Introduction

This report was requested and funded by the

Office of Dietary Supplements, National

Institutes of Health. It is one of several reports

focusing on the role of omega-3 fatty acids in the

prevention or treatment of various diseases. Three

Evidence-based Practice Centers (EPCs) produced

this series of reports: the Southern California

EPC, based at RAND, the Tufts-New England

Medical Center EPC, and the University of

Ottawa EPC. This particular report focuses on

the effects of omega-3 fatty acids on immunemediated diseases, bone metabolism, and

gastrointestinal/renal diseases. 

Over the past 40 years, an increasing number

of physiological functions have been attributed to

omega-3 fatty acids, including movement of

calcium and other substances into and out of

cells, relaxation and contraction of muscles,

inhibition and promotion of clotting, regulation

of secretion of substances that include digestive

enzymes and hormones, control of fertility, cell

division, and growth.1 In addition, omega-3 fatty

acids may play an important role in brain

development and function. Some evidence has

suggested that omega-3 fatty acids in the diet may

protect against heart attack and stroke, as well as

certain inflammatory diseases like arthritis, lupus,

and asthma.1 The major dietary sources of omega3 fatty acids in the U.S. population are fish, fish

oil, vegetable oils (principally canola and

soybean), walnuts, wheat germ, and some dietary

supplements.

Methods

Key Questions

We consulted with three technical expert

panels (TEPs) on this project. The respective

panels focused on the following conditions: 

• Rheumatoid arthritis, systemic lupus

erythematosis (SLE), and bone

density/osteoporosis

• Renal disease and diabetes

• Gastrointestinal diseases 

The TEPs advised us on refining the

preliminary questions posed to us by AHRQ,

determining the proper inclusion/exclusion

criteria for the study and the populations of

interest, establishing the proper outcomes

measures, and conducting the appropriate

analyses. 

Based on the original questions that we

received from AHRQ and input from our TEPs,

we addressed the following questions in this

study:

Diabetes

What is the evidence in adults or children with

a) type II diabetes, or b) insulin resistance/the

metabolic syndrome for an effect of omega-3 fatty

acids on:

• Total cholesterol

• HDL cholesterol

• LDL cholesterol

• Triglycerides

Evidence Report/Technology Assessment

Number 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

Summary

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service

Agency for Healthcare Research and Quality
2

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 in adults or children with

inflammatory bowel disease that 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 in adults or children with rheumatoid

arthritis that omega-3 fatty acids affect:

• Pain

• Number of swollen joints

• Disease activity

• Patients’ global assessment

• Joint damage

What is the evidence in adults or children with rheumatoid

arthritis that omega-3 fatty acids can replace other more potent

anti-inflammatory or immunosuppressive drugs such as steroids

and nonsteroidal anti-inflammatory 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 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 in adults or children with immunemediated renal disease that 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 immunemediated renal disease?

Systemic Lupus Erythematosus

What is the evidence in adults or children with SLE that

omega-3 fatty acids affect disease activity, damage, or patient

perceptions of outcomes in SLE?

What is the evidence in adults or children with SLE that

omega-3 fatty acids can replace steroids or other

immunosuppressive drugs?

What is the evidence that the benefits of omega-3 fatty acids

in the treatment of SLE are influenced by the concomitant

administration of various immunosuppressive agents?

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: 

• The effect of omega-3 fatty acids on subpopulations 

• The effects of covariates, dose, source, and exposure

duration on the outcomes of interest 

• The sustainment of effect

In addition to answering these questions, we evaluated the

data on adverse events, including clinical bleeding,

gastrointestinal complaints or nausea, diarrhea, headache,

dermatological problems, and withdrawal from study due to an

adverse event.

Search Strategy

We searched the following online databases to identify

literature: 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), and Dissertation Abstracts

(1861-December 2002). We developed a core search strategy

and applied it to each relevant disease category: rheumatoid

arthritis, bone density, SLE, renal disease, diabetes, and

gastrointestinal diseases. We also reviewed the reference lists of

all applicable articles and contacted our technical expert panel

as well as industry experts to identify unpublished data.

Selection Criteria

Two reviewers independently reviewed each article

considered for inclusion in the study. Any disagreements

between the reviewers were resolved through consensus. We

included any articles pertaining to the effects of omega-3 fatty

acids on diabetes mellitus, inflammatory bowel disease

(ulcerative colitis and Crohn’s disease), rheumatoid arthritis,

SLE, renal disease, osteoporosis, or bone mineral status. We

included only articles that presented research on human

subjects and those that reported the results of randomized

clinical trials or controlled clinical trials; we accepted

observational studies only for bone mineral status. Language

was not a barrier to inclusion. 

Data Extraction and Analysis

For each article included in the study, two reviewers

independently extracted data 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. Any disagreements

between the reviewers were resolved through consensus. For

each article, we then evaluated the quality of the design and

execution of trials using a system developed by Jadad;

determined a combined applicability grade based on

applicability to the U.S. population and health state; performed

a meta-analysis of those studies that sufficiently assessed

interventions, populations, and outcomes to justify pooling;

and performed a qualitative analysis of the remaining studies.

Results 

We screened 4,212 article titles. From these article titles, we

reviewed the 1,097 full-text articles relevant to our topics. Of

these full-text articles, 115 met our selection criteria and

underwent detailed review; 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 SLE, and 4 for bone density and fractures).

All of these 83 articles were randomized controlled trials, except

for one observational study of bone density. We had a sufficient

number of articles to perform quantitative meta-analyses for

rheumatoid arthritis, inflammatory bowel disease, and diabetes.

Due to the limited number of articles we identified for renal

failure, SLE, and bone mineral metabolism, we performed

qualitative analyses for these conditions. 

Overall, our analyses yielded variable results both within and

among disease categories. Our findings are summarized for

each condition studied.

Diabetes/Metabolic Syndrome. Among 18 studies of type

II diabetes or the metabolic syndrome, 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.

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 three studies.

There was a statistically non-significant reduction in

requirement for corticosteroids for omega-3 fatty acids relative

to placebo in two studies. No studies evaluated the effect of

omega-3 fatty acids on requirement for other

immunosuppressive agents.

Rheumatoid Arthritis. Among nine studies reporting

outcomes in patients with rheumatoid arthritis, omega-3 fatty

acids had no effect on patient report of pain, swollen joint

count, Erythrocyte Sedimentation Rate (ESR), and patient’s

global assessment by meta-analysis. A previously performed

meta-analysis2 reached the same conclusions for swollen joint

count, ESR, and patient’s global assessment. That metaanalysis found a statistically significant improvement in tender

joint count compared to placebo (rate difference = -2.9, 95%

CI, -3.8, -2.1). The one study that assessed the effect on joint

damage found no effect. In a qualitative analysis of seven

studies that assessed the effect of omega-3 fatty acids on antiinflammatory drug or corticosteriod requirement, six

demonstrated reduced requirement for these drugs. No studies

assessed the effect on requirements for disease modifying antirheumatic 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.

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 and no effect on progression to end stage renal

disease. 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 assessed the effects

of omega-3 fatty acids on requirements for corticosteroids

Systemic Lupus Erythematosis. Among three 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 one 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 four 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.

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

3
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. 

Discussion

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, SLE, and osteoporosis.

• Additional research on the effects of omega-3 fatty acids

needs 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.

Availability of the Full Report

The full evidence report from which this summary was taken

was prepared for the Agency for Healthcare Research and

Quality (AHRQ) by the Southern California/RAND Evidencebased Practice Center, Los Angeles, CA, under Contract No.

290-02-0003. The full report is expected to be available in

March 2004. At that time, printed copies may be obtained free

of charge from the AHRQ Publications Clearinghouse by

calling 800-358-9295. Requesters should ask for Evidence

Report/Technology Assessment No. 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. In addition, Internet users will

be able to access the report and this summary online through

AHRQ’s Web site at www.ahrq.gov.

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 Omega3 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. Summary, Evidence

Report/Technology Assessment No. 89. (Prepared by the

Southern California/RAND Evidence-based Practice Center,

Los Angeles, CA.) AHRQ Publication No. 04-E012-1.

Rockville, MD: Agency for Healthcare Research and Quality.

March 2004.

References

1. Innis S. Essential dietary lipids. In: Ziegler EE, Filer, LJ Jr, editors.

Present knowledge in nutrition. Washington, DC: International Life

Sciences Institute; 1996.

2. Fortin P, Lew R, Liang M, et al. Validation of a meta-analysis: The

effects of fish oil in rheumatoid arthritis. J Clin Epidemiol

1995;48(11):1379-90.

www.ahrq.gov

AHRQ Pub. No. 04-E012-1

March 2004

ISSN 1530-440X