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Omega-3 Fatty Acids - Type 2 Diabetes
Summary
Under its Evidence-based Practice Program, the Agency for Healthcare
Research and Quality (AHRQ) is developing scientific information
for other agencies and organizations on which to base clinical guidelines,
performance measures, and other quality improvement tools. Contractor
institutions review all relevant scientific literature on assigned
clinical care topics and produce evidence reports and technology
assessments, conduct research on methodologies and the effectiveness
of their implementation, and participate in technical assistance
activities.
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 immune-mediated 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 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.
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.
- 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 immune-mediated
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 immune-mediated 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).
- 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.
- 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.
- 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 meta-analysis 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 anti-inflammatory drug or corticosteriod
requirement, six 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.
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 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.
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