Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT04327713 |
| Other study ID # |
DNSG-Fish oil |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 28, 2020 |
| Est. completion date |
April 2021 |
Study information
| Verified date |
November 2020 |
| Source |
University of Toronto |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Fish oil contains a large amount of long-chain omega-3 polyunsaturated fatty acids, which are
considered an important component of a healthy diet. As many patients do not eat fish,
supplementation with fish oil is a common strategy to provide sufficient amounts of these
particular fatty acids in daily life. Fish oil supplementation has been investigated for
decades for its cardio-protective effects and its ability to lower serum triglycerides.
People with diabetes mellitus have an increased risk for cardiovascular events and show
alterations in lipids with high triglycerides. Whether there is a benefit of fish oil
supplementation in this high risk group remains unclear with major international diabetes
associations recommending against the use of fish oil supplements. The European Association
for the Study of Diabetes (EASD) has not made any recommendations about the use of fish oils
in people with diabetes since 2004. To inform the update of the EASD clinical practice
guidelines for nutrition therapy, the Diabetes and Nutrition Study Group (DNSG) of the EASD
has commissioned the proposed systematic review and meta-analysis of randomized controlled
trials of the effect of fish oil supplementation on cardiovascular outcomes in people with
diabetes and use the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) approach to assess the certainty of the evidence.
Description:
Background: Cardiovascular disease (CVD) accounts for a large proportion of annual deaths
around the world. In both the general population as well as in high-risk subgroups, achieving
a healthy diet is one approach to lower the risk for CVD. Fish oil supplements have been
widely investigated for cardiovascular indications, showing consistent reductions in
triglycerides with variable effects on other intermediate risk factors (glycemia, blood
pressure, inflammation) which have not translated into reductions in patient-important
clinical outcomes. Recent systematic reviews and meta-analyses of the available randomized
trials have failed to show a meaningful cardiovascular benefit of fish oil supplementation.
It is unclear whether this lack of benefit holds across all groups, especially groups with a
high triglyceride phenotype and at high cardiovascular risk such as those with diabetes. No
systematic review and meta-analysis has specifically synthesized the evidence of the effect
of fish oil supplementation on cardiovascular outcomes in people with diabetes. On the basis
of several recent large cardiovascular outcomes trials in people with diabetes or that
included subgroups of people with diabetes, the 2019 American Diabetes Association and 2018
Diabetes Canada clinical practice guidelines recommended against the use of fish oil
supplementation for cardiovascular risk reduction in people with diabetes. The European
Association for the Study of Diabetes (EASD) have made a similar recommendation but have not
updated their clinical practice guidelines since 2004. To inform the update of the EASD
clinical practice guidelines for nutrition therapy, the Diabetes and Nutrition Study Group
(DNSG) of the EASD has commissioned a series of evidence syntheses. The proposed systematic
review and meta-analysis of randomized controlled trials will assess the effect of fish oil
supplementation on cardiovascular outcomes in people with diabetes and use the Grading of
Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the
certainty of the evidence.
Need for proposed research: There is an urgent need for a synthesis of the evidence of the
effect of fish oil supplementation on cardiovascular outcomes in people with diabetes to
inform the update of the EASD clinical practice guidelines for nutrition therapy. High
quality systematic reviews and meta-analyses of randomized controlled trials with assessment
of the certainty of the evidence using GRADE provide the strongest form of evidence synthesis
to support clinical practice guidelines and public health policy development.
Objective: To inform the update of the European Association for the Study of Diabetes (EASD)
clinical practice guidelines for nutrition therapy, the investigators will conduct a
systematic review and meta-analysis of randomized controlled trials of the effect of fish oil
supplementation on cardiovascular outcomes in people with diabetes and use the GRADE approach
to assess the certainty of the evidence.
Design: The planning and conduct of the proposed meta-analyses will follow the Cochrane
handbook for systematic reviews of interventions. The reporting will follow the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
Data sources: MEDLINE, EMBASE, and The Cochrane Central Register of Controlled Trials
databases will be searched using appropriate search terms supplemented by hand searches of
references of included studies.
Study selection: Randomized controlled trials conducted in humans with a follow-up duration ≥
52 weeks investigating the effect of fish oil supplementation compared to placebo on
cardiovascular outcomes will be included. Eligible studies will be conducted in people with
diabetes or contain data from a subgroup of people with diabetes. Studies that are not
randomized, have a shorter duration (<52 weeks), use multi-modal interventions that do not
allow for the isolation of the effect of fish oil supplementation, provide fish oil in the
form of a prescription pharmaceutical drug (e.g. icopsant ethyl), lack a suitable control
group/comparator, are not conducted in people with diabetes, and/or do not report viable
cardiovascular outcomes data will be excluded.
Data extraction: Two investigators will independently extract relevant data and assess risk
of bias using the Cochrane Risk of Bias tool Version 2. Events and total participants in
intervention group and control groups will be extracted. When avaialble, risk ratios, odds
ratios and hazard ratios for clinical outcomes will be extracted or derived from clinical
event data across exposure to either fish oil supplementation or placebo. All disagreements
will be resolved by consensus. Corresponding authors of relevant publications will be asked
for additional data if needed.
Outcomes: The primary outcome will be total CVD incidence. Secondary outcomes will be major
adverse cardiovascular events (MACE), CVD mortality, all-cause mortality, coronary heart
disease (CHD) incidence, CHD mortality, MI incidence, stroke incidence, and arrhythmia.
Data synthesis: Risk ratios of clinical outcomes using total events and number of people in
intervention and control groups will be calculated for each RCT. Reported relative ratio
measures will be used for studies not reporting raw numbers and hazard ratio and odds ratios
will be considered equivalent to risk ratios.
Data will be pooled using the Mantel-Haenszel method with random effects models. Results will
be reported as pooled risk ratios with 95% confidence intervals (95% CI). Heterogeneity will
be assessed by the Cochrane Q statistic and quantified by the I2 statistic with I2>50% and
P(Q) <0.1 considered evidence of substantial heterogeneity.
If there are ≥10 trials, a priori subgroup analyses will be undertaken to explore sources of
heterogeneity including sex, age, type of diabetes (type 1 or type 2 diabetes), prevention
type (primary, secondary), intervention type (supplements, supplemented foods, dietary
advice), comparator, study design, follow-up duration,baseline glycemic control, risk of
bias, funding source. Significant unexplained heterogeneity will be investigated by
additional post hoc subgroup analyses. Meta-regression analyses will assess the significance
of subgroups analyses.
Sensitivity analysis will be performed by removing one study at a time. A study will be
considered influential if it changes the direction or significance of effect and/or
heterogeneity.
If there are ≥10 trials, publication bias will be assessed by the inspection of funnel plots
and using Begg's and Egger's tests. If publication bias is suspected, we will attempt to
adjust for funnel plot asymmetry by imputing the missing study data using the Duval and
Tweedie trim and fill method.
Evidence Assessment: The certainty of the evidence for each outcome will be assessed using
the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
Knowledge translation plan: The results will be disseminated through talks or posters at
regional, national, and international scientific meetings and publication in high impact
factor journals. We will target public health and scientific communities interested in
nutrition, cardiovascular diseases and diabetes. Their feedback will be incorporated in order
to improve the public health message and to define key areas for future research.
Applicant/Co-applicant: Decision Makers will network among opinion leaders to increase
awareness and participate directly as committee members in the development of future
guidelines.
Significance: The proposed project will aid in knowledge translation related to the role of
fish oil supplementation in the prevention of cardiovascular diseases in the high-risk group
of T2DM patients, strengthening the evidence-base for guidelines and improving health
outcomes by educating healthcare providers and patients, stimulating industry innovation, and
guiding future research design.
