and headaches appears to be higher among patients receiving omega-3 fatty acids than among those in control groups. Strong conclusions cannot be drawn from this observation because adverse events were not reported in a standard manner in clinical trials, either in terms of the events defined or the frequency with which they were recorded. Additionally, the underlying conditions being studied will affect the rates of specific adverse events.

Conclusions

The quantity and strength of evidence for effects of omega-3 fatty acids on outcomes in the conditions assessed varies greatly. The findings of many studies among type II diabetics provide strong evidence that omega-3 fatty acids reduce serum triglycerides but have no effect on total cholesterol, HDL cholesterol and LDL cholesterol. For rheumatoid arthritis, the available evidence suggests that omega-3 fatty acids reduce tender joint counts and may reduce requirements for corticosteroids, but does not support an effect of omega-3 fatty acids on other clinical outcomes. There are insufficient data available to draw conclusions about the effects of omega-3 fatty acids on inflammatory bowel disease, renal disease, SLE, bone density, or fractures or the effects of omega-3 fatty acids on insulin resistance among type II diabetics.

Future Research

We offer the following observations and recommendations regarding future research on the effects of omega-3 fatty acids on lipids and glycemic control in type II diabetes and the metabolic syndrome and on inflammatory bowel disease, rheumatoid arthritis, renal disease, systemic lupus erythematosus, and osteoporosis.

Additional research on the effects of omega-3 fatty acids need to be performed on inflammatory bowel disease, renal disease, SLE, bone density, or fractures or the effects of omega-3 fatty acids on insulin resistance among type II diabetics before recommendations regarding the use of omega-3 fatty acids for these conditions can be made.
Studies of inflammatory bowel disease that include patients with both Crohn's disease and ulcerative colitis should report data separately for these groups.
Studies that assess the effects of omega-3 fatty acids should use standard validated instruments to assess clinical outcomes.
Trials that assess the effects of omega-3 fatty acids should be designed to evaluate the effect of source, dose, treatment duration, and the sustainment of effect after discontinuation of omega-3 fatty acid consumption.
Studies of omega-3 fatty acids should explicitly define both the quantity of the omega-3 fatty acid source and of the specific omega-3 fatty acids present in a study dose of that source.
Trials of omega-3 fatty acids should include a baseline assessment of dietary omega-3 and omega-6 fatty acid intake.
In controlled trials that assess the effects of omega-3 fatty acids, analysis should include and report explicit testing of the effects of the omega-3 fatty acid relative to the control substance.
In studies that use a crossover design, outcome data for all study arms should be reported at the end of each treatment period.

Acronyms

AA	Arachidonic acid

Ab	Antibody

AHRQ	Agency for Healthcare Research and Quality

Al	Adequate intake

ALA	Alpha-linolenic acid

AMDR	Acceptable macronutrient distribution ranges

ANCOVA	Analysis of covariance

ANOVA	Analysis of variance

Ca	Calcium

CCT	Controlled clinical trial

CI	Confidence interval

CRP	C-reactive protein

CSFII	Continuing Food Survey of Intakes by Individuals

d	day

D6D	Delta-6 Desaturase

DGLA	Dihomo-gamma-linolenic acid

DHA	Docosahexaenoic acid

DPA	Docosapentaenoic acid

DRI	Dietary Reference Intake

Ds-DNA	Double-stranded DNA

EF	Effect size

EFA	Essential fatty acid

EPA	Eicosapentaenoic acid

EPC	Evidence-Based Practice Center

ESR	Erythrocyte sedimentation rate

FNB	Food and Nutrition Board

g	grams

GI	Gastrointestinal

GLA	Gamma-linolenic acid

HDL	High density lipoprotein

IBD	Inflammatory bowel disease

IL-1ß	Interleukin 1ß

JRA	Juvenile rheumatoid arthritis

IOM	Institute of Medicine

LA	Linoleic acid

LC PUFA	Long-chain polyunsaturated fatty acid

LDL	Low density lipoprotein

MA	Metaanalysis

MANOVA	Multivariate analysis of variance

MeSH Term	Medical Subject Headings Term

mg/dl	Milligrams per deciliter

min	Minutes

Mo	Month

n	Number

n-3	Omega-3

n-6	Omega-6

NA	Not applicable

NHANES III	The Third National Health and Nutrition Examination

NCI	National Cancer Institute

NEI	National Eye Institute

NEMC	New England Medical Center

NHANES	National Health and Nutrition Examination

NHLBI	National Heart, Lung and Blood Institute

NIAAA	National Institute of Alcohol Abuse and Alcoholism

NIAID	National Institute of Allergy and Infectious Diseases

NIAMS	National Institute of Arthritis and Musculoskeletal and Skin Diseases

NICHD	National Institute of Child Health and Human Development

NIDDK	National Institute of Diabetes and Digestive and Kidney Diseases

NIH	National Institutes of Health

NNH	Number needed to harm

NR	Not reported

NSAIDS	Non-Steroidal Anti-Inflammatory Drugs

ODS	Office of Dietary Supplements

PG	Prostaglandin

PGD	Prostaglandin-D

PGE	Prostaglandin-E

PGF	Prostaglandin-F

PGL	Prostaglandin-L

PGH	Prostaglandin-H

PUFA	Polyunsaturated fatty acid

QRF	Quality review form

RA	Rheumatoid arthritis

RCT	Randomized controlled trial

RDA	Recommended daily allowances

RXT	Randomized crossover trial

Sd	Standard deviation

SCEPC	Southern California Evidence-Based Practice Center

SLE	Systemic lupus erythematosus

SEM	Standard errors of the means

TEP	Technical expert panel

TNF-a	Tumor necrosis factor-a

TX	Treatment

TXA	Thromboxane-A

UCLA	University of California, Los Angeles

VLCFA	Very long chain fatty acid

VLN-3FA	Very long chain n-3 fatty acids

wk	Week

Appendix A. Methodologic Approach

A.1 Preliminary Research Questions

Table A.1.1 Preliminary research questions

General Questions: Questions posed for all three participating EPCs, for years 1 and 2.

What is the evidence that variable clinical effects may reflect differences in:
- Serving size (fish vs. dietary supplement);
- Source (fish, food, plant) vs. dietary supplement (fish oil, plant oil);
- Specific type(s) of omega-3 fatty acids (docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and alpha-linolenic acid (ALA), fish, fish oil), or the ratio of omega-6/omega-3 fatty acids used;
- Manufacturer (different purity, presence of other potentially active agents)?
What is the evidence for adverse events, side effects, or counter-indications associated with omega-3 fatty acids (DHA, EPA, DPA, ALA, fish oil, fish)?
What is the evidence that omega-3 fatty acids are associated with adverse events in specific subpopulations such as diabetics?
What are the mean and median intakes of DHA, EPA, DPA, ALA, fish, fish oil, omega-6, omega-6/omega-3 ratio in the US population?
What is the evidence that omega-3 fatty acids influence overall energy balance?
What is the evidence that accurate interpretation of the results of clinical studies is dependent on knowing the absolute fatty acid content of the baseline data, the relative fatty acid content of the baseline diet, or the tissue ratios of fatty acids (omega-6/omega-3) during the investigative period?

DISEASE-SPECIFIC QUESTIONS: questions posed to the SCEPC for Year 1 of the project:

Immune-Mediated Diseases

What is the evidence that in adults or children with type I diabetes, omega-3 fatty acids increase insulin sensitivity?
What is the evidence that in adults or children with rheumatoid arthritis, omega-3 fatty acids decrease pain or the number of swollen joints?
What is the evidence that omega-3 fatty acids help maintain bone mineral status?
What is the evidence that in adults or children with inflammatory bowel disease (ulcerative colitis and Chrohn's disease), omega-3 fatty acids lower leukotriene B4 or prostaglandin E2 levels?
What is the evidence that in adults or children with systemic lupus erythematosis, omega-3 fatty acids prolong longevity?

Gastrointestinal/Renal

What is the evidence for the efficacy of omega-3 fatty acids in treatment of Crohn's disease, ulcerative colitis, renal inflammation, and glomerulosclerosis?
What is the evidence for the efficacy of omega-3 fatty acids in treatment of the hypertriglyceridemia of type II diabetes, insulin resistance, or the metabolic syndrome?
What is the evidence that omega-3 fatty acids influence the regulation of gene expression in the progression/prevention of obesity, and intestinal and liver diseases?

A.2 Technical Expert Panel

The members of our technical expert panels are listed in Table A.2.1. We conducted our TEP meetings via teleconference. We held a conference call with the rheumatoid arthritis, systemic lupus erythematosis, and bone density TEP on February 7, 2003; the renal/diabetes TEP on February 12, 2003; and the gastrointestinal TEP on February 12, 2003. Dr. Rosaly Correa-de-Araujo, the Task Order Officer, and Jacqueline Besteman, Director of the Evidence-Based Practice Center Program, represented AHRQ on these calls; Dr. Anne Thurn, Director of the Evidence-Based Review Program, represented ODS; and Dr. Paul Shekelle, Director of the SCEPC, Dr. Catherine MacLean, the Task Order Director, and Rena Hasenfeld, the Project Manager, represented the SCEPC. The key comments and recommendations of each TEP are summarized in Table A.2.2. The TEP continued to advise the SCEPC throughout the project via mail, fax, e-mail, and phone calls.

Table A.2.1 Technical expert panel members

Rheumatoid Arthritis, Systemic Lupus Erythematosis, and Bone Density TEP
Name	Area of Expertise	Institution

Judith Ashley, PhD, MSPH, RD	Omega-3 Fatty Acids	University of Nevada School of Medicine

William S. Harris, PhD	Omega-3 Fatty Acids	University of Missouri-Kansas City School of Medicine

Robert P. Heaney, MD	Bone	Creighton University

David A. Isenberg, MD	SLE	University College London Medical School

Joel Kremer, MD	Rheumatoid Arthritis	The Center for Rheumatology

Bruce A. Watkins, PhD	Omega-3 Fatty Acids	Purdue University

Josiah F. Wedgwood, MD, PhD	Rheumatoid Arthritis	National Institute of Allergy and Infectious Diseases

Renal Disease and Diabetes TEP
Name	Area of Expertise	Institution

Judith Ashley, PhD, MSPH, RD	Omega-3 Fatty Acids	University of Nevada School of Medicine

Mayer B. Davidson, MD	Diabetes	Charles R. Drew University of Medicine and Science

James V. Donadio, MD	Renal Diseases	Mayo Medical School

William S. Harris, PhD	Omega-3 Fatty Acids	University of Missouri-Kansas City School of Medicine

Michael D. Jensen, MD	Diabetes	Mayo Medical School

William F. Keane, MD	Renal Diseases	Merck and Co., Inc.

Catherine Meyers, MD	Renal Diseases	NIDDK, Division of Kidney, Urologic & Hematologic Diseases

Gastrointestinal Diseases TEP
Name	Area of Expertise	Institution

Judith Ashley, PhD, MSPH, RD	Omega-3 Fatty Acids	University of Nevada School of Medicine

Andrea Belluzzi, MD	Irritable Bowel Disease	S Orsola Hospital, Bologna, Italy

Frank Hamilton, MD	Irritable Bowel Disease	NIDDK, Division of Digestive Diseases & Nutrition

William S. Harris, PhD	Omega-3 Fatty Acids	University of Missouri-Kansas City School of Medicine

Stephen James, MD	Inflammatory Bowel Disease	NIDDK, Division of Digestive Diseases & Nutrition

Michael Ken May, PhD	Inflammatory Bowel Disease	NIDDK, Division of Digestive Diseases & Nutrition

William F. Stenson, MD	Inflammatory Bowel Disease	Washington University

Table A.2.2 Key TEP comments and recommendations

Rheumatoid Arthritis, Systemic Lupus Erythematosis, and Bone Density TEP

1. What is the evidence that in adults or children with rheumatoid arthritis, omega-3 fatty acids decrease pain or the number of swollen joints?

• Restrict the search to randomized control trials.

• Include children with juvenile rheumatoid arthritis for now.

• If possible, the outcome measures should include: disease activity, damage, and patient perception (i.e. patient global assessment).

2. What is the evidence that omega-3 fatty acids help maintain bone mineral status?

• Include both randomized controlled trials and observational studies.

• The populations of interest are older women and women with osteoporosis.

• Outcomes for randomized controlled trials will likely be measures of bone density and biologic markers.

• Outcomes for observational studies are more likely to include fracture rates.

• There is a need to adjust for ethnicity in the analyses because bone shape may affect the • rate of fractures.

• In studies that report t-scores, there is a need to note the standard used to compute the t-score; WHO and NHANES are two different standards that may be used.

3. What is the evidence that in adults or children with systemic lupus erythematosus, omega-3 fatty acids prolong longevity?

• Restrict the study to randomized controlled trials.

• Longevity is not the correct outcome to assess.

• Recommended outcomes for assessment include disease activity, damage, and • patient perception (i.e. patient global assessment).

General Comments

• Note reported side effects of omega-3 fatty acids when reviewing the literature.

Renal Disease and Diabetes TEP

1. What is the evidence for the efficacy of omega-3 fatty acids in treatment of hypertriglyceridemia of type II diabetes, insulin resistance, or the metabolic syndrome?

• The question should be re-worded in the following way: What is the evidence in adults or children for the efficacy of omega-3 fatty acids in treatment of hyperlipedemia in a) type II diabetes, or b) insulin resistance/the metabolic syndrome?

• Do not to limit the review to hypertriglyceridemia; collect data on other lipids, as well.

• The question pertains specifically to the effect of omega-3 fatty acids on lipids in two different clinical syndromes: type II DM and the insulin resistance/metabolic syndrome.

• The question pertains to both adults and children.

2. What is the evidence that in adults or children with type I diabetes, omega-3 fatty acids increase insulin sensitivity?

• Since insulin resistance is not a feature of type I diabetes, the questions should be re-worded in the following way: What is the evidence in adults and children for an effect of omega-3 fatty acids on insulin sensitivity in a) type II diabetes, or b) the metabolic syndrome?

3. What is the evidence for the efficacy of omega-3 fatty acids in treatment of renal inflammation and glomerulosclerosis?

• There was no consensus on how “renal inflammation” and “glomerulosclerosis” should be defined.

• There was no consensus about whether to assess the effect of omega-3 fatty acids on the progression of renal disease.

• Randomized controlled trials should be examined to determine whether sufficient evidence exists to assess the effect of omega-3 fatty acids on renal inflammation and/or the progression of renal acute or chronic renal insufficiency.

• The question may be re-worded after the literature review has been completed.

Gastrointestinal Diseases TEP

1. What is the evidence for the efficacy of omega-3 fatty acids in treatment of Crohn's disease and ulcerative colitis?

• There are so few studies on the efficacy of omega-3 fatty acids in treating inflammatory bowel disease that it may be necessary to do a qualitative rather than a quantitative review of the literature.

• Efficacy is not uniformly defined in IBD. However, a recent NIH conference addressed defining efficacy in Crohn's disease.

• There are many potential confounders/effect modifiers for IBD, especially for Crohn's disease, including disease characteristics (severity, presence or absence of fistulas in Crohn's), medication use, and population characteristics.

2. What is the evidence that in adults or children with inflammatory bowel disease (ulcerative colitis and Crohn's disease), omega-3 fatty acids lower leukotriene B4 or prostaglandin E2 levels?

• A review of the effect of omega-3 fatty acids on leukotriene B4 or prostaglandin E2 should not be included in the report since neither is a measure of prevention or efficacy in IBD.

• There are no studies of the effects of omega-3 fatty acids on IBD in children.

General Comments

• Take note of the omega-3 preparation.

• Abstract and report side effects.

A.3 Search Strategies

Table 3.1 Core search strategy

exp fatty acids, omega-3/
fatty acids, essential/
Dietary Fats, Unsaturated/
linolenic acids/
exp fish oils/
(n 3 fatty acid$ or omega 3).tw.
docosahexa?noic.tw,hw,rw.
eicosapenta?noic.tw,hw,rw.
alpha linolenic.tw,hw,rw.
(linolenate or cervonic or timnodonic).tw,hw,rw.
menhaden oil$.tw,hw,rw.
(mediterranean adj diet$).tw.
((flax or flaxseed or flax seed or linseed or rape seed or rapeseed or canola or soy or soybean or walnut or mustard seed) adj2 oil$).tw.
(walnut$ or butternut$ or soybean$ or pumpkin seed$).tw.
(fish adj2 oil$).tw.
(cod liver oil$ or marine oil$ or marine fat$).tw.
(salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov$).tw.
(fish consumption or fish intake or (fish adj2 diet$)).tw.
diet$ fatty acid$.tw.
or/1–19
dietary fats/
(randomized controlled trial or clinical trial or controlled clinical trial or evaluation studies or multicenter study).pt.
random$.tw.
exp clinical trials/ or evaluation studies/
follow-up studies/ or prospective studies/
or/22–25
21 and 26
(Ropufa or MaxEPA or Omacor or Efamed or ResQ or Epagis or Almarin or Coromega).tw.
(omega 3 or n 3).mp.
(polyunsaturated fat$ or pufa or dha or epa or long chain or longchain or lc$).mp.
29 and 30
20 or 27 or 28 or 31

Table 3.2 Literature searches by disease category

Diabetes

exp fatty acids, omega-3/
fatty acids, essential/
Dietary Fats, Unsaturated/
linolenic acids/
exp fish oils/
(n 3 fatty acid$ or omega 3).tw.
docosahexa?noic.tw,hw,rw.
eicosapenta?noic.tw,hw,rw.
alpha linolenic.tw,hw,rw.
(linolenate or cervonic or timnodonic).tw,hw,rw.
menhaden oil$.tw,hw,rw.
(mediterranean adj diet$).tw.
((flax or flaxseed or flax seed or linseed or rape seed or rapeseed or canola or soy or soybean or walnut or mustard seed) adj2 oil$).tw.
(walnut$ or butternut$ or soybean$ or pumpkin seed$).tw.
(fish adj2 oil$).tw.
(cod liver oil$ or marine oil$ or marine fat$).tw.
(salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov$).tw.
(fish consumption or fish intake or (fish adj2 diet$)).tw.
diet$ fatty acid$.tw.
or/1–19
dietary fats/
(randomized controlled trial or clinical trial or controlled clinical trial or evaluation studies or multicenter study).pt.
random$.tw.
exp clinical trials/ or evaluation studies/
follow-up studies/ or prospective studies/
or/22–25
21 and 26
(Ropufa or MaxEPA or Omacor or Efamed or ResQ or Epagis or Almarin or Coromega).tw.
(omega 3 or n 3).mp.
(polyunsaturated fat$ or pufa or dha or epa or long chain or longchain or lc$).mp.
29 and 30
20 or 27 or 28 or 31
hyperinsulin?emia.tw.
hyperinsulinemia/
exp diabetes mellitus/
diabetes.tw.
insulin.tw.
metabolic syndrome$.tw.
exp insulin resistance/
or/33–39
32 and 40
41 and human/

Inflammatory Bowel Disease and Renal Disease

exp fatty acids, omega-3/
fatty acids, essential/
Dietary Fats, Unsaturated/
linolenic acids/
exp fish oils/
(n 3 fatty acid$ or omega 3).tw.
docosahexa?noic.tw,hw,rw.
eicosapenta?noic.tw,hw,rw.
alpha linolenic.tw,hw,rw.
(linolenate or cervonic or timnodonic).tw,hw,rw.
menhaden oil$.tw,hw,rw.
(mediterranean adj diet$).tw.
((flax or flaxseed or flax seed or linseed or rape seed or rapeseed or canola or soy or soybean or walnut or mustard seed) adj2 oil$).tw.
(walnut$ or butternut$ or soybean$ or pumpkin seed$).tw.
(fish adj2 oil$).tw.
(cod liver oil$ or marine oil$ or marine fat$).tw.
(salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov$).tw.
(fish consumption or fish intake or (fish adj2 diet$)).tw.
diet$ fatty acid$.tw.
or/1–19
dietary fats/
(randomized controlled trial or clinical trial or controlled clinical trial or evaluation studies or multicenter study).pt.
random$.tw
exp clinical trials/ or evaluation studies/
follow-up studies/ or prospective studies/
or/22–25
21 and 26
(Ropufa or MaxEPA or Omacor or Efamed or ResQ or Epagis or Almarin or Coromega).tw.
(omega 3 or n 3).mp.
(polyunsaturated fat$ or pufa or dha or epa or long chain or longchain or lc$).mp.
29 and 30
20 or 27 or 28 or 31
exp inflammatory bowel diseases/
inflammatory bowel.tw.
(hemorrhagic proctocolitis or ulcerative proctocolitis).tw.
(hemorrhagic rectocolitis or ulcerative rectocolitis).tw.
(ileocolitis or ileitis or enteritis or crohn$ or pancolitis or proctitis or colitis).tw.
exp nephritis/
((renal or kidney) and inflammation).tw.
(glomerulo$ or nephritis or nephropath$).tw.
or/33–40
32 and 41
42 and human/

Rheumatoid Arthritis

exp fatty acids, omega-3/
fatty acids, essential/
Dietary Fats, Unsaturated/
linolenic acids/
exp fish oils/
(n 3 fatty acid$ or omega 3).tw
docosahexa?noic.tw,hw,rw.
eicosapenta?noic.tw,hw,rw.
alpha linolenic.tw,hw,rw.
(linolenate or cervonic or timnodonic).tw,hw,rw.
menhaden oil$.tw,hw,rw.
(mediterranean adj diet$).tw.
((flax or flaxseed or flax seed or linseed or rape seed or rapeseed or canola or soy or soybean or walnut or mustard seed) adj2 oil$).tw.
(walnut$ or butternut$ or soybean$ or pumpkin seed$).tw.
(fish adj2 oil$).tw.
(cod liver oil$ or marine oil$ or marine fat$).tw.
(salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov$).tw.
(fish consumption or fish intake or (fish adj2 diet$)).tw.
diet$ fatty acid$.tw.
or/1–19
dietary fats/
(randomized controlled trial or clinical trial or controlled clinical trial or evaluation studies or multicenter study).pt.
random$.tw.
exp clinical trials/ or evaluation studies/
follow-up studies/ or prospective studies/
or/22–25
21 and 26
(Ropufa or MaxEPA or Omacor or Efamed or ResQ or Epagis or Almarin or Coromega).tw.
(omega 3 or n 3).mp
(polyunsaturated fat$ or pufa or dha or epa or long chain or longchain or lc$).mp
29 and 30
20 or 27 or 28 or 31
exp arthritis, rheumatoid/
(rheumat$ adj2 arthritis).tw.
stills diseas$.tw.
caplans syndrome$.tw
feltys syndrome$.tw
rheumatoid nodule$.tw.
sjogrens syndrome$.tw.
ankylosing spondylitis.tw
rheumat$.tw
or/33–41
32 and 42
limit 43 to human

Systemic Lupus Erythematosus

exp fatty acids, omega-3/
fatty acids, essential/
Dietary Fats, Unsaturated/
linolenic acids/
exp fish oils/
(n 3 fatty acid$ or omega 3).tw.
docosahexa?noic.tw,hw,rw.
eicosapenta?noic.tw,hw,rw.
alpha linolenic.tw,hw,rw.
(linolenate or cervonic or timnodonic).tw,hw,rw.
menhaden oil$.tw,hw,rw.
(mediterranean adj diet$).tw.
((flax or flaxseed or flax seed or linseed or rape seed or rapeseed or canola or soy or soybean or walnut or mustard seed) adj2 oil$).tw.
(walnut$ or butternut$ or soybean$ or pumpkin seed$).tw.
(fish adj2 oil$).tw.
(cod liver oil$ or marine oil$ or marine fat$).tw.
(salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov$).tw.
(fish consumption or fish intake or (fish adj2 diet$)).tw.
diet$ fatty acid$.tw.
or/1–19
dietary fats/
(randomized controlled trial or clinical trial or controlled clinical trial or evaluation studies or multicenter study).pt.
random$.tw.
exp clinical trials/ or evaluation studies/
follow-up studies/ or prospective studies/
or/22–25
21 and 26
(Ropufa or MaxEPA or Omacor or Efamed or ResQ or Epagis or Almarin or Coromega).tw.
(omega 3 or n 3).mp.
(polyunsaturated fat$ or pufa or dha or epa or long chain or longchain or lc$).mp.
29 and 30
20 or 27 or 28 or 31
exp Lupus Erythematosus, Systemic/
(lupus glomerulonephritis or lupus nephritis).tw.
(libman-sacks or lupus erythematosus disseminatus or systemic lupus erythematosus).tw.
(lupus vasculitis or lupus meningoencephalitis or central nervous system systemic lupus).tw.
or/33–36
32 and 37
limit 38 to human

Bone Density/Osteoporosis

exp fatty acids, omega-3/
fatty acids, essential/
Dietary Fats, Unsaturated/
linolenic acids/
exp fish oils/
(n 3 fatty acid$ or omega 3).tw.
docosahexa?noic.tw,hw,rw.
eicosapenta?noic.tw,hw,rw.
alpha linolenic.tw,hw,rw.
(linolenate or cervonic or timnodonic).tw,hw,rw.
menhaden oil$.tw,hw,rw.
(mediterranean adj diet$).tw.
((flax or flaxseed or flax seed or linseed or rape seed or rapeseed or canola or soy or soybean or walnut or mustard seed) adj2 oil$).tw.
(walnut$ or butternut$ or soybean$ or pumpkin seed$).tw.
(fish adj2 oil$).tw.
(cod liver oil$ or marine oil$ or marine fat$).tw.
(salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov$).tw.
(fish consumption or fish intake or (fish adj2 diet$)).tw.
diet$ fatty acid$.tw.
or/1–19
dietary fats/
(randomized controlled trial or clinical trial or controlled clinical trial or evaluation studies or multicenter study).pt.
random$.tw.
exp clinical trials/ or evaluation studies/
follow-up studies/ or prospective studies/
or/22–25
21 and 26
(Ropufa or MaxEPA or Omacor or Efamed or ResQ or Epagis or Almarin or Coromega).tw.
(omega 3 or n 3).mp.
(polyunsaturated fat$ or pufa or dha or epa or long chain or longchain or lc$).mp.
29 and 30
20 or 27 or 28 or 31
bone density/
(bone mineral or bone densit$ or bone mass).tw.
exp Bone Demineralization, Pathologic/
Bone Demineral$.tw.
exp Bone Resorption/
(bone loss$ or bone resportion).tw.
exp Densitometry/
or/33–39
32 and 40
limit 41 to human

Table 3.3 Industry experts that were contacted for data about efficacy of omega-3 fatty acids

Name	Affiliation
Ian Newton	Roche Vitamins

Herb Wool, PhD	BASF Corporation

Annette Dickinson	Council for Responsible Nutrition

Figure A.3.1 Letter sent to industry experts

graphic element

A.4 Inclusion/Exclusion Criteria

Table A.4.1 Inclusion/Exclusion Criteria at Screening Stage.*

Assessed the effect of omega-3 fatty acids on arthritis (including rheumatoid arthritis and juvenile rheumatoid arthritis), bone mineral metabolism, diabetes, IBD, lupus, or renal disease

Presented research on human subjects

Reported the results of randomized or controlled clinical trials or cohort/case control studies;† we accepted observational studies for bone mineral status only.

For cross-over studies, reported outcomes for each arm before the cross-over at the end of the first phase of treatment‡

Language was not a barrier to inclusion;

†

We defined a randomized controlled trial (RCT) as one in which the participants were assigned to one of two (or more) study groups using a process of random allocation (e.g., random number generation, coin flips); we defined a controlled clinical trial (CCT) as one in which participants were either: (1) assigned to one of two (or more) study groups using a quasi-random allocation method (e.g., alternation, date of birth, patient identifier), or (2) possibly assigned to one of two (or more) study groups using a process of random or quasi-random allocation;

‡

We did not use data from the end of the study period in studies with a cross-over design because as a result of this design, the treatment and placebo groups from these studies are not comparable to the treatment and placebo groups of the non-cross-over randomized controlled trials with which they would be pooled in a meta-analysis. For example, one half of the placebo group in a cross-over trial will have been exposed to treatment with omega-3 fatty acids prior to placebo and hence the measured effect could be biased by earlier treatment with Omega-3 fatty acids.

A.5 Evidence Grading System

Table A.5.1 Summary Score for Methodologic Quality

Summary Score	Jadad Score	Concealment of Allocation
A	5	Performed

B	5	Not performed, or Not reported
	3 or 4	Performed, Not performed, or Not reported
	0,1, or 2	Performed

C	0, 1, or 2	Not performed or not reported

Even though a study may focus on a specific target population, limited study size, eligibility criteria and patient recruitment process may result in a narrow population sample that is of limited applicability, even to the target population. To capture this parameter, we categorize studies into the applicability scale described in Table A.5.1.

Table A.5.2 Applicability ratings

Applicability		Health state
I	Sample is representative of the U.S. population.	A General population. Typical healthy people similar to Americans without known cardiovascular diseases.

II	Sample is representative of a relevant sub-group of the target population, but not the entire population. For example, a study that is restricted to women or a fish oil study in Japan where the background diet is very different from that of the US would fall into this category.	B Diseased population. Subjects with any of the following: inflammatory bowel disease, rheumatoid arthritis, renal disease, systemic lupus erythematosus or osteoporosis.

III	Sample is representative of a narrow subgroup of subjects only, and not well applicable to other subgroups. For example, a study of oldest old men or a study of a population on highly controlled diet.

Figure A.5.1 Jadad score of methodologic quality.*

graphic element

* Jadad A, Moore A, Carrol D, et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials. 1996;17:1–12.

Table A.6.1 Peer Reviewers

Peer Reviewer	Area of Expertise	Affiliation
Richard Glassock, MD	nephrology	UCLA

David Heber, MD	nutrition	UCLA

Ted Kraegen, PhD	diabetes, nutrition	Garvan Research Institute, Sydney

Kenneth Saag, MD, MPH	osteoporosis, SLE	University of Alabama

Walter Willett, MD	epidemiology, nutrition	Harvard University

Robert Zurier, MD	rheumatoid arthritis, omega-3 fatty acids	University of Massachusetts Medical School

Appendix B. Coding/Data Abstraction Forms

B.2 Literature Screener Form

B.3 Quality review form

References and Included Studies

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10.

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11.

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12.

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14.

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15.

Joint Task Group (CHPA, CRN, NFI). Food Labeling: Health Claims and Label Statement - Omega-3 Fatty Acids and Coronary Heart Disease. Docket No: 91N-0103.

16.

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17.

Geusens P, Wouters C, Nijs J, Jiang Y, Dequeker J. Long-term effect of omega-3 fatty acid supplementation in active rheumatoid arthritis: A 12-month, double-blind, controlled study. Arthritis & Rheumatism. 1994; 37(6): 824–829. [PubMed]

18.

Kremer J, Bigauoette J, Michaler A. Effects of manipulations of dietary fatty acids on clinical manifestations of rheumatoid arthritis. Lancet. 1985; 1(8422): 184–187. [PubMed]

19.

Kremer J, Lawrence D, Jubiz W, DiGiacomo R, Rynes R, Bartholomew L. et al. Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Clinical and immunologic effects. Arthritis & Rheumatism. 1990; 33(6): 810–820. [PubMed]

20.

Magalish T, Ivanov E, Iubitskaia N. Ultraphonophoresis of omega-3 polyunsaturated fatty acids in the complex therapy of rheumatoid arthritis. Voprosy.Kurortologii., Fizioterapii.i.Lechebnoi.Fizicheskoi.Kultury 2002 ;(2):43–44.

21.

Magaro M, Altomonte L, Zoli A, Mirone L, De Sole P, Di Mario G. et al. Influence of diet with different lipid composition on neutrophil chemiluminescence and disease activity in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases. 1988; 47(10): 793–796. [PubMed] [

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22.

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23.

Nordstrom D, Honkanen V, Nasu Y, Antila E, Friman C, Konttinen Y. Alpha-linolenic acid in the treatment of rheumatoid arthritis: A double blind, placebo-controlled and randomized study: Flaxseed vs safflower seed. Rheumatology International. 1995; 14(6): 231–234. [PubMed]

24.

Tulleken J, Limburg P, Muskiet F, van Rijswijk M. Vitamin E status during dietary fish oil supplementation in rheumatoid arthritis. Arthritis & Rheumatism. 1990; 33(9): 1416–1419. [PubMed]

25.

Skoldstam L, Borjesson O, Kjallman A, Seiving B, Akesson B. Effect of six months of fish oil supplementation in stable rheumatoid arthritis. A double blind, controlled study. Scand J Rheumatol. 1992; 21: 178–85. [PubMed]

26.

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27.

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28.

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29.

Hansen G, Nielsen L, Kluger E, Thysen M, Emmertsen H, Stengaard-Pedersen K. et al. Nutritional status of Danish rheumatoid arthritis patients and effects of a diet adjusted in energy intake, fish-meal, and antioxidants. Scandinavian Journal of Rheumatology. 1996; 25(5): 325–330. [PubMed]

30.

Kjeldsen-Kragh J, Lund J, Riise T, Finnanger B, Haaland K, Finstad R. et al. Dietary omega-3 fatty acid supplementation and naproxen treatment in patients with rheumatoid arthritis. Journal of Rheumatology. 1992; 19(10): 1531–1536. [PubMed]

31.

Kremer J, Lawrence D, Petrillo G, Litts L, Mullaly P, Rynes R. et al. Effects of high-dose fish oil on rheumatoid arthritis after stopping nonsteroidal antiinflammatory drugs: Clinical and immune correlates. Arthritis & Rheumatism. 1995; 38(8): 1107–1114. [PubMed]

32.

Lau C, Morley K, Belch J. Effects of fish oil supplementation on non-steroidal anti-inflammatory drug requirement in patients with mild rheumatoid arthritis--a double-blind placebo controlled study. British Journal of Rheumatology. 1993; 32(11): 982–989. [PubMed]

33.

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34.

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35.

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36.

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37.

Espersen G, Grunnet N, Lervang H, Nielsen G, Thomsen B, Faarvang K. et al. Decreased interleukin-1 beta levels in plasma from rheumatoid arthritis patients after dietary supplementation with n-3 polyunsaturated fatty acids. Clinical Rheumatology. 1992; 11(3): 393–395. [PubMed]

38.

Lau C, McLaren M, Belch J. Effects of fish oil on plasma fibrinolysis in patients with mild rheumatoid arthritis. Clinical & Experimental Rheumatology. 1995; 13(1): 87–90. [PubMed]

39.

Loeschke K, Ueberschaer B, Pietsch A, Gruber E, Ewe K, Wiebecke B. et al. n-3 fatty acids only delay early relapse of ulcerative colitis in remission. Digestive Diseases & Sciences. 1996; 41(10): 2087–2094. [PubMed]

40.

Mantzaris G, Archavlis E, Zografos C, Petraki K, Spiliades C, Triantafyllou G. A prospective, randomized, placebo-controlled study of fish oil in ulcerative colitis. Hellenic Journal of Gastroenterology. 1996; 9(2): 138–141.

41.

Hawthorne A, Daneshmend T, Hawkey C, Shaheen M, Edwards T, Filipowicz B, et al. Fish oil in ulcerative colitis: Final results of a controlled cliinical trial. Gastroenterology 98:A174.

42.

Greenfield S, Green A, Teare J, Jenkins A, Punchard N, Ainley C. et al. A randomized controlled study of evening primrose oil and fish oil in ulcerative colitis. Alimentary Pharmacology & Therapeutics. 1993; 7(2): 159–166. [PubMed]

43.

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44.

Almallah Y, Richardson S, O'Hanrahan T, Mowat N, Brunt P, Sinclair T. et al. Distal procto-colitis, natural cytotoxicity, and essential fatty acids. American Journal of Gastroenterology. 1998; 93(5): 804–809. [PubMed]

45.

Almallah Y, Ewen S, El Tahir A, Mowat N, Brunt P, Sinclair T. et al. Distal proctocolitis and n-3 polyunsaturated fatty acids (n-3 PUFAs): the mucosal effect in situ. Journal of Clinical Immunology. 2000; 20(1): 68–76. [PubMed]

46.

Aslan A, Triadafilopoulos G. Fish oil fatty acid supplementation in active ulcerative colitis: a double-blind, placebo-controlled, crossover study. American Journal of Gastroenterology. 1992; 87(4): 432–437. [PubMed]

47.

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Anonymous Lectures given at the 9th Aachen Dietetics Further Education Meeting, 21–23 September, 2001. Ernahrung and Medizin 2002;

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